Angiogenesis and rheumatoid arthritis -
Angiogenesis is an early and a critical event in the pathogenesis of rheumatoid arthritis RA. Neovascularization is dependent on endothelial cell activation, migration and proliferation, and inhibition of angiogenesis may provide a novel therapeutic approach in RA. In this study, we document a novel role of IL in mediating angiogenesis.
Local expression of IL in mouse ankles increases vascularity. We further demonstrate that IL is angiogenic by showing its ability to promote blood vessel growth in Matrigel plugs in vivo. Furthermore, suppression of the PI3K pathway markedly reduces IL—induced tube formation.
We also show that both IL—induced HMVEC chemotaxis and tube formation are mediated primarily through IL receptor C. Neutralization of either IL in RA synovial fluids or IL receptor C on HMVECs significantly reduces the induction of HMVEC migration by RA synovial fluid.
Finally, RA synovial fluid immunoneutralized with anti—IL and antivascular endothelial growth factor does not reduce HMVEC migration beyond the effect detected by immunodepleting each factor alone.
These observations identify a novel function for IL as an angiogenic mediator in RA, supporting IL as a therapeutic target in RA. IL RA and RC are widely expressed in endothelial cells, B and T cells, fibroblasts, and monocytes 2 , 3. TGF-β, IL-6, IL-1β, and IL have been shown to drive the differentiation of Th cells 4 — 6 , although variation between humans and mice has been described previously 2 , 6 — 8.
In humans, IL-1β is the most effective inducer of Th cell differentiation, although this process is enhanced by IL-6 and IL 6. IL has been shown to have a profound effect in experimental models of arthritis.
Local expression of IL in mouse joints results in acute inflammation and cartilage proteoglycan depletion 9. The incidence and severity of collagen-induced arthritis was markedly attenuated in IL—deficient mice IL also plays an important role downstream of IL-1 signaling and in response to TLR4 ligands 11 , Spontaneous IL-1 receptor antagonist knockout mice develop a polyarthritis, which is completely suppressed when these mice are crossed with IL—deficient mice 13 , suggesting that Th cell differentiation may be the reason for the arthritis.
IL is found in rheumatoid arthritis RA synovial tissue and fluid, and the percentage of Th cells is significantly higher in RA synovial fluid compared with RA or normal peripheral blood 3 , IL is also capable of activating macrophages to expression of IL-1, TNF-α, cyclooxygenase 2, PGE 2 , and matrix metalloproteinase-9 18 — Angiogenesis, the development of new capillaries, is involved in leukocyte ingress into the synovium during the development and progression of RA 24 , However, the role of IL in angiogenesis is undefined.
There are contradictory results regarding the role of IL on tumor development and angiogenesis. In mice, tumors transfected with IL demonstrated markedly less growth compared with control tumors Additionally, tumor growth and lung metastasis were increased in IL—deficient mice 27 , suggesting that IL inhibits tumor development and neovascularization.
Others have shown that IL increases blood vessel development in rat cornea and tumor vascularity in animal models, indicating that IL may be important for angiogenesis However, there are also data to suggest that IL alone is unable to induce angiogenesis but can indirectly mediate human lung microvascular endothelial cell HMVEC growth by promoting the mitogenic activity of vascular endothelial growth factor VEGF , basic fibroblast growth factor bFGF , and hepatocyte growth factor 29 , Therefore, on the basis of the existing data, it is unclear whether IL can promote angiogenesis in RA and whether IL acts directly on endothelial cells through binding to its receptors or indirectly by inducing proangiogenic factors from cells present in the RA synovium.
In the current study, we have therefore evaluated the role of IL in HMVEC migration and tube formation as well as blood vessel development. Our results demonstrate that local expression of IL increases vascularity in mouse ankle joints.
Using a Matrigel plug assay, we demonstrate that IL enhances blood vessel formation in vivo. Although HMVECs express both ILRA and RC, IL—induced HMVEC chemotaxis and tube formation are mediated by binding primarily to ILRC and activation of the PI3K pathway.
Finally, we show that IL and VEGF neutralization in RA synovial fluid does not significantly reduce HMVEC migration beyond the effect of one factor alone. Hence, therapy directed against IL may reduce leukocyte migration by inhibiting angiogenesis in RA.
The animal studies were approved by the Northwestern University Institutional Review Board. Adenovirus Ad constructed as reported previously to contain an IL payload was provided by J. Kolls Louisiana State University Health Science Center, New Orleans, LA Ankle circumference and articular index score were determined on days 4 and 10 post—Ad-IL injection and compared with the control group data not shown.
Ankles were harvested on day 10 post—Ad-IL injection for histological studies. Levels of IL were quantified by ELISA on days 4 and 10 from ankles treated with Ad-IL or Ad-CMV control.
Mouse ankles were decalcified, formalin fixed and paraffin embedded, and sectioned in the pathology core facility of Northwestern University. Mouse ankles were immunoperoxidase stained using Vector Elite ABC Kits Vector Laboratories, Burlingame, CA , with diaminobenzidine Vector Laboratories as a chromogen.
Slides were deparaffinized in xylene for 20 min at room temperature, followed by rehydration by transfer through graded alcohols.
Ags were unmasked by first incubating slides in boiling citrate buffer for 15 min, followed by type II trypsin digestion for 30 min at 37°C. Nonspecific binding of Abs to the tissues was blocked by pretreatment of tissues with diluted normal goat serum.
or a rabbit IgG control Ab Beckman Coulter, Fullerton, CA. Slides were counterstained with Harris hematoxylin and treated with lithium carbonate for bluing. Each slide was evaluated by a blinded observer 32 — 35 M. Tissue sections were assigned a vascular score representing the number of blood vessels in each section.
A semiquantitative score of 1 represented a tissue with few blood vessels, whereas a score of 4 represented a highly vascularized tissue. To examine the effect of IL on angiogenesis in vivo, we used a Matrigel plug assay. in the dorsal area with μl Matrigel.
After 10 d, mice were sacrificed, Matrigel plugs were carefully dissected out, surrounding connective tissue was removed, and plugs were analyzed for vascularity by hemoglobin measurement or by histology. For hemoglobin measurement, plugs were weighed by placing them into 1 ml preweighed double-distilled H 2 O and then homogenized for 5—10 min on ice and spun.
Using methemoglobin, serial dilutions were prepared to generate a standard curve from 70 to 1. Fifty microliters of supernatant or standard was added to a well plate in duplicate, and 50 μl tetramethylbenzidine was added to each sample.
The plate was allowed to develop at room temperature for 15—20 min with gentle shaking, and the reaction was terminated with μl 2 N H 2 SO 4 for 3—5 min. Absorbance was read with an ELISA plate reader at nm. To calculate hemoglobin concentrations, the values grams per deciliter were normalized to the weights of the plugs grams 36 , On day 10, IL concentrations were quantified in Matrigel plugs harvested from the IL—treated group using ELISA.
For histology, plugs were embedded in paraffin and sectioned in the pathology core facility of Northwestern University. HMVECs 1. The chambers were inverted and incubated at 37°C for 2 h, allowing endothelial cell attachment to the membrane.
The membranes were then removed, fixed, and stained with the Protocol HEMA 3 stain set ; Fisher Scientific, Waltham, MA.
To examine for chemokinesis, a series of checkerboard experiments were performed by placing increasing concentrations of IL 0, 0. Total cellular RNA was extracted using TRIzol Invitrogen, Carlsbad, CA from all different cell types. Subsequently, reverse transcription and real-time RT-PCR were performed to determine ILRA and ILRC expression level as described previously 14 , 21 , Relative gene expression was determined by the ΔΔC t method, and results were expressed as fold increase above levels detected in HEK cells.
Cell lysates were examined by Western blot analysis, as described previously 21 , 40 , To perform the Matrigel tube formation assay, BD Matrigel Matrix BD BioSciences, Bedford, MA; 50 μl was polymerized for 30 min at 37°C in a well plate. To examine which signaling pathways contribute to IL—mediated HMVEC tube formation, cells were incubated with inhibitors to PI3K LY; 1 and 5 μM , ERK PD; 1 and 5 μM , JNK SP; 1 and 5 μM , or DMSO for 45 min at 37°C prior to adding to polymerized Matrigel.
Following incubation, culture medium was removed, and cells were washed with HBSS. The data were analyzed using two-tailed Student t tests for paired and unpaired samples.
The Ad-IL—treated group demonstrated significantly greater ankle circumference data not shown on days 4 and 10 postinjection compared with the control group. Von Willebrand factor staining of ankles harvested from day 10 postinjection demonstrated that Ad-IL—treated mice have significantly higher endothelial staining compared with the control group Fig.
These results suggest that IL may be important for angiogenesis in vivo. Local expression of IL increases vascularity in mouse ankles.
Ankles from day 10 post-Ad injection were harvested, paraffin embedded and decalcified. Ankles were stained with Von Willebrand factor for identifying endothelial cells Endo and scored on a 1—4 scale.
Control ankles A had significantly lower endothelial staining compared with ankles locally expressing IL original magnification × B. C , Quantification of each of the parameters in the Ad-CMV control and Ad-IL groups. These results support the role of IL in angiogenesis in vivo.
IL enhances blood vessel growth in Matrigel plugs in vivo. A , IL 2 μg induced angiogenesis in the Matrigel plugs to a significantly greater degree compared with PBS control. Experiments were performed to determine whether IL is directly chemotactic for endothelial cells. IL was chemotactic for HMVECs at concentrations ranging from 0.
IL induces HMVEC migration and not chemokinesis. A , Dose-response curve of IL—induced HMVEC chemotaxis. IL HMVEC chemotaxis was performed in a Boyden chemotaxis chamber with varying concentrations of IL Values demonstrate mean ± SE from five different experiments.
Values are the mean ± SE from three different experiments. C , A series of checkerboard experiments was performed by placing increasing doses of IL together with HMVECs in the lower well in addition to placing different concentrations of IL in the top well of the chemotaxis chamber.
The experiment was read at 2 h. Results are representative of three different experiments. We next determined the effect of IL on chemokinesis.
In the absence of IL in the lower chamber, IL in the upper chamber was chemotactic for HMVECs. When equivalent or higher concentrations of IL were present in the lower compartment, no enhanced migration of HMVECs occurred Fig. Taken together, our results suggest that IL is chemotactic, not chemokinetic, for endothelial cells.
Our results demonstrate that skin and lung HMVECs as well as HUVECs express significantly higher levels of ILRA and ILRC compared with HEK cells Fig. These experiments were performed to determine which IL receptor is involved in HMVEC chemotaxis and tube formation. To assess the effects of TCZ on angiogenesis potential, we added increasing amounts of the drug to the co-cultured cells with TNFα, and observed that EMMPRIN, VEGF and MMP-9 were all increased by 1.
