Fibroblast-like synoviocytes (FLS) represent a specialised cell type located inside joints in the synovium.These cells play a crucial role in the pathogenesis of chronic inflammatory diseases, such as rheumatoid arthritis.. Fibroblast-like synoviocytes in normal tissues. ADAM12 is primarily involved in cell adhesion and fusion, ECM restructuring and cell signalling. Conclusions: PI3K/Akt pathway was associated with TNF-α-induced activation of OA FLS, which may involve in the pathogenesis of osteoarthritis. For all the selected factors, additional and background information was acquired via PubMed. Kerna et al.. [11] reported an enhanced level of inflammation, lining layer thickness, number of CD4+ T cells and macrophage infiltration in patients with very early OA compared with late-stage OA. In this review we discuss factors that have been reported to be involved in synovial fibrosis. 2017;13(3):155–163. In this sense, blockade of mediators produced by neighbouring joint cells, such as synovial … Not only are levels of miR203 raised in longstanding RA compared to osteoarthritis and normal synovial fibroblasts, but expression in the earliest phases of RA when disease is not fully differentiated occurs at an intermediate level, suggesting that the epigenetic control of synovial fibroblast behaviour remains plastic in the earliest phases of disease [69]. . . RA and OA samples were collected from the discarded tissue of patients following knee joint replacement surgery. METHODS: The authors used microarray messenger RNA expression profiling of synovial fibroblasts … As OA progresses, the synovium undergoes hyperplasia, sublining fibrosis, increased vascularization, and increased cell proliferation, migration and invasion (3). eCollection 2020. Synovial fibrosis contributes to joint pain and stiffness, which are the main symptoms of OA [2–4]. However, in unilateral urethral obstruction–induced fibrosis, there was no difference in the degree of interstitial fibrosis detected between wild-type and TIMP-1–deficient mice [67]. To validate CTGF as a potential antifibrotic target, it is important to determine whether CTGF is necessary for the persistence of TGF-β-induced synovial fibrosis, especially since a CTGF blocking antibody (FG-3019) is available. Obes Rev. (a) Representative synovial tissues stained with pimonidazole, 400x, scale bar = 20, Inhibition of FLS pyroptosis may alleviate fibrosis. Therefore it is better not inhibited in an OA joint unless it is specifically blocked in the synovium to prevent fibrosis, which is unfortunately not yet possible. A vast number of factors can contribute to fibrosis, many of which are cell type or disease specific. Huang Z, Shi X, Li X, Zhang L, Wu P, Mao J, Xing R, Zhang N, Wang P. Biomed Res Int. The most abundant cells in the synovium are fibroblasts (SF). Urotensin II is a potent vasoconstrictor that is involved in cardiac remodelling, and it may influence cardiovascular homeostasis and pathology [68, 69]. TIMP-1 is induced by TGF-β and is typically proposed as an enhancer of fibrosis development, but does not induce fibrosis itself [65, 66]. osteoarthritis-associated genes in synovial fibroblasts in culture Aditi Gupta†, Corinne Niger†, Atum M Buo, Eric R Eidelman, Richard J Chen and Joseph P Stains* Abstract Background: Recent work has shown that the gap junction protein connexin43 (Cx43) is upregulated in cells of the joint during osteoarthritis (OA). Most likely the role of TIMP-1 may vary between the various types of fibrosis, and its role in synovial fibrosis has yet to be discovered. Frazier K Williams S Kothapalli D Klapper H Grotendorst GR. Zhang L, Xing R, Huang Z, Zhang N, Zhang L, Li X, Wang P. Mediators Inflamm. Synovial inflammation is probably involved in the genesis of pain, as inflammatory mediators, such as prostaglandin E 2, bradykinin, 5-hydroxy- tryptamine and histamine, are released within the joint and increase the sensitivity of periph-eral pain receptors [10]. Bank RA Verzijl N Lafeber FP Tekoppele JM. Epub 2019 Mar 1. Clipboard, Search History, and several other advanced features are temporarily unavailable. Zhao LR, Xing RL, Wang PM, Zhang NS, Yin SJ, Li XC, Zhang L. Mol Med Rep. 2018 Apr;17(4):5463-5469. doi: 10.3892/mmr.2018.8520. Because it is estimated that over half of all OA patients suffer from synovial fibrosis, it is important that this pathological process receives more attention, especially as fibrosis is one of the main causes of joint stiffness [2–4, 101]. To identify these downstream targets of TGF-β for fibrosis therapy, one should first understand how TGF-β signals in fibrosis. Oga et al.. [85] have shown that both PGF2α and TGF-β increased the promoter activity of COL1A2, and simultaneous addition of both factors synergistically increased the COL1A2 promoter activity. Elevated serum levels of ADAM12-S are associated with elevated serum inflammatory markers, severity of skin fibrosis and increased activity of interstitial lung disease in dcSSc, suggesting a profibrotic role for ADAM12 [76]. -, Meng X. M., Nikolic-Paterson D. J., Lan H. Y. TGF-β: the master regulator of fibrosis. Ideally, to prevent fibrosis, one would like to block TGF-β, the top of the fibrotic cascade. Connective tissue growth factor (CTGF) was added to the list, because this is a well-known fibrotic factor that has also been shown to induce synovial fibrosis. The Smad-independent TAK-1 pathway has been shown to have profibrotic effects in regulating the expression of ECM proteins, including collagens and fibronectin [41]. Obese osteoarthritis patients exhibit an inflammatory synovial fibroblast