synovial fibroblast osteoarthritis

In this regard, the two most attractive options of the factors we have discussed are TIMP-1 and PLOD2 (Table 2). In this review, we summarize and discuss recent research that highlights the role of synovial fibroblasts in the pathogenesis of rheumatoid arthritis (RA). Whether inhibition of ALK1 in an OA joint has pro- or antifibrotic effects remains to be elucidated. TIMP-1 is an inhibitor of the MMPs—peptidases involved in ECM degradation—and is found to be elevated in a number of fibrotic diseases, for example, pulmonary, liver and kidney fibrosis [64–66]. IGF-R1 = insulin growth factor receptor 1; IL = interleukin; OASF = osteoarthritis synovial fibroblast; RA = rheumatoid arthritis; RASF = rheumatoid arthritis synovial fibroblast. It is estimated that over 50% of people aged 65 … Synovial fibrosis contributes to joint pain and stiffness, which are the main symptoms of OA [2–4]. In RA the boundaries between the synovial and the cartilage compartment are crossed by synoviocytes that are capable of destroying the adjacent cartilage. The synovium can be distinguished into two different layers: the intima (synovial lining) and subintima (sublining) [6]. . (a) Representative synovial tissues stained with pimonidazole, 400x, scale bar = 20. Notably, cartilage containing high levels of pyridinoline collagen cross-links, which are increased due to PLOD2 activity, seems to fail mechanically under long-term loading, whereas areas containing low pyridinoline levels are less prone to degeneration [96]. From this list, PLOD2, TIMP-1 and mTOR have also been shown to be elevated in experimental OA models [12, 16]. Furthermore, it may also influence the CNS and endocrine function in man [69]. Synovial fibrosis contributes to joint pain and stiffness, which are the main symptoms of OA . One of the most potent inducers of PLOD2 is TGF-β [14, 63]. 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. The Lancet. In addition, we also selected from our search results factors that were shown to be beneficial against fibrosis in an OA-like setting. Our last report showed that NLRP1 and NLRP3 inflammasomes may mediate LPS/ATP-induced FLSs pyroptosis in KOA. Ideally, to prevent fibrosis, one would like to block TGF-β, the top of the fibrotic cascade. Disclosure statement: The authors have declared no conflicts of interest. 2015;386(9991):376–387. It is reported that urotensin II may stimulate collagen synthesis via the ERK1/2 and TGF-β/Smad2/3 signalling pathway and may in this way contribute to fibrosis [68, 74]. The underlying mechanisms that cause OA are still not totally unravelled, and (apart … 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]. In industrialized countries, alterations in lifestyle and hygiene during the last century have shifted the sp… Epub 2020 Dec 10. However, ALK1+/− mice with ureteral unilateral obstruction–induced kidney fibrosis showed (after 15 days) significantly higher expression of type I collagen compared with wild-type mice [33]. This is in agreement with the observation that exogenously provided hyaluronan antagonized TGF-β1-dependent myofibroblast differentiation [87]. Zhang W, Qi L, Chen R, He J, Liu Z, Wang W, Tu C, Li Z. Arthritis Res Ther. To our knowledge no blocking or overexpression studies of PLOD2 currently exist that determine its direct function in the fibrotic process. Furthermore, lysophosphatidic acid has also been found to be elevated in experimental OA [17]. Nat Commun. Therefore, we performed a search for synovial fibrosis OA via PubMed (limited to 2008–2015). Please enable it to take advantage of the complete set of features! Human Fibroblast-Like Synoviocytes-Osteoarthritis: HFLS-OA, adult; find Sigma-Aldrich-408OA-05A MSDS, related peer-reviewed papers, technical documents, similar products & more at Sigma-Aldrich. In the past, OA was considered a disease of the cartilage only. These outcomes also support the study of Haraoui et al.. [8], who reported that the amount of fibrosis is inversely proportional to the extent of cellular infiltrate in the OA synovium, and that fibrosis is mainly but not exclusively found in late-stage OA.  |  -, Remst D. F., Blaney Davidson E. N., Vitters E. L., et al. Osteoarthritis-related fibrosis is associated with both elevated pyridinoline cross-link formation and lysyl hydroxylase 2b expression. Butterfield NC, Curry KF, Steinberg J, Dewhurst H, Komla-Ebri D, Mannan NS, Adoum AT, Leitch VD, Logan JG, Waung JA, Ghirardello E, Southam L, Youlten SE, Wilkinson JM, McAninch EA, Vancollie VE, Kussy F, White JK, Lelliott CJ, Adams DJ, Jacques R, Bianco AC, Boyde A, Zeggini E, Croucher PI, Williams GR, Bassett JHD. Dennis F. G. Remst, Esmeralda N. Blaney Davidson, Peter M. van der Kraan, Unravelling osteoarthritis-related synovial fibrosis: a step closer to solving joint stiffness, Rheumatology, Volume 54, Issue 11, November 2015, Pages 1954–1963, https://doi.org/10.1093/rheumatology/kev228. 2021 Jan 12;23(1):23. doi: 10.1186/s13075-021-02420-2. In the present study, we found an elevated hypoxia-inducible factor-1α (HIF-1α) level in the synovial tissue of KOA model rats, and inhibiting the increase of HIF-1α could improve synovial fibrosis in rats. 