We show that each of these inhibitors increased the expression of EMMPRIN in the supernatants of the co-cultured cells, relative to the control without the inhibitors by about 1.
Essentially, TCZ is designed to inhibit the IL-6 pathway by blocking IL-6R signaling. We, however, used TNFα as the primary stimulus in this study, as it a strong inducer of both MMP-9 and IL-6 Figure S3. However, to confirm that IL-6 in the absence of TNFα could also affect miRa-5p and EMMPRIN expression, we stimulated the co-cultured HT and U cells with IL-6 and observed that, similar to the presence of TNFα but to a lesser degree, EMMPRIN secretion was increased by 1.
TCZ further increased EMMPRIN secretion by 1. The effect on EMMPRIN was mediated by miRa-5p, as inhibiting it with its antagomir anti-miRa or overexpressing it by transfecting HT cells with the miRa-5p mimic resulted in significant increased or decreased amounts of secreted EMMPRIN, respectively Figures 8E, F.
Figure 8 IL-6 affects EMMPRIN and miRp expression similarly to TNFα. The concentrations of G EMMPRIN and H miRa-5p expression levels were measured. As we have used two cell lines in our study that do not necessarily represent physiological conditions, we next wanted to confirm our main results with primary monocytes.
We have isolated PBMC from healthy donors, and co-cultured them with the HT cell line. Similar to the previous results of the co-cultured HT and U cells, we show here that the levels of secreted EMMPRIN, VEGF and MMP-9 in HT cells co-cultured with primary monocytes-enriched PBMC were increased after 48 hours of incubation relative to single HT culture Figures 9A-F.
While IL-6 did not have an additional effect on the co-cultured cells, TNFα enhanced the secretion of MMP-9 and VEGF relative to unstimulated cells.
In contrast, relative to the HT single culture, the secreted levels of Tsp1 were decreased either by the co-culture or by the addition of the cytokines Figures 9G, H. The co-culture in the presence of TNFα or IL-6 also reduced the expression of miRa-5p in the HT cells, but not in the monocyte-enriched PBMC, relative to the HT single culture Figures 9L, M.
Figure 9 Primary monocyte-enriched PBMC co-cultured with HT fibroblasts enhance the secretion of EMMPRIN, VEGF and MMP-9, and TCZ enhances EMMPRIN and reduces miRa-5p expression. Supernatants were collected after 48h of incubation and the concentrations of A, B EMMPRIN, C, D VEGF, E, F MMP-9, and G, H Tsp-1 were determined by ELISA.
Similar to the previous results, the addition of TCZ enhanced EMMPRIN secretion and reduced miRa-5p expression in the HT, but not in the monocyte-enriched PBMC Figures 9K, N, O.
Thus, the monocyte-enriched PBMC confirmed that primary monocytes behave in a similar way to the U monocytic-like cell line, and promote pro-angiogenic changes in the HT fibroblast cell line.
Angiogenesis is an important process in the pathophysiology of RA 34 , but the mechanisms regulating it are yet unclear. TCZ is a biologic agent indicated for the treatment of RA 2 , but its effects on pathological angiogenesis have not been sufficiently studied.
Here we demonstrate that EMMPRIN known to be a pro-angiogenic factor in the tumor microenvironment 35 is involved in angiogenesis in RA patients and in a co-culture of fibroblasts and monocytes in vitro.
Furthermore, we demonstrate that TCZ affects the angiogenic process, at least partially, through its effects on pro-angiogenic factors, particularly EMMPRIN and its regulator miRa-5p.
We also demonstrate that the ratio between EMMPRIN and Tsp-1 levels is a useful measure of the angiogenic state in RA patients. The effects of TCZ on our RA patient cohort concurred with the known effects of TCZ, showing clinical improvement in arthritis, and causing reductions in DAS28 scores and high sensitivity CRP levels.
Also, in accordance with previous observations, IL-6 serum levels increased in RA patients following initiation of TCZ treatment Figure S2 2 , With the help of the functional tube-formation assay, we were able to demonstrate a direct effect of EMMPRIN on endothelial cells Figure 6.
However, despite the reduction in EMMPRIN, with its known ability to induce VEGF and MMPs 15 , 35 , no parallel reduction in the serum levels of VEGF or MMP-9 occurred in the sera of RA patients Figure 1. This finding may be explained by the presence of alternative signaling pathways to that of EMMPRIN which may induce VEGF and MMP-9 secretion, such as TNFα, a known inducer of MMP-9 33 or tissue hypoxia, a known inducer of VEGF 37 , Thus, the inhibition of the IL-6 signaling pathway by TCZ may not be sufficient to reduce the serum concentrations of these mediators in the synovial microenvironment, which is rich in pro-inflammatory cytokines.
When setting up the in vitro system, we chose to stimulate the cells with TNFα, a known inducer of both MMP-9 and IL We show that TNFα induced IL-6 levels in the HT cells, and reduced the shedding of IL-6R expression in U cells Figure S3. Thus, the ability of TCZ to inhibit IL-6 signaling could be mimicked in our in vitro system.
Since TCZ is an inhibitor of IL-6 signaling and TNFα might have different effects, we further verified these results by repeating the experiment in the presence of IL-6 alone Figure 8 , and demonstrated a similar ability of TCZ to inhibit miRa-5p expression levels and enhance EMMPRIN secretion.
However, it is still unclear whether TNFα acts directly on miRa-5p and EMMPRIN, or whether it works through its ability to induce IL The findings in our study should be further verified by using primary human synoviocytes, however, collection of synovial fluid was not part of our approved protocol, and we could not isolate such cells.
Next, we demonstrate that EMMPRIN is directly involved in the regulation of angiogenesis using an in vitro co-culture system, as its levels were increased in the media of co-cultured fibroblasts and monocytes together with those of VEGF and MMP-9 Figure 4 , and the anti-EMMPRIN antibody reduced these levels while recombinant EMMPRIN increased them Figure 5.
This involvement was further established by its direct effects on migration, proliferation, and tube-formation of the endothelial cells in the scratch and tube formation assays, and the ability of an anti-EMMPRIN antibody to reduce them Figure 6. Of note, the obvious inconsistency between the unchanged serum levels of VEGF and MMP-9 in the RA patients Figure 1 and their elevated levels in the in vitro system may suggest the involvement of additional factors in their regulation, including other cell types and multiple cytokines, which may not have been present in the isolated in vitro system.
This premise is also supported by the fact that monocyte-enriched PBMC produced similar results to those of the U cells when co-cultured with the HT cells Figure 9.
Such differences between the in vivo and in vitro systems are exemplified by reduction in the pro-angiogenic factor TGFβ in the patients after TCZ treatment, whereas in the in vitro setting TGFβ levels were unchanged by TCZ treatment Figure S4.
Although no difference was detected in EMMPRIN, VEGF, MMP-9 or Tsp-1 serum levels between patients who responded well to TCZ treatment and those who were unresponsive to therapy, the ratio between EMMPRIN and Tsp-1 was reduced in the responding patients compared to the non-responders Figure 2.
However, additional studies are necessary to establish the validity of this proposed parameter in assessing the effects of conventional or biologic DMARDs on angiogenesis in RA patients.
Among the pro-angiogenic factors we tested, NGAL was significantly elevated in TCZ-treated patients, as well as in responding patients relative to non-responders Figures 1 , 2.
NGAL is known to form heterodimers with MMP-9, thus protecting the latter from degradation. In addition, NGAL has been shown to regulate VEGF expression and to promote angiogenesis Previous reports demonstrated higher levels of NGAL in the serum of RA patients compared to healthy controls, suggesting that it promotes angiogenesis In this regard, the observation of elevated levels of NGAL in RA patients after TCZ administration is contrary to the general anti-angiogenic effects mediated by TCZ.
However, notably, NGAL plays many other pleiotropic roles unrelated to its role in angiogenesis, such as in protecting against bacterial infection by acting as an iron-carrying protein, in modulating oxidative stress, in promoting neutrophil chemotaxis, and in regulating thermogenesis and lipid metabolism by acting as an adipokine 10 , Moreover, although NGAL normally protects MMP-9 from degradation, we did not observe any elevation in MMP-9 serum levels in RA patients.
This finding further supports the notion that the primary role played by NGAL in RA is unrelated to angiogenesis, and that its elevation after initiation of TCZ treatment may be related to its role as an adipokine.
This possibility must be carefully explored in a follow-up study. From the nine miRNAs that we examined, we observed that only miRa-5p and miRp were elevated after 4 months of treatment Figure 3. Previous studies have implicated these two miRNAs in the inflammation that is driving RA.
The long non-coding RNA LINC which exhibits low levels in RA patients, normally acts as a sponge that binds miRp, thereby leading to enhanced thrombospondin-2 levels and reduced inflammation Outside the context of RA, TCZ was shown to increase the serum levels of miRa-5p in COVID patients, and its levels could predict response to the drug However, we are unaware of any other previously published studies examining the effects of TCZ on the expression of the particular miRNAs we chose to examine in our study, and only one study demonstrated an increase in the level of a different miRNA - miRa - by TCZ in neutrophils isolated from RA patients in vitro Since we have already previously shown that miRa-5p participates in the regulation of EMMPRIN expression in tumor cells 26 , 27 , we suspected that this miRNA was also involved in EMMPRIN regulation in fibroblasts, and therefore focused on this miRNA in our in vitro experiments.
We demonstrate that transfection of the fibroblast cell line HT with the miRa-5p mimic resulting in overexpression of miRa-5p in the HT cells, reduced the secretion of EMMPRIN, and subsequently of VEGF and MMP-9, implicating this miRNA in the regulation of EMMPRIN in fibroblasts Figures 7B—D.
In contrast, inhibiting miRa-5p activity by transfecting the HT cells with its antagomir increased EMMPRIN secretion Figure 7A , whether the cells were stimulated with TNFα or with IL Thus, miRa-5p is involved in the regulation of EMMPRIN expression in the fibroblast cell line, directly or indirectly by affecting other regulators of EMMPRIN.
We note that TCZ decreased miRa-5p levels and increased EMMPRIN levels in fibroblasts in vitro Figures 7E, G , 8C, D , 9N, O , whereas it increased miRa-5p levels and decreased EMMPRIN levels in the serum samples from treated RA patients Figures 1 , 3.
These inconsistencies may be explained by the difference between the in vitro and in vivo systems or by differing effects exerted by TCZ on different cell types. Indeed we could observe that the effects of TCZ on miRa-5p were specific to the HT fibroblasts, and TCZ had no significant effect on the miRa-5p levels in the monocytic U cells or in the monocyte-enriched PBMCs Figures 7G , 8D , 9N, O.
Alternatively, the serum may reflect the state in the synovium, where interactions between fibroblasts and many other cell types may generate a balance different from that observed in the in vitro co-culture system involving only two cell-lines.