phenotype, which is regulated by the long non coding RNA MALAT1 November 2019 Arthritis and Rheumatology 72(4) Since rheumatoid arthritis synovial fibroblasts (RASFs) mediate most relevant pathways of joint destruction, molecular insights into these cells constitute an important target for novel therapeutic approaches that inhibit the destruction of cartilage and bone in RA. . . Most interestingly, both ADAM12-S and ADAM12-L were upregulated in the synovial tissue of patients with OA and positively correlated with the grade of synovial fibrosis, suggesting a role for ADAM12 in OA-related synovial fibrosis [11, 77]. Furthermore, this IL-6 inflammatory response, mediated by chondrocyte-synovial fibroblast cross-talk, was enhanced by the obesity-related adipokine leptin. . Would you like email updates of new search results? Chemokines and their corresponding receptors have been well characterized in RA progression, but less so in OA pathogenesis. This may be worth investigating, because besides the potential antifibrotic effects, inhibition of ALK1 is expected to reduce MMP13 expression in chondrocytes and therefore MMP-mediated cartilage damage—a potential win–win situation [90, 91]. as rheumatoid arthritis (RA) or osteoarthritis (OA). . Finnson KW Parker WL ten Dijke P Thorikay M Philip A. van der Slot-Verhoeven AJ van Dura EA Attema Jet al. Multiple studies have shown that the synovia of patients suffering from early or advanced OA have some form of pathology [7–10]. Furthermore, in a TGF-β-driven murine model of dermal fibrosis, inhibition of TGF-β-dependent ERK phosphorylation showed strong and dose-dependent antifibrotic effects on skin thickening [42]. Relationship between the pyroptosis of fibroblast‑like synoviocytes and HMGB1 secretion in knee osteoarthritis. However, elevated plasma concentrations of PGF2α metabolites found in idiopathic pulmonary fibrosis are significantly associated with both disease severity and prognosis [84]. In addition, both the synovial fibroblasts and the chondrocytes in the cartilage strongly induce CTGF expression upon TGF-β stimulation [14, 59]. From this list, PLOD2, TIMP-1 and mTOR have also been shown to be elevated in experimental OA models [12, 16]. Pros and cons of inhibiting CTGF, PLOD2 or TIMP-1 for the synovium and cartilage. The intima forms an interface between the cavity containing SF and the subintimal layer. Because we focused on the synovium, mTOR and lysophosphatidic acid were not described in greater detail, as these factors were only found to be elevated in chondrocytes/cartilage and not in synovial fibroblasts or the synovium. Because TGF-β is a potent inducer of CTGF, we cannot rule out the possibility that it is essential for the induction of persistent synovial fibrosis. These observations indicate a profibrotic role for ALK1. The PGF2α isoforms 8-iso-PGF2α and 15-keto-dihydro-PGF2α were found to be significantly increased in the SF of patients with OA [86]. Remst DF Blaney Davidson EN Vitters ELet al. We observed in OA-induced fibrosis that both PLOD2 expression and the number of pyridinoline cross-links per collagen triple helix in the synovium were elevated [27]. This elevation suggests that PLOD2 may be crucial in OA-related synovial fibrosis. Oehler et al.. [9] divided osteoarthritic synoviopathy into four different subtypes based on the nature of the synovium: hyperplastic, inflammatory, fibrotic or detritus-rich. Please enable it to take advantage of the complete set of features! National Center for Biotechnology Information, Unable to load your collection due to an error, Unable to load your delegates due to an error, The synovial tissue of KOA rats was in a state of aggravated hypoxia. 2019 Apr 15;223:69-73. doi: 10.1016/j.lfs.2019.02.060. Understanding how synovial fibrosis contributes to OA pathology and symptoms might provide avenues for future OA therapies. We found that TIMP-1 is elevated in the synovium of both human end-stage OA patients and mice with experimental OA [12]. Objective: To compare selected immunohistological features of inflammation in synovial tissue from patients with early and late osteoarthritis (OA). Therefore, inhibition of TIMP-1 in an OA joint is not the preferred option for interfering with OA-related synovial fibrosis. Imbalanced MMP-3 and MMP-12 serum levels in systemic lupus erythematosus patients with Jaccoud’s arthropathy and a distinctive MRI pattern, Anti-NuMA antibodies: clinical associations and significance in patients with primary Sjögren’s syndrome or systemic lupus erythematosus, Ten-year analysis of the risk of severe outcomes related to low-dose glucocorticoids in early Rheumatoid Arthritis, The number of risk factors for persistent disease determines the clinical course of early arthritis, Management of fatigue with physical activity and behavioural change support in vasculitis: a feasibility study, About the British Society for Rheumatology,, A disintegrin and metalloproteinase domain 12, Receive exclusive offers and updates from Oxford Academic, A COMPARISON OF BENORYLATE AND NAPROXEN IN DEGENERATIVE ARTHRITIS, CHANGES IN STIFFNESS FOLLOWING SHORT- AND LONG-TERM APPLICATION OF STANDARD PHYSIOTHERAPEUTIC TECHNIQUES, 2-Methoxyestradiol inhibits hypoxia-induced scleroderma fibroblast collagen synthesis by phosphatidylinositol 3-kinase/Akt/mTOR signalling, Less collagen synthesis might attenuate the inflammatory cascade [, May prevent CTGF-mediated joint/cartilage destruction in OA [, CTGF/CCN2 may play a role as an anti-ageing factor by stabilizing articular cartilage [, Less pyridinoline cross-links in the collagens triple-helixes.