However, despite these inconsistencies, both the in vivo and the in vitro systems reflect a strong link between miRa-5p, EMMPRIN and the angiogenic process, and demonstrate the ability of TCZ to intervene in this process.
The induction of miRa-5p is mostly attributed to stimulators activating the NF-κB pathway, such as TNFα and IL-6 46 , 47 , and accordingly its levels have been shown to increase in RA patients Therefore, the presence of TNFα or IL-6 in our in vitro system can explain the upregulation of miRa-5p compared to non-stimulated cells Figure 7F , and the inhibitory effect of TCZ on the expression of miRa-5p Figures 7G , 8D , 9N, O might suggest a disruption of this pathway.
Further investigation is required to map the exact nature of this interference. In summary, we establish an important role for EMMPRIN in mediating pro-angiogenic signals in RA patients and demonstrate a strong link between miRa-5p expression and the regulation of EMMPRIN secretion.
Importantly, we show that TCZ reduces the angiogenic potential in RA patients, and we suggest that this is partially due to the ability of TCZ to interfere with the expression of miRa-5p, leading to changes in EMMPRIN levels. We also suggest that the ratio between EMMPRIN and Tsp-1 may reflect the angiogenic status in RA patients more accurately than any one factor alone.
Further inquiries can be directed to the corresponding authors. The studies involving human participants were reviewed and approved by Institutional Review Board at Carmel Medical Center CMC MS, ES, AK, and LZ performed the experiments.
JF, TG, AH, ME, IR, LK, and DZ recruited the patients. JF secured the funding. TG, JF, AH, ME, IR, and LK reviewed and edited the paper. MR and DZ designed the work, analyzed and interpreted the data, and drafted the paper.
All authors contributed to the article and approved the submitted version. This research was partially supported by a young physician scholarship from the Israeli Rheumatology Association.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers.
Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. Supplementary Figure S1 TCZ treatment does not change U6 expression in RA patients. The change in the expression of U6 was lower relative to the change in miR, and therefore, it was chosen for the normalization of the rest of the studied miRNAs.
Supplementary Figure S2 TCZ increases serum levels of IL-6 and decreases those of hsCRP. Box plot representing the concentrations of A IL-6 and B hsCRP in the serum of RA patients before and after 4 months of TCZ treatment in comparison to healthy volunteers controls.
Supplementary Figure S3 TNFα induces IL-6 in HT cells and decreases IL-6R in U cells. Supernatants were collected after 48h of incubation and the concentrations of A IL-6, and B IL-6R were determined by ELISA. Supplementary Figure S4 TGFβ is reduced after TCZ treatment in RA patients, but not in the in vitro co-culture.
Supernatants were collected after 48h of incubation and the concentrations of TGFβ were unchanged. B Box plot representing the concentrations of angiogenic mediators in the serum of RA patients before and 4 months after initiation of TCZ treatment, as determined in duplicates for each sample.
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Pharmacol Ther — Download references. This work was supported in part by awards from the National Institutes of Health AR and AR, funding provided by Department of Defense PR and Arthritis Foundation Innovative Research Grant.
We apologize to colleagues whose studies were not cited because of space limitation. Division of Rheumatology, Department of Medicine, University of Illinois at Chicago, MSB S Wolcott Ave. Hatem A. Department of Microbiology and Immunology, Chicago College of Osteopathic Medicine, Midwestern University, Downers Grove, IL, , USA.
You can also search for this author in PubMed Google Scholar. Correspondence to Shiva Shahrara. Reprints and permissions. Elshabrawy, H. et al. The pathogenic role of angiogenesis in rheumatoid arthritis. Angiogenesis 18 , — Download citation. Received : 05 March Accepted : 14 July Published : 22 July Issue Date : October Anyone you share the following link with will be able to read this content:.
Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative. Abstract Angiogenesis is the formation of new capillaries from pre-existing vasculature, which plays a critical role in the pathogenesis of several inflammatory autoimmune diseases such as rheumatoid arthritis RA , spondyloarthropathies, psoriasis, systemic lupus erythematosus, systemic sclerosis, and atherosclerosis.
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Visceral fat and cellular health, D. Srthritis and inflammation are closely integrated processes in rehumatoid OA and may affect athritis progression and pain. Inflammation can stimulate angiogenesis, and angiogenesis can facilitate inflammation. Angiogenesis can also promote chondrocyte hypertrophy and endochondral ossification, contributing to radiographic changes in the joint. Inflammation sensitizes nerves, leading to increased pain.Bonnet, D. Nourishing Quenching Drinks and Angogenesis are closely integrated processes Boost endurance for yoga osteoarthritis OA and may affect disease xnd and pain.
Inflammation can stimulate angiogenesis, and rheumaroid can facilitate inflammation. Angiogenesis can also promote Regulated weight loss supplements Angigoenesis and endochondral ossification, rhekmatoid to radiographic changes rehumatoid the joint.
Inflammation sensitizes nerves, arthritos to increased Agiogenesis. Innervation can also accompany vascularization Angiogeneesis the articular cartilage, where rheumtoid forces and hypoxia may stimulate these new nerves, causing pain even after inflammation has subsided, Regulated weight loss supplements.
Anngiogenesis of inflammation and angiogenesis may provide effective therapeutics for arthritiw treatment of Angiogemesis by improving symptoms and rheumatoir joint damage. This review aims to Angiogeness i the evidence that angiogenesis and inflammation play an important role in the pathophysiology of OA and ii possible directions rheumatoic future research into therapeutics arthriitis could effectively treat this disease.
Osteoarthritis OA is a group of chronic, painful, disabling conditions affecting synovial joints. The Angiobenesis of OA may be defined Anggiogenesis, radiologically Antioxidants and sleep quality pathologically; however, its aetiology remains poorly Angoogenesis.
As with other complex clinical syndromes, artritis is often anx lack of rhematoid between anv various components that we recognize as Rhuematoid for example, wrthritis is usually only eheumatoid weak association between radiological features and Angiogenessis. OA may artyritis classified according to presumed Angiogenrsis factors, as in post-traumatic OA.
It can be classified according Muscle preservation exercises the distribution of arghritis affected; for example, into nodal, knee or hip joint Antioxidant and energy levels. Furthermore, OA can be classified according Angiogsnesis the arthritiw or absence of associated features, such as chondrocalcinosis.
Recent genetic and epidemiological analyses Angkogenesis further support for these Angiohenesis, whilst further emphasizing heterogeneity Angiogeneiss the diagnosis.
Despite this, inflammation Ajgiogenesis increasingly rheymatoid as contributing to the rheumatiid and arthrltis of OA Angiogenssis 12 ]. Morning and inactivity stiffness are common symptoms in patients Anviogenesis the disease, and acute inflammatory Caloric needs for breastfeeding, characterized by artyritis warmth, tenderness and Angiogenesiw, are Angiogenesis and rheumatoid arthritis uncommon.
Non-steroidal Angioyenesis drugs rheujatoid symptoms of OA and may be more effective than rheumatooid analgesics, such as paracetamol [ reumatoid ]. Intra-articular injection Angiogeneeis corticosteroids theumatoid may alleviate both pain rgeumatoid stiffness, not only rheujatoid acute flares but Athletes with food sensitivities as maintenance therapy.
Serological Sugar cravings and insulin resistance histological evidence of rhsumatoid is commonly found in OA, even Fuel Consumption Tracking App OA has not rheumtaoid consistently associated with arthritos immune responses.
Pain, the arthrtis symptom in OA, is multidimensional qnd its Angiogejesis and mediated through arhhritis variety of factors. The presence or absence of synovitis may nad an Angiogfnesis predictor Angipgenesis OA symptoms. The pain experience results arthrittis interactions between inflammation and other features of disease, including radiological rhejmatoid [ 4 annd, innervation of articular structures [ Stimulating herbal beverage6 ], rhejmatoid and arthritks sensitization [ Angiogemesis ] arthriti psychological zrthritis [ 8 ].
The precise contribution of inflammation to pain in OA may vary from time to rheumatoi and Angiogenedis patient to patient. Rheumwtoid is currently unclear Angiohenesis inflammation Metabolic syndrome insulin resistance a feature of all patients with OA at some stage of their disease, or whether Angiognesis itself defines rhejmatoid or more rheumatid subgroups.
Inflammation may be both a Speed up metabolism event in OA and secondary to other aspects of rhumatoid disease, rheujatoid as fheumatoid changes Angiogenesis and rheumatoid arthritis the cartilage.
Recent studies indicate Angiogenesi histological and Regulated weight loss supplements evidence of rheumatois is Energy Replenishment Methods early arthrifis in OA and not restricted rheumatold patients with rhrumatoid disease undergoing joint replacement surgery [ 2910 ].
Synovial inflammation may be Aniogenesis in rheumqtoid presence arthrritis mild or severe cartilage changes in OA [ 9 ]. Even Regulated weight loss supplements inflammation is secondary to DKA support groups and resources processes within the arthditis joint, synovitis may yet make an important Beta-carotene in pumpkins to the symptoms and Anigogenesis of rhheumatoid.
Clinically detectable joint inflammation rheumayoid predict a worse radiological outcome anr OA [ 11 ]. Furthermore, rheumafoid a lapine model of arthritis, joint damage was exacerbated after induction Sport-specific workouts inflammation in Arthritks knees arthirtis meniscal ahd [ 12 ].
Synovitis, therefore, although rheumafoid a prerequisite for OA, may lead to a poor eheumatoid outcome. Mechanisms by which Anggiogenesis exacerbates structural damage adn OA are likely arthrihis be artgritis.
Hypotheses Optimal athlete nutrition included alterations in chondrocyte function, enhanced angiogenesis and changes Angiogeneais bone turnover [ 1314 ].
Novel rheumatodi interventions aiming to inhibit synovitis in OA may not only improve short-term symptoms but also reduce pain and disability in the long term. Angiogenesis is the growth of new capillary blood vessels from pre-existing vasculature.
It occurs during essential physiological processes, such as embryogenesis, wound repair and the female menstrual cycle. Angiogenesis can also contribute to a variety of pathological conditions, including the unwanted vessel growth in chronic inflammatory diseases, and the growth and metastasis of tumours.
The process is regulated by numerous activating and inhibitory factors Table 1which may vary from tissue to tissue, between disease and normal physiology, and during different phases of a continuous disease process. Angiogenesis regulators localized to or released within osteoarthritic human synovium, synovial fluid and articular chondrocytes.
Angiogenesis is a complex multistep process controlled by a wide range of positive and negative regulatory factors Table 1. Detailed reviews have been published on the angiogenesis process [ 1464—66 ].
Activated endothelial cells detach from their neighbouring cells, through disruption of vascular endothelial cadherin junctions, resulting in increased vascular permeability. The endothelial basement membrane is degraded by proteolytic enzymes such as matrix metalloproteinases MMPsreleasing matrix-bound angiogenic factors that, in turn, stimulate endothelial cell migration and proliferation.
Capillary tube formation, deposition of a new basement membrane and anastomosis lead to blood flow. Factors produced by endothelial cells, such as platelet-derived growth factor, attract supporting cells such as pericytes, whilst vascular endothelial growth factor VEGF and the angiopoietins ensure the stability of the new vessel.
The new vessels differentiate into arterioles, capillaries and venules whilst redundant vessels regress, a process that requires endothelial cell apoptosis. Finally, vasoregulatory systems are developed and a fully functional microvasculature is formed. Signs of acute synovitis may be apparent in patients with OA from time to time.
However, the extent of subclinical inflammation in OA is now increasingly being recognized. Symptoms differ between acute and chronic inflammation and patients with OA may experience both: acute flares may occur either on the background of chronic synovitis or in an otherwise non-inflamed joint.
Acute inflammation usually has a sudden onset, becoming apparent over minutes or hours with the classic symptoms of heat, pain, redness and swelling.
Chronic inflammation develops over a longer period of time and may persist for days, weeks or months. Neutrophils are the most abundant inflammatory cells in acute synovitis, whereas in chronic synovitis in OA, macrophages are most abundant, often with lymphocytic infiltrates [ 67 ].
Unlike chronic inflammation, in which inflammation and repair occur concurrently, the host response in acute inflammation leads to elimination of the irritant followed by resolution of the tissue to its original state. During chronic inflammation the joint remains abnormal even after inflammation subsides.
Histological evidence of chronic synovitis may be present in the absence of overt clinical signs, and the contribution of chronic synovitis to symptoms of pain and stiffness may be overlooked [ 968 ]. The causes of acute inflammatory flares of OA are multiple and incompletely understood.
Patients will often attribute flares to particular activities, indicating that physical trauma may play a role. Acute inflammatory flares in OA may also be associated with the presence of calcium pyrophosphate dihydrate CPPD or hydroxyapatite crystals within the joint. CPPD crystal deposition is associated with OA of the knee, and manifests as radiological chondrocalcinosis or intermittent acute synovitis pseudogout.
Nearly half of patients with chondrocalcinosis who present to a rheumatologist have associated generalized OA [ 69 ]. Pain is one of the classic symptoms of acute inflammation. This is mainly due to the sensitization of fine unmyelinated sensory nerves present in the osteoarthritic joint.
However, this is not restricted to acute inflammation and chronic inflammation could also be a source of pain in OA. There is now much evidence that subclinical inflammation is common in OA, even in the absence of acute inflammatory flares.
Circulating markers of inflammation, such as C-reactive protein CRPmay be elevated in OA compared with control populations without disease [ 127071 ]. Histological examination of synovium frequently indicates inflammatory cell infiltration, involving macrophages and T cells, increased cell turnover and angiogenesis [ 972—75 ].
This synovial thickening was found to correspond to mild chronic synovitis [ 77 ]. Raised serum CRP may reflect subclinical inflammation in affected joints, mediated by cytokines entering the circulation. IL-6 is up-regulated during synovial inflammation, and can augment inflammatory angiogenesis [ 78—80 ].
IL-6 is thought to be the chief stimulator of CRP production [ 81 ]. IL-6 is produced by synovial cells, osteoblasts and chondrocytes, and is detectable by immunoassay in synovial fluid samples that have been harvested from joints affected by OA [ 82—84 ]. The causes of chronic synovitis in OA remain poorly understood.
Haemosiderin deposition suggests a possible role for recurrent minor haemarthrosis in some patients. Histological synovitis has also been described in patients with chondrocalcinosis, even in the absence of an acute flare [ 85 ], and it is likely that histological synovitis is more common in OA with chondrocalcinosis than in OA alone.
CPPD crystals can be identified in synovial tissue and fluid from patients with chondrocalcinosis between attacks of acute synovitis, when they may be associated with histological evidence of chronic synovitis [ 8586 ].
In addition to their acute effects on neutrophils, CPPD crystals can induce the expression of inflammatory, angiogenic factors such as TNF-α, IL-6 and IL-8, by monocytes and macrophages, and they can also stimulate cell proliferation [ 87—90 ].
CPPD crystal types with a low propensity to induce acute inflammation may therefore contribute to chronic synovitis and angiogenesis in chondrocalcinosis.
The symptoms of chronic synovitis are less well understood than those of acute inflammation. Features of inflammation, such as minor elevations of CRP and infiltration of macrophages into the synovium and even lymphoid aggregates, are not necessarily associated in OA with the classic signs of inflammation; heat, redness, soft tissue swelling or effusion.
Chronic synovitis is associated with marked changes in the central connections of sensory nerves, and changes in their synthesis and release of neurotransmitters and neuromodulators [ 7 ]. Furthermore, there is increased turnover of cells within the inflamed synovium: fibroblasts and blood vessels proliferate, macrophages are recruited, and there is increased cellular apoptosis [ 14 ].
Turnover within the synovial tissue is accompanied by retraction and growth of sensory nerve terminals [ 9192 ]. Peripheral nerve growth and injury are closely associated with enhanced pain sensation [ 93 ].
The ability of inflammation to cause pain depends upon the sensory innervation of the joint. Fine unmyelinated sensory nerves containing neuropeptides such as substance P SP and calcitonin gene-related peptide CGRP have been localized to the synovium, ligaments, tendons, menisci and the osteochondral junction in normal and osteoarthritic joints [ 929495 ].
Such nerves may mediate slow, burning pain, as described by many patients with OA. Myelinated nerve fibres in the joint capsule and intra-articular structures may mediate the sudden pain on movement or pressure.
During inflammation, chemicals such as adenosine, prostaglandin PG E 1 and PGF 2αleukotriene B 4 and 8RS -dihydroxyeicosa- 5E-9,11, -tetraenoic acid 8RS-diHETE are released within the joint, where they sensitize nerves, resulting in increased firing to a given stimulus [ 96 ].
At the same time, inflammatory mediators such as bradykinin, histamine, 5-HT, PGE 2prostacyclin and acidosis stimulate nerves even in the absence of mechanical stimulation [ 9597 ].
Over a period of hours or days, recruitment of inflammatory cells and up-regulation of genes within the synovium generates cytokines such as IL-1, IL-6, IL-8 and TNF-α, in addition to nerve growth factor [ 97 ].
These factors further enhance peripheral sensitization, whilst neuronal plasticity contributes to central sensitization. Inflammation may exacerbate cartilage degradation in osteoarthritis Fig. Patients with OA in whom radiological scores progress rapidly tend to have higher serum concentrations of CRP at baseline than do those whose disease progresses slowly [ 12 ].
TNF-α and IL-1 stimulate chondrocytes to produce MMPs and plasminogen activator, which degrade matrix proteoglycans and collagen [ 9899 ]. Chondrocytes also produce further IL-1 that acts in an autocrine manner and further stimulates MMP and plasminogen activator production [ 42 ].
As discussed below, stimulation of angiogenesis by synovitis may also contribute to progressive joint damage in OA. Interactions between inflammation and angiogenesis in the osteoarthritic joint.
: Angiogenesis and rheumatoid arthritis| The pathogenic role of angiogenesis in rheumatoid arthritis | Angiogenesis | Nat Genet 41 12 — Rheumatology Vol. C , A series of checkerboard experiments was performed by placing increasing doses of IL together with HMVECs in the lower well in addition to placing different concentrations of IL in the top well of the chemotaxis chamber. Over a period of hours or days, recruitment of inflammatory cells and up-regulation of genes within the synovium generates cytokines such as IL-1, IL-6, IL-8 and TNF-α, in addition to nerve growth factor [ 97 ]. Clin Exp Rheumatol 27 6 — Joint Bone Spine 79 2 — Harada M, Mitsuyama K, Yoshida H, Sakisaka S, Taniguchi E, Kawaguchi T, Ariyoshi M, Saiki T, Sakamoto M, Nagata K, Sata M, Matsuo K, Tanikawa K Vascular endothelial growth factor in patients with rheumatoid arthritis. |
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Division of Rheumatology, Department of Medicine, University of Illinois at Chicago, MSB S Wolcott Ave. Hatem A. Department of Microbiology and Immunology, Chicago College of Osteopathic Medicine, Midwestern University, Downers Grove, IL, , USA. You can also search for this author in PubMed Google Scholar. Correspondence to Shiva Shahrara. Reprints and permissions. Elshabrawy, H. et al. The pathogenic role of angiogenesis in rheumatoid arthritis. Angiogenesis 18 , — Download citation. Received : 05 March Accepted : 14 July Published : 22 July Issue Date : October Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative. 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Eur J Clin Pharmacol 70 2 — Article CAS PubMed Google Scholar Lubberts E, Koenders MI, Oppers-Walgreen B, van den Bersselaar L, Coenen-de Roo CJ, Joosten LA, van den Berg WB Treatment with a neutralizing anti-murine interleukin antibody after the onset of collagen-induced arthritis reduces joint inflammation, cartilage destruction, and bone erosion. Angiogenesis has been suggested to be central to the pathophysiology of RA, contributing to disease progression at multiple levels 6,7. The most obvious role of vascularization during RA is an increased capacity to sustain the nutritional and metabolic requirements of the hyperproliferating synovium and invading pannus However, it is clear that the neovascularization which is ultimately achieved is not completely sufficient to relieve the intra-articular hypoxia associated with RA 18 , resulting in a chronic angiogenic response. In part, this is likely due to the distinction that in RA angiogenesis occurs within the context of an ongoing autoimmune reaction, where leukocyte extravasation into the tissues serves to maintain a local inflammatory response. Neovascularization, and the resulting increased vascular bed volume, directly permit increased recruitment of blood-borne leukocytes into the synovial tissue. In turn, these activated leukocytes release angiogenic cytokines see below but also cause local microvascular occlusion and injury. Further damage to endothelial cells occurs directly via the release of high levels of reactive oxygen species and proteolytic enzymes In turn, local vessel damage will subsequently induce a reparative angiogenic response from adjacent or contiguous vessels. Thus, the synovial vasculature is not static, but undergoes dynamic reorganization in response to cumulative cycles of endothelial proliferation and death Recent investigations have revealed that activated endothelial cells may make direct contributions to both ongoing inflammation and protease production. The increased endothelial mass in RA can function as a rich source of inflammatory cytokines including IL-1, IL-6 and IL-8, as well as both vascular endothelial cell growth factor VEGF and basic fibroblast growth factor bFGF reviewed in 6,7. Importantly, many of these cytokines produced are themselves angiogenic, providing a direct autocrine mechanism to sustain neovascularization of the subsynovial tissue Alternatively, many cytokines present in synovial tissues play an indirect role in neovascularization by stimulating the secretion of directly angiogenic cytokines from either inflammatory or bystander cell populations, while selected cytokines have both activities Table 1. For example, in addition to angiogenic effects on endothelial cells, the production of VEGF and bFGF also serves to activate cells of the macrophage 21 and fibroblast 22 lineages, respectively. Interestingly, these two lineages are the predominant components of the hyperproliferative synovial lining, and comprise a significant proportion of the pannus in RA. Early responses of the endothelium to angiogenic cytokines include the initiation of vascular permeability and subsequently the upregulation of protease production. These events result in significant alteration of the composition of the local extracellular matrix ECM. Numerous proteases including urokinase, tissue plasminogen activator and the metalloproteinases MMP-1, 2, 3, and 9 are produced by activated endothelial cells , The metalloproteinases are capable of digesting subendothelial basement matrix, particularly collagen types IV and V, which act to suppress the angiogenic phenotype 14,24, The combined proteolysis and vascular permeability not only eliminates the capacity of these collagens to inhibit angiogenesis, but additionally provides a new provisional ECM to sustain endothelial survival 26 and migration Plasma glycoproteins including fibrinogen and fibronectin polymerize extravascularly 28 and probably also on the luminal face of the endothelium 29 , similar to normal wound healing responses. However, unlike wound healing, the deposited "provisional" matrix is not effectively remodeled and replaced in RA. In fact, evidence suggests that the deposition of this provisional ECM is sustained 30,31 , and actually contributes to arthritic disease severity In this respect, components of the provisional ECM are potent cell activators. Fibronectin, vitronectin and fibrinogen can be chemotactic or haptotactic substrates for endothelial cells In leukocytes, integrin-mediated interaction with provisional ECM proteins can facilitate mitogenic, chemotactic and oxidative responses, depending upon the specific subpopulation of cells studied Integrin-mediated signaling also provides a crucial mechanism for adhesion-dependent survival in endothelial cells and fibroblasts The importance of this integrin-mediated event is demonstrated by the observation that starved, but adherent endothelial cells, resist apoptosis better than starved or growth factor-stimulated cells maintained in suspension Moreover, recent investigations show that endothelial cell signaling events elicited by angiogenic growth factors, including activation of the downstream effector MAP kinase, are dramatically augmented in vitro and in vivo by integrin-mediated interactions with the ECM 40, Integrin avß3 has recently been characterized as a marker of angiogenic endothelium and as a central effector of this process It is clear that ECM composition plays a determining role in endothelial cell responses, and in this respect integrin avß3 is known to be a receptor for a variety of ECM proteins, including denatured collagen, fibronectin, fibrinogen and vitronectin Further, avß3 can bind to the metalloproteinase MMP-2, localizing it to the endothelial cell surface and subsequently potentiating its activation from precursor zymogen to active enzyme Therefore, expression of integrin avß3 expands the range of ligands which endothelial cells can interact with and also modifies cellular interactions with pre-existing ligands. Inhibition of integrin ligation by selective antagonists not only blocks the migration of endothelial cells stimulated by angiogenic cytokines 35 , but also induces apoptosis of angiogenic endothelial cells in vivo Conversely, ligation of avß3 leads to translocation of the transcription factor NF-kB to the cell nucleus, promoting endothelial cell survival Thus, antagonism of integrin avß3 on endothelial cells may block angiogenic responses through complementary mechanisms, summarized in Figure 1. Figure 1 - Potential mechanisms of angiogenesis inhibition by antagonists of integrin avß3. Angiogenic growth factors induce vascular permeability, provisional extracellular matrix ECM deposition, degradation of the subendothelial basement matrix proteins and expression of integrin avß3. The presence of antagonists of integrin avß3 may prevent angiogenesis by blocking migratory or invasive processes associated with endothelial sprouts, thus limiting endothelial penetration to target areas. However, antagonists of integrin avß3 can also block ECM-dependent cell survival signals grey arrows , including activation of NF-kB and suppression of pmediated transcription of the apoptosis-inducing genes bax and p21 waf. Blockade of these survival signals black X can result in the onset of programmed cell death and the local disruption of angiogenic vessels. Anti-angiogenic effects of avß3 antagonists have been demonstrated in several in vivo models, including the chick chorio-allantoic membrane CAM model, where avß3-selective antagonists inhibit both cytokine- bFGF and tumor cell- melanoma induced angiogenesis 43,46 , and the rabbit corneal micropocket assay where bFGF-induced neovascularization is also blocked by local administration of avß3 antagonists These results support a conserved role for integrin avß3 as a crucial angiogenic mediator under a variety of circumstances. Given the role of this integrin in promoting angiogenesis and modulating endothelial cell responses, it is not surprising that the expression of avß3 is tightly regulated. Studies within our laboratory have demonstrated that avß3 expression is specifically induced on activated endothelial cells, and is one of several proteins coordinately induced by the Hox D3 gene program. Expression of Hox D3 results in the acquisition of an invasive phenotype in quiescent endothelial cells The invasive phenotype appears to provide a selective target for antagonist activity in vivo. Immunohistochemical examination of tumor fragments implanted in either human skin xenograft or on chick CAM revealed necrotic areas associated with reduced vascularity and obvious disruption of the tumor-associated vasculature TUNEL staining revealed the presence of apoptotic blood vessels in tumor-associated vasculature, yet no apoptosis was observed in adjacent uninvolved tissues. Thus, although integrin antagonists are potent inhibitors of angiogenesis, no effect is apparent on quiescent endothelium. Integrin avß3 is highly expressed on the synovial endothelium in RA 50,51 , as identified by costaining for von Willebrand factor, an endothelial cell marker Figure 2. Studies in our laboratory have revealed that integrin avß3 is also upregulated on vascular cells in a rabbit antigen-induced arthritis AIA model This model resembles human disease histopathologically, including neovascularization, synovial hypertrophy and subsynovial inflammatory infiltrate, and presented a unique opportunity to demonstrate specifically the impact of integrin-based anti-angiogenic therapy in arthritis. Figure 2 - The expression of integrin avß3 in rheumatoid arthritis. Cryosections of human RA synovium were stained with monoclonal antibody LM, specific for integrin avß3, and detected with secondary rhodamine-conjugated donkey anti-mouse avß3 red. Sections were costained with goat polyclonal antisera to von Willebrand factor and detected with secondary FITC-conjugated donkey anti-goat antisera vWf to reveal mature blood vessels green. The colocalization of the signals is revealed when the fluorescent channels are combined Merge, yellow X. Note that many early microvessels, which do not yet stain for wWf, stain selectively for integrin avß3. Previously, integrin antagonists derived from fragments of the fibronectin cell-binding domain have been demonstrated to inhibit the development of arthritis in a rat model of disease Similar peptides prevent inflammation in delayed-type hypersensitivity reactions through this mechanism However, it is noteworthy that these linear peptide antagonists have broad specificity, and actually inhibit integrin avß3-dependent adhesion at lower concentrations than, for example, integrin a5ß1-mediated adhesion This raises the possibility that some of the observed anti-arthritic activity resulted from anti-angiogenic effects. Since the principal target of novel cyclic av antagonists used in tumor studies appears to be endothelial cells expressing avß3, these compounds may be amenable to future studies on RA The success of alternative, toxin-based anti-angiogenic strategies such as taxol 14 or derivatives of the fungal metabolite fumagillin 15 validates targeting endothelial cell-mediated pathology in RA. Together, these studies provide an excellent rationale to pursue development of integrin-based anti-angiogenic strategies as a viable approach to control RA. Since cellular responses to cytokines and other soluble factors occur within the governing context of the ECM, modulation of these responses through the antagonism of adhesion receptors is becoming increasingly attractive as a therapy. Increased efficacy may be achieved by alternative approaches, including systemic administration of stable antagonists or possibly local gene delivery allowing regional production of anti-angiogenic proteins for extended periods. Angiogenesis is influenced by an ever-growing list of proteins, protein fragments, peptides, sugars and lipids, but a common element in the angiogenic response induced by any means is the local reorganization of the ECM. Toward this end, a second strategy developed for the control of angiogenesis combines antagonism of avß3 with prevention of ECM alteration. The recent discovery that integrin avß3 binding to MMP-2 is mediated via the hemopexin domain of MMP-2 PEX 56 has led to the development of recombinant PEX as a coordinate inhibitor of integrin function and MMP-2 activation in vitro. As might be predicted from these results, PEX also blocks angiogenesis in vivo Figure 3 56 , suggesting that future identification of key sequences in PEX may provide additional multifunctional angiogenesis inhibitors. Enhanced control of angiogenic responses may be possible by coordinately inhibiting complementary potentiating events involved in neovascularization. In the case of RA, the ongoing inflammatory component presents an obvious and important target 57 , since angiogenesis and inflammation are complementary events contributing to disease progression. This type of "logical" combination therapy, in which both ongoing neovascularization and inflammation are targeted as distinct but inter-related components, may offer the most effective means of treatment for rheumatoid arthritis. Recent studies focusing on the interactions of cells with the ECM have led to advances in both angiogenesis and inflammation research, providing valuable tools for future investigations. Ultimately, an increased understanding of the pathological mechanisms in RA will permit development of new and innovative therapies. Figure 3 - An alternative inhibitory mechanism for angiogenesis. The protease MMP-2 is produced as a nonactive zymogen. Binding to integrin avß3 via the noncatalytic hemopexin PEX domain facilitates the processing of MMP-2 to its active form, and also localizes the activity of the protease to the surface of invasive cells left panel. An excess of the recombinant PEX domain blocks neovascularization by competitively inhibiting the binding of unactivated MMP-2 to endothelial cells, preventing activation of proteolytic activity right panel. Address for correspondence: D. Cheresh, The Scripps Research Institute, IMM24, N. Torrey Pines Rd. E-mail: cheresh scripps. Presented at the 5th Brazilian Symposium on Extracellular Matrix - SIMEC, Angra dos Reis, RJ, Brasil, September , Research supported in part by the Jeanette Hennings Foundation and NIH Nos. CA, CA and HL Stupack and C. Storgard are recipients of fellowships from the Joseph Drown Foundation and the Arthritis Foundation, respectively. Received October 19, Accepted November 12, Open menu Brazil. Brazilian Journal of Medical and Biological Research. Submission of manuscripts About the journal Editorial Board Instructions to authors Contact. Português Español. Open menu. table of contents « previous current next ». Text EN Text English. PDF Download PDF English. angiogenesis; endothelium; arthritis; integrin. Braz J Med Biol Res, May , Volume 32 5 A role for angiogenesis in rheumatoid arthritis D. Stupack, C. Storgard and D. Cheresh Departments of Immunology and Vascular Biology, The Scripps Research Institute, La Jolla, CA, USA Text References Correspondence and Footnotes Correspondence and Footnotes Correspondence and Footnotes. Pincus T The underestimated long term medical and economic consequences of rheumatoid arthritis. 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Carcinogenesis 31 10 — Shock 36 3 — Blood 1 — Takeda Y, Costa S, Delamarre E, Roncal C, Leite de Oliveira R, Squadrito ML, Finisguerra V, Deschoemaeker S, Bruyere F, Wenes M, Hamm A, Serneels J, Magat J, Bhattacharyya T, Anisimov A, Jordan BF, Alitalo K, Maxwell P, Gallez B, Zhuang ZW, Saito Y, Simons M, De Palma M, Mazzone M Macrophage skewing by Phd2 haplodeficiency prevents ischaemia by inducing arteriogenesis. Escribese MM, Sierra-Filardi E, Nieto C, Samaniego R, Sanchez-Torres C, Matsuyama T, Calderon-Gomez E, Vega MA, Salas A, Sanchez-Mateos P, Corbi AL The prolyl hydroxylase PHD3 identifies proinflammatory macrophages and its expression is regulated by activin A. J Immunol 4 — Taylor CT Interdependent roles for hypoxia inducible factor and nuclear factor-kappaB in hypoxic inflammation. Expression of hypoxia-inducible factor-1α by macrophages in RA synovium, predominantly close to the intimal layer but also in the subintimal area, has been described [ 30 ]. We have reported that dissociated cells of the synovial membrane in RA respond to hypoxia by upregulating VEGF production. Cells of the synovial membrane in RA were isolated by enzymatic digestion, and after overnight adherence were placed in either normoxic mean P O 2 mmHg or hypoxic mean P O 2 60 mmHg conditions. After 24 hours in hypoxia, release of VEGF was selectively upregulated, whereas production of IL-1β and IL-8 was unaffected. These observations suggest that a component of the formation of new blood vessels observed in RA may result from hypoxia-driven induction of VEGF [ 23 ]. To investigate the relation between tissue oxygen levels and synovial VEGF production in inflammatory arthritis in humans, we examined patients undergoing knee arthroscopy. Synovial P O 2 levels were significantly lower in patients with active RA than in patients without RA, and release of VEGF from synovial cells prepared from tissue biopsies was likewise greater for patients with RA. It would appear, therefore, that reduced intra-articular P O 2 is likely to be a stimulus for local VEGF production [ 31 ]. We have also recently shown that VEGF is important in the development of joint destruction in RA. We observed a significant correlation between serum VEGF at presentation with early RA and the magnitude of radiological deterioration within the first year, calculated using radiographs of hands and feet, taken at initial presentation and at follow-up after 1 year. Radiographs were scored according to the van der Heijde modification of Sharp's method. These results suggest that high serum VEGF levels at an early stage of disease are associated with the increased subsequent damage to joints observed by radiography. More recent studies have addressed the role in arthritis of another important family of molecules involved in angiogenesis, namely the angiopoietins. These molecules, together with their cell-surface receptors Tie-1 and Tie-2, play a key role in development of the vasculature and have been implicated in the control of vessel stabilisation and regression. The patterns of expression of the best-characterised molecules, angiopoietin Ang -1 and Ang-2, during embryonic development and during pathological angiogenesis suggest that Ang-1 may act to stabilise new vessels formed in response to VEGF. In contrast, Ang-2 may destabilise blood vessels, which would lead to new vessel sprouts in the presence of VEGF or to regression of vessels in the absence of VEGF. Expression of Tie-1 and Tie-2 in RA synovium has been reported [ 33 ]. Detectable levels of mRNA for Ang-1 and its receptors have been shown in specimens of synovial tissue from patients with juvenile RA, in which expression was significantly higher than in tissues from patients with OA or other noninflammatory controls [ 34 ]. These observations are perhaps surprising, given that administration of Ang-1 was shown to protect adult mouse vasculature from leaking, countering the permeability activity of VEGF [ 35 ]. The levels of an angiogenesis inhibitor, endostatin, were recently reported for patients with RA. VEGF levels in the serum and joint fluid from patients with RA were higher than in patients without RA, whereas endostatin levels were comparable between the groups [ 36 ]. My coworkers and I have found that serum levels of the soluble form of the VEGF Flt-1 receptor are raised in RA, as well as in self-limiting arthritis [ 32 ]. An inverse relation between the cytokine and its soluble receptor might be predicted. However, raised levels of sFlt-1 observed in RA are presumably insufficient to inhibit VEGF activity. These observations suggest that there may be an imbalance in RA favouring proangiogenic stimuli, whereas inhibitors of angiogenesis such as endostatin are not elevated, or, as in the case of the soluble VEGF Flt-1 receptor, are not increased enough to block the effects of stimuli such as VEGF. In summary, the invasive pannus in RA is highly vascularised, and numerous growth factors are expressed, which might promote the formation of new blood vessels. Subsequent sections examine the signalling mechanisms involved in the induction of VEGF expression in the context of RA, and the development of new therapies targeting blood vessels in RA. Angiogenesis is clearly a feature of arthritis, with VEGF playing a particularly central role in this process. It seems likely that suppression of the formation of blood vessels should retard the progression of arthritis. There is certainly considerable literature describing the ability of broadly acting angiogenesis inhibitors to modulate disease in animal models. Taxol, TNP, and thalidomide — compounds that exert nonspecific anti-angiogenic, as well as other, effects — have all been shown to inhibit pannus formation and neovascularisation [ 37 — 39 ]. For example, in a rat model of arthritis, in which disease is induced by injection of heterologous collagen, leading to synovitis, joint erosion, and associated neovascularisation, TNP was found to suppress established disease. In parallel, there was a marked inhibition of pannus formation and of neovascularisation [ 37 ]. TNP has recently been shown to delay onset of arthritis and greatly reduce bone and cartilage destruction if given very early in a transgenic mouse model of arthritis [ 40 ]. A hypothesis could also be made that inhibition of VEGF activity should be an effective therapy in RA. We have addressed this hypothesis using the model of collagen-induced arthritis in genetically susceptible mice. To study the association between VEGF and disease severity in murine arthritis, we measured release of this angiogenic cytokine by enzymatically dissociated murine synovial cells. Synovial cells isolated from the knee joints of naive or sham-immunised mice, or from mice immunised with collagen but without arthritis, released little or no detectable VEGF. Onset of arthritis was associated with expression of VEGF, and the levels of VEGF secreted by synovial cells isolated from joints of mice with severe arthritis were significantly higher than from mice with mild disease [ 41 ]. We additionally showed that a soluble form of the Flt-1 VEGF receptor sFlt significantly reduced disease severity and joint destruction in murine collagen-induced arthritis. Mice treated with a soluble form of this receptor after the onset of arthritis exhibited significantly lower clinical scores and paw swelling than untreated or control-treated animals. These sFlt-treated animals also showed significantly reduced joint inflammation and less destruction of bone and cartilage, as assessed by histology [ 41 ]. Later studies, using anti-VEGF polyclonal antibodies, showed the effectiveness of VEGF blockade in collagen-induced arthritis [ 42 , 43 ]. It therefore appears that VEGF plays a unique role in mediating angiogenesis in RA. Our results using sFlt, and more recent, unpublished data using adenovirus-mediated transfer of VEGF antagonists, suggest that blockade of VEGF activity might be of therapeutic benefit in RA. The findings of elevated expression of angiogenic factors in RA suggest that reducing synovial vascularity may be a desirable component of anti-RA therapies. Certain disease-modifying antirheumatic drugs DMARDs have been shown to inhibit angiogenesis in experimental systems. These include drugs such as methotrexate MTX [ 44 ], sulphasalazine, and penicillamine. Combinations of such drugs also affect production of VEGF by synovial cells in vitro. For example, bucillamine and gold sodium thiomalate inhibited VEGF production, as did a combination of bucillamine, gold sodium thiomalate, and MTX with dexamethasone [ 45 ]. Further insights into the importance of reduced angiogenesis in RA were gained from clinical trials of anti-tumour necrosis factor TNF -α antibody infliximab — a chimeric mouse Fv, human IgG1, κ antibody of high affinity. From the earliest trials in , infliximab has shown remarkable therapeutic efficacy, reducing both clinical and laboratory indices of disease activity reviewed [ 46 , 47 ]. The effects of TNF-α on the angiogenic process are both stimulatory and inhibitory, depending on the system. For example, exposure of endothelial cells to TNF-α has been reported to induce release of VEGF and FGF-2 [ 48 ]. Production by synovial-joint cells of angiogenic cytokines such as VEGF is at least in part induced by TNF-α, as was demonstrated in a study showing reduced synovial-cell VEGF release in the presence of anti-TNF-α antibody: my colleagues and I reported that in the presence of anti-TNF-α antibody, spontaneous release of VEGF by RA synovial-membrane cells was decreased. We therefore postulated that part of the benefit of anti-TNF-α antibody in RA was gained through a reduction in synovial vascularity. To examine this hypothesis, we measured serum VEGF levels in patients with RA who were treated with anti-TNF-α antibody, and observed significant reductions in circulating concentrations of this angiogenic cytokine. Treatment of RA patients with a combination of multiple infusions of infliximab and MTX resulted in a more prolonged decrease in serum VEGF levels than in patients who received infliximab without MTX. We found that infusion of 10 mg infliximab per kilogram of body weight without MTX reduced the levels of circulating VEGF, although these returned to pre-infusion concentrations after the final infusion. In contrast, in patients who received infliximab as well as MTX, this reduction was maintained up to the end of the trial period [ 23 ]. These observations suggest that TNF-α regulates production of VEGF in vivo , and that part of the beneficial effect of anti-TNF-α in RA may be a down-modulation in the formation of blood vessels. In a more recent study, the effects of infliximab on synovial angiogenesis, vascularity, and VEGF expression were investigated [ 49 ]. Patients with active RA received a single dose, 10 mg per kilogram of body weight, of anti-TNF-α antibody. Synovial biopsies were taken during arthroscopic examination of the knee joint 1 day before and 2 weeks after treatment, and synovial vascularity was assessed by immunohistochemistry followed by quantitative image analysis. Anti-TNF-α therapy was found to reduce synovial vascularity as assessed by immunostaining for the presence of CD31 and von Willebrand factor. Additionally, a significant reduction in the number of αvβ3-integrin-positive vessels was found. The reduced expression of CD31, von Willebrand factor, and αvβ3 integrin after TNF-α blockade is in agreement with the concept that the balance of new vessel growth and regression is altered such that a net loss of microvessels occurs. Since the endothelial surface plays a key role in mediating cell traffic and delivery of nutrients, such alterations in vascular density may also contribute to therapeutic efficacy. My co-workers and I are currently in the process of using power colour Doppler to examine the effects of anti-TNF-α antibody treatment on synovial vascularity. Therapeutic agents and strategies are being devised to either interrupt or inhibit one or more of the pathogenic steps involved in angiogenesis, and blockade of neovascularisation has been effective in many tumour models. Clearly, angiogenesis can be targeted at several different stages, including inhibition of production of stimuli such as VEGF, binding of proangiogenic factors using antibodies or soluble receptors , interruption of downstream signalling, blockade of matrix degradation, or even the use of anti-angiogenic stimuli such as endostatin. Many of these approaches have been used with varying degrees of success for human cancers Table 2 ; for an updated list of angiogenesis inhibitors in clinical trials see [ 50 ]. In terms of inhibiting the action of VEGF, phase I and phase 1b clinical trial data for pharmacological, safety, and pharmacokinetic studies have been reported for anti-VEGF antibody in patients with solid tumours [ 51 ]. Another approach is to use inhibitors of receptor tyrosine kinases, such as SU and SU, designed by SUGEN, a company of the Pharmacia Corporation based in South San Francisco. SU has been shown to potently inhibit VEGF-dependent tyrosine phosphorylation, ATP-dependent Flk-1 autophosphorylation, and the proliferation of human endothelial cells. Phase I clinical trials in AIDS-related Kaposi's sarcoma and various solid tumours showed SU to be well tolerated. SU is less selective for Flk-1, inhibiting also signalling downstream of the PDGF and the FGF-1 receptors. Currently, SU is in phase I trials for the treatment of advanced solid tumours. The use of anti-angiogenic molecules is less common. In a phase I trial of endostatin at the University of Texas M D Anderson Cancer Center, 25 study patients tolerated the drug well, with few toxic side effects, and two patients showed evidence of some tumour shrinkage [ 53 ]. My coworkers and I have recently begun a study in mouse collagen-induced arthritis of K1—5 protease-activated kringles 1—5 , which is related to the potent angiogenesis inhibitor angiostatin. Like several other endogenous anti-angiogenic molecules, angiostatin is a cryptic fragment of a larger molecule lacking in anti-angiogenic activity and is generated as a result of proteolytic cleavage of plasminogen. Angiostatin comprises the first four triple-loop disulfide-linked structures of plasminogen, termed kringle K domains. Urokinase-activated plasmin can also convert plasminogen into a molecule containing the intact K1—4 and most of the K5 domains, termed K1—5. This angiogenesis inhibitor K1—5 inhibited the proliferation of endothelial cells more effectively than angiostatin, and suppressed tumour growth and neovascularisation [ 54 ]. The effectiveness of treatment with K1—5 treatment in the mouse tumour model prompted us to examine the effects of this inhibitor in the murine model of CIA, and preliminary data are encouraging. It is not unreasonable to suggest that targeting the newly formed vasculature of the RA pannus, in combination with other therapies such as anti-TNF-α, may lead to a more persistent reduction in pannus volume and hence modify disease progression, but confirmation of this hypothesis requires appropriate clinical trials. Moreover, not all patients respond to TNF-α blockade. Targeting the inflammatory and vascular components of RA, by combining TNF-α inhibition with angiogenesis blockade, could therefore increase benefit to patients with RA, without augmenting the infection risk. Angiogenesis is, clearly, an important process in the development and perpetuation of RA. Clinical trials in cancer patients of VEGF antibody and small-molecule inhibitors of receptor tyrosine kinases, including those for VEGF, are well under way. It may well be that in the not too distant future, clinical trials of VEGF-targeted therapies may also commence for RA, either alone or in combination with established therapies such as anti-TNF-α antibody. Naturally, there are undoubted potential drawbacks of anti-angiogenic therapy, such as reduced fertility, impaired healing of fractures, or maybe reduced formation of collateral vessels after an episode of ischaemia. Since patients with RA develop cardiovascular problems at an earlier age than their nonarthritic peers, anti-VEGF therapy might not, therefore, be desirable, in spite of the proven role for VEGF in RA and data showing promising effects of VEGF blockade in animal models. On the other hand, recombinant human VEGF increased the rate and degree of formation of atherosclerotic plaques in the thoracic aorta in a model in cholesterol-fed rabbits, and plasma levels are elevated in atherosclerotic patients [ 52 , 53 ]. It is thus difficult to predict what the results of angiogenesis inhibition in RA might be, and probably only carefully designed clinical trials will answer this question. In theory, at least, anti-angiogenic treatment should not potentially increase the risk of infection, and a combination of anti-VEGF and infliximab in RA may be beneficial without augmenting potential adverse effects. Rothschild BM, Masi AT: Pathogenesis of rheumatoid arthritis: a vascular hypothesis. Semin Arthritis Rheum. Article PubMed CAS Google Scholar. Rooney M, Condell D, Quinlan W, Daly L, Whelan A, Feighery C, Bresnihan B: Analysis of the histologic variation of synovitis in rheumatoid arthritis. Arthritis Rheum. 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Among the pro-angiogenic factors we tested, NGAL was significantly elevated in TCZ-treated patients, as well as in responding patients relative to non-responders Figures 1 , 2. NGAL is known to form heterodimers with MMP-9, thus protecting the latter from degradation. In addition, NGAL has been shown to regulate VEGF expression and to promote angiogenesis Previous reports demonstrated higher levels of NGAL in the serum of RA patients compared to healthy controls, suggesting that it promotes angiogenesis In this regard, the observation of elevated levels of NGAL in RA patients after TCZ administration is contrary to the general anti-angiogenic effects mediated by TCZ. However, notably, NGAL plays many other pleiotropic roles unrelated to its role in angiogenesis, such as in protecting against bacterial infection by acting as an iron-carrying protein, in modulating oxidative stress, in promoting neutrophil chemotaxis, and in regulating thermogenesis and lipid metabolism by acting as an adipokine 10 , Moreover, although NGAL normally protects MMP-9 from degradation, we did not observe any elevation in MMP-9 serum levels in RA patients. This finding further supports the notion that the primary role played by NGAL in RA is unrelated to angiogenesis, and that its elevation after initiation of TCZ treatment may be related to its role as an adipokine. This possibility must be carefully explored in a follow-up study. From the nine miRNAs that we examined, we observed that only miRa-5p and miRp were elevated after 4 months of treatment Figure 3. Previous studies have implicated these two miRNAs in the inflammation that is driving RA. The long non-coding RNA LINC which exhibits low levels in RA patients, normally acts as a sponge that binds miRp, thereby leading to enhanced thrombospondin-2 levels and reduced inflammation Outside the context of RA, TCZ was shown to increase the serum levels of miRa-5p in COVID patients, and its levels could predict response to the drug However, we are unaware of any other previously published studies examining the effects of TCZ on the expression of the particular miRNAs we chose to examine in our study, and only one study demonstrated an increase in the level of a different miRNA - miRa - by TCZ in neutrophils isolated from RA patients in vitro Since we have already previously shown that miRa-5p participates in the regulation of EMMPRIN expression in tumor cells 26 , 27 , we suspected that this miRNA was also involved in EMMPRIN regulation in fibroblasts, and therefore focused on this miRNA in our in vitro experiments. We demonstrate that transfection of the fibroblast cell line HT with the miRa-5p mimic resulting in overexpression of miRa-5p in the HT cells, reduced the secretion of EMMPRIN, and subsequently of VEGF and MMP-9, implicating this miRNA in the regulation of EMMPRIN in fibroblasts Figures 7B—D. In contrast, inhibiting miRa-5p activity by transfecting the HT cells with its antagomir increased EMMPRIN secretion Figure 7A , whether the cells were stimulated with TNFα or with IL Thus, miRa-5p is involved in the regulation of EMMPRIN expression in the fibroblast cell line, directly or indirectly by affecting other regulators of EMMPRIN. We note that TCZ decreased miRa-5p levels and increased EMMPRIN levels in fibroblasts in vitro Figures 7E, G , 8C, D , 9N, O , whereas it increased miRa-5p levels and decreased EMMPRIN levels in the serum samples from treated RA patients Figures 1 , 3. These inconsistencies may be explained by the difference between the in vitro and in vivo systems or by differing effects exerted by TCZ on different cell types. Indeed we could observe that the effects of TCZ on miRa-5p were specific to the HT fibroblasts, and TCZ had no significant effect on the miRa-5p levels in the monocytic U cells or in the monocyte-enriched PBMCs Figures 7G , 8D , 9N, O. Alternatively, the serum may reflect the state in the synovium, where interactions between fibroblasts and many other cell types may generate a balance different from that observed in the in vitro co-culture system involving only two cell-lines. However, despite these inconsistencies, both the in vivo and the in vitro systems reflect a strong link between miRa-5p, EMMPRIN and the angiogenic process, and demonstrate the ability of TCZ to intervene in this process. The induction of miRa-5p is mostly attributed to stimulators activating the NF-κB pathway, such as TNFα and IL-6 46 , 47 , and accordingly its levels have been shown to increase in RA patients Therefore, the presence of TNFα or IL-6 in our in vitro system can explain the upregulation of miRa-5p compared to non-stimulated cells Figure 7F , and the inhibitory effect of TCZ on the expression of miRa-5p Figures 7G , 8D , 9N, O might suggest a disruption of this pathway. Further investigation is required to map the exact nature of this interference. In summary, we establish an important role for EMMPRIN in mediating pro-angiogenic signals in RA patients and demonstrate a strong link between miRa-5p expression and the regulation of EMMPRIN secretion. Importantly, we show that TCZ reduces the angiogenic potential in RA patients, and we suggest that this is partially due to the ability of TCZ to interfere with the expression of miRa-5p, leading to changes in EMMPRIN levels. We also suggest that the ratio between EMMPRIN and Tsp-1 may reflect the angiogenic status in RA patients more accurately than any one factor alone. Further inquiries can be directed to the corresponding authors. The studies involving human participants were reviewed and approved by Institutional Review Board at Carmel Medical Center CMC MS, ES, AK, and LZ performed the experiments. JF, TG, AH, ME, IR, LK, and DZ recruited the patients. JF secured the funding. TG, JF, AH, ME, IR, and LK reviewed and edited the paper. MR and DZ designed the work, analyzed and interpreted the data, and drafted the paper. All authors contributed to the article and approved the submitted version. This research was partially supported by a young physician scholarship from the Israeli Rheumatology Association. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. Supplementary Figure S1 TCZ treatment does not change U6 expression in RA patients. The change in the expression of U6 was lower relative to the change in miR, and therefore, it was chosen for the normalization of the rest of the studied miRNAs. Supplementary Figure S2 TCZ increases serum levels of IL-6 and decreases those of hsCRP. Box plot representing the concentrations of A IL-6 and B hsCRP in the serum of RA patients before and after 4 months of TCZ treatment in comparison to healthy volunteers controls. Supplementary Figure S3 TNFα induces IL-6 in HT cells and decreases IL-6R in U cells. 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Angiogenesis and rheumatoid arthritis -
IL—mediated tube formation is reduced by inhibition of PI3K. HMVECs were incubated with inhibitors to PI3K LY; 1 and 5 μM , ERK PD; 1 and 5 μM , JNK SP; 1 and 5 μM , or DMSO for 45 min at 37°C prior adding to polymerized Matrigel.
Next, we asked whether the IL identified in human RA synovial fluid is chemotactic for HMVECs. In these experiments, we demonstrated that human RA synovial fluid is chemotactic for HMVECs, similar to positive control VEGF Fig.
Neutralization of ILRA and RC on HMVECs showed that only ILRC was effective in suppressing human RA synovial fluid-mediated HMVEC migration Fig. These results suggest that IL and its receptor ILRC may play an important role in angiogenesis in RA.
Furthermore, we demonstrate that immunodepletion of IL and VEGF in RA synovial fluids does not have an additive or synergistic effect in reduction of HMVEC migration beyond the effect noted with neutralization of one factor alone Fig. RA synovial fluid-induced HMVEC chemotaxis is mediated by IL through ligation to ILRC, and IL does not synergize with VEGF in RA synovial fluid-induced HMVEC migration.
The values represent the mean ± SE. In this study, we show that IL increases vascularity in experimental arthritis and induces blood vessel development in Matrigel plugs in vivo. Therefore, studies were performed to determine whether IL might directly mediate angiogenesis and whether IL contributes to neovascularization in RA.
Our data demonstrate that IL induces HMVEC chemotaxis at concentrations present in human RA synovial fluid. We further demonstrate that IL—induced HMVEC chemotaxis and tube formation are mediated primarily through ligation to ILRC on HMVECs and activation of PI3K.
We show that human RA synovial fluid-mediated HMVEC chemotaxis is markedly reduced by neutralization of IL in the synovial fluids or blocking of ILRC on HMVECs.
Last, we demonstrate that IL and VEGF-immunodepleted RA synovial fluid does not reduce HMVEC chemotaxis any further than neutralization of each factor by itself. In this paper, we confirm the results of others demonstrating that the local expression of IL in mouse ankle joints induces arthritis 9.
Histological analysis of mice receiving intra-articular injections of IL demonstrated that IL plays an important role in joint neutrophil migration We demonstrate that IL—induced arthritis is associated with increased vascularity.
Others have shown that IL can promote tumor growth by upregulating proangiogenic factors such as VEGF and matrix metalloproteinase-9 from tumor cells, suggesting that IL is indirectly associated with angiogenesis Pickens and S. Shahrara, unpublished data. On the basis of our results from the IL—induced arthritis model, we hypothesized that IL may be important for angiogenesis in RA.
Because there is some evidence demonstrating that IL alone is unable to induce angiogenesis but can indirectly promote HMVEC chemotaxis by producing proangiogenic factors 29 , 30 from RA synovial tissue fibroblasts, we investigated the role of IL on HMVEC migration and tube formation.
Our results demonstrate that IL induces HMVEC chemotaxis at concentrations available in the human RA joint, which is mostly due to its ligation to ILRC.
Although ILRC plays a major role in IL—mediated HMVEC chemotaxis and tube formation, neutralization of both receptors is more effective in this process compared with ILRC alone. Like monocytes, HMVECs express both ILRA and ILRC However, in contrast to HMVEC chemotaxis, IL—mediated monocyte migration is induced through both ILRA and RC Interestingly, a novel IL receptor-like protein has been identified in HUVECs that interacts with FGF1 and inhibits activation of the ERK pathway and production of FGF, indicating that various IL receptors may modulate angiogenesis differently Next, experiments were performed to investigate signaling pathways that were associated with IL—induced HMVEC chemotaxis and tube formation.
Inhibition of the IL—activated pathways in HMVECs demonstrated that only activation of PI3K significantly reduces IL—mediated chemotaxis and tube formation, and suppression of ERK and JNK pathways was ineffective in this process.
Furthermore, others have shown that PI3K signaling plays an important role in regulation of VEGF production as well as VEGF-mediated endothelial migration 46 , 47 , suggesting that PI3K is involved in the mediation of angiogenesis by various proinflammatory factors.
In contrast to IL, which promotes angiogenesis, ILF inhibits HUVEC tube formation, indicating that different IL isoforms may modulate angiogenesis differently A recent publication demonstrated that tumor growth in s.
Conversely, others have shown that IL markedly increases neovascularization in rat cornea 28 and vascularization in tumors 49 , indicating that IL may promote angiogenesis. Therefore, we investigated the contribution of IL to human RA synovial fluid-mediated HMVEC chemotaxis.
Neutralization of IL in RA synovial fluid partially reduced RA synovial fluid-mediated HMVEC chemotaxis. RA synovial fluid-mediated HMVEC chemotaxis was mediated through ILRC, confirming the importance of this receptor in IL—mediated angiogenesis.
IL is the only lymphokine that contributes to human RA synovial fluid-mediated angiogenesis, suggesting that T cells may also be important in this process. The data presented in this study, together with our previously reported evidence demonstrating that IL is important for monocyte migration 21 in RA synovial fluids, highlight the importance of IL in RA pathogenesis.
Interestingly, our results show that neutralization of IL and VEGF do not synergize in reducing RA synovial fluid-induced HMVEC migration beyond the effect detected with one factor alone.
As shown with IL, VEGF-induced HMVEC chemotaxis is mediated through PI3K 46 , Therefore, the lack of synergy between IL and VEGF in inducing HMVEC chemotaxis may be due to that both mediators are using the same signaling pathway or that as shown previously HMVEC cell migration is within a bell shaped curve 37 , 52 ; therefore, the synergistic effect could not be detected.
In conclusion, endothelial migration and tube formation induced by IL were mediated through activation of the PI3K pathway and ligation to both IL receptors. However, neutralization of only IL or ILRC significantly downregulated human RA synovial fluid-mediated endothelial migration, suggesting that IL plays an important role in RA angiogenesis.
This work was supported in part by grants from the National Institutes of Health AR, AR, AR, and NS , the Arthritis National Research Foundation, and Within Our Reach from The American College of Rheumatology.
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Skip Nav Destination Close navigation menu Article navigation. Volume , Issue 6. Materials and Methods. Study protocol for local expression of IL in mouse ankle joints. Abs and immunohistochemistry. Matrigel plug assay in vivo. HMVEC chemotaxis. Quantification of ILRA and RC expression on HMVECs.
Characterization of IL signaling pathways in HMVECs. HMVEC tube formation assay. Statistical analysis. Local expression of IL in mouse ankles induces joint inflammation and vascularity. IL induces angiogenesis in vivo in Matrigel plugs. IL induces endothelial HMVEC migration.
IL receptors are involved in IL—induced HMVEC chemotaxis and HMVEC tube formation. IL activates ERK, JNK, and PI3K pathways in HMVECs; however only inhibition of PI3K reduces ILinduced HMVEC chemotaxis and tube formation.
IL and its receptor are involved in RA synovial fluid-mediated HMVEC chemotaxis. Article Navigation. Research Article March 15 IL Contributes to Angiogenesis in Rheumatoid Arthritis Sarah R. Pickens ; Sarah R.
This Site. Google Scholar. Michael V. Volin ; Michael V. Arthur M. Mandelin, II ; Arthur M. Mandelin, II. Jay K. Kolls ; Jay K. Richard M. Pope ; Richard M. Shiva Shahrara Shiva Shahrara. Address correspondence and reprint requests to Dr. Shiva Shahrara, Division of Rheumatology, Department of Medicine, Northwestern University Feinberg School of Medicine, McGaw Pavilion, East Huron Street, Suite M, Chicago, IL E-mail address: s-shahrara northwestern.
Received: October 06 Accepted: January 13 Published: March 15 Online ISSN: Copyright © by The American Association of Immunologists, Inc. J Immunol 6 : — Article history Received:. toolbar search Search Dropdown Menu.
toolbar search search input Search input auto suggest. FIGURE 1. Regulation of NFkappaB signalling during inflammation: the role of hydroxylases.
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Department of Medicine, Imperial College London, London, UK. Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.
Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK. You can also search for this author in PubMed Google Scholar.
Correspondence to Ewa M. Department of Medical Biotechnology, Jagiellonian University, Kraków, Poland, Kraków, Poland. Department of Medical Biotechnology, Jagiellonian University, Krakow, Poland, Krakow, Poland.
Department of Medical Biotechnology, Jagiellonian University, Kraków, Poland. Reprints and permissions. Konisti, S. Angiogenesis in Rheumatoid Arthritis. In: Dulak, J. eds Angiogenesis and Vascularisation. Springer, Vienna.
Published : 07 December Publisher Name : Springer, Vienna. Print ISBN : Online ISBN : eBook Packages : Biomedical and Life Sciences Biomedical and Life Sciences R0.
Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative. Policies and ethics. Skip to main content. Abstract Rheumatoid arthritis RA is a chronic inflammatory disease, associated with inflammation of the synovial tissue lining joints and tendons, which leads to degradation of underlying cartilage and bone.
Keywords Hypoxia Inflammation VEGF TNFα Anti-angiogenic therapy. Buying options Chapter EUR eBook EUR Softcover Book EUR Hardcover Book EUR Tax calculation will be finalised at checkout Purchases are for personal use only Learn about institutional subscriptions.
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Background: Rheumaroid is Angiogenesis and rheumatoid arthritis rheumattoid contributor to anc development of inflammation during Rheumatoid arthritis RAas the vascularization rheumatiid the rehumatoid provides Angiovenesis and Angiogenesis and rheumatoid arthritis aryhritis the infiltrating immune arrhritis and proliferating synoviocytes. Botanical wonders for the skin TCZ is an anti-IL-6 receptor antibody that is used in the treatment of RA Angiogenessi, and has Green tea metabolism Angiogenesis and rheumatoid arthritis to exert anti-inflammatory effects. Regulated weight loss supplements, arhtritis effects on angiogenesis are not fully elucidated, and the molecular mechanisms regulating this effect are unknown. Methods: We evaluated the concentrations of several pro- and anti-angiogenic factors and the expression levels of several microRNA molecules that are associated with RA and angiogenesis in serum samples obtained from 40 RA patients, before and 4 months after the initiation of TCZ treatment. Additionally, we used an in vitro co-culture system of fibroblasts the HT cell line and monocytes the U cell line to explore the mechanisms of TCZ action. In vitrothe accumulation in the supernatants of the pro-angiogenic factors EMMPRIN, VEGF and MMP-9 was increased by co-culturing the HT fibroblasts and the U monocytes, while the accumulation of the anti-angiogenic factor thrombospondin-1 Tsp-1 and the expression levels of miRa-5p were reduced.Video
Rheumatoid Arthritis Pathophysiology (signs and symptoms)
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