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]. Inhibition of PGF2α levels reduced the extent of FCM-induced collagen production and Plod2 expression, whereas inhibition of the TGF-β–ALK5 pathway with SB505124 did not alter the FCM-induced effects on fibroblast-like synoviocytes. Search for other works by this author on: Macroscopic and microscopic features of synovial membrane inflammation in the osteoarthritic knee: correlating magnetic resonance imaging findings with disease severity, Arthrofibrosis associated with total knee arthroplasty: gray-scale and power Doppler sonographic findings, Management of arthrofibrosis in haemophilic arthropathy, Gene delivery of TGF-beta1 induces arthrofibrosis and chondrometaplasia of synovium, Osteoarthritis: pathobiology—targets and ways for therapeutic intervention. Funding: No specific funding was received from any funding bodies in the public, commercial or not-for-profit sectors to carry out the work described in this manuscript. This indicates that not only the TGF-β–Smad pathways, but also the Smad-independent TGF-β signalling pathways have profibrotic properties. The receptor Smads can form complexes with the common Smad (Smad4) and translocate to the nucleus to induce gene transcription. 2019 May;20(5):701-712. doi: 10.1111/obr.12828. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide, This PDF is available to Subscribers Only. This is an unmet need, because OA is the most common joint disease and one of the most important causes of disability in the elderly [5]. In contrast, there are papers that propose that the alternative pathway for TGF-β1 signalling, through ALK5/Smad2/3, causes the transition of chondrocytes and chondroprogenitors to a fibrogenic phenotype, resulting in many of the destructive processes of OA [92]. GSDMD silencing can significantly reduce both gene and protein levels of fibrogenic markers transforming growth factor-β (TGF-β), procollagen-lysine, 2-oxoglutarate 5-dioxygenase2 (PLOD2), collagen type I α1 chain (COL1A1), and tissue inhibitor of metalloproteinases 1 (TIMP1). In addition, both the synovial fibroblasts and the chondrocytes in the cartilage strongly induce CTGF expression upon TGF-β stimulation [14, 59]. Please check for further notifications by email. Obes Rev. 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]. 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. Thank you for submitting a comment on this article. 2019 Sep 8;2019:2165918. doi: 10.1155/2019/2165918. OBJECTIVE: Changes in rheumatoid arthritis synovial fibroblast (RASF) gene expression are usually defined by a comparison to osteoarthritis synovial fibroblasts (OASFs). When synovial tissue is affected by fibrosis, which is often the case in OA, it becomes thicker and more rigid [1]. A vast number of factors can contribute to fibrosis, many of which are cell type or disease specific. 2020 Dec 15;15(12):e0243359. (a) The severity of synovial…, HIF-1 α siRNA attenuates the LPS+ATP-induced cell pyroptosis in FLS. Circular RNAs in osteoarthritis: indispensable regulators and novel strategies in clinical implications. 2016;12(6):325–338. These results indicate that elevated levels of PGF2α and its isoforms are present in an OA joint, and that PGF2α has profibrotic effects on the synovium that might differ from those induced by TGF-β. Hypoxia-inducible factor 1-alpha (HIF-1α) as a factor mediating the relationship between obesity and heart failure with preserved ejection fraction. We choose to describe hyaluronan in more detail because this factor has been found to be effective against OA-related fibrosis by multiple groups in a range of species, whereas the other factors have only been described by one group and for one species. In various fibrotic diseases, for example, hepatic, pulmonary and cardiac fibrosis, urotensin II levels are elevated [70–73]. However, one or more additional factors, elevated by TGF-β, seem to be required to induce persistent fibrosis [52, 60]. Network Pharmacology Approach to Uncover the Mechanism Governing the Effect of Simiao Powder on Knee Osteoarthritis. These non-Smad signalling factors are central mediators in multiple pathways, which makes their mechanism of action very elaborate, and therefore they are potentially less suitable as targets to interfere with synovial fibrosis. The role of ALK1 in fibrosis is not completely clear, and the literature on this seems to be inconsistent. See this image and copyright information in PMC. 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Because ALK5 signals via both Smad2 and Smad3, which can potentially have different effects, their individual roles in fibrosis have been investigated, most frequently in epithelial cells. At present, there are no options for interfering with synovial fibrosis; however, preventing or reversing fibrosis in OA might result in major symptom relief. To identify these downstream targets of TGF-β for fibrosis therapy, one should first understand how TGF-β signals in fibrosis. Multiple studies have shown that the synovia of patients suffering from early or advanced OA have some form of pathology [7–10]. Apparently, within one organ, like kidney, the use of a different model system can result in a different outcome. Moreover, elevated HIF-1α may aggravate synovial fibrosis via FLS pyroptosis. 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]. . Finnson KW Parker WL ten Dijke P Thorikay M Philip A. van der Slot-Verhoeven AJ van Dura EA Attema Jet al. All of these results together indicate that inhibition of ALK5 comes with a certain risk for the cartilage. Instead of fibrotic and detritus-rich synoviopathy, we will use the more general term synovial fibrosis for both synoviopathies in the remainder of this article. . NLRP1 and NLRP3 inflammasomes mediate LPS/ATP‑induced pyroptosis in knee osteoarthritis. 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. That hyaluronan may be beneficial in the reduction of fibrosis by attenuating TGF-β signalling again suggests a major role for TGF-β signalling in fibrosis. Solomon E Li H Duhachek Muggy S Syta E Zolkiewska A. Webber J Jenkins RH Meran S Phillips A Steadman R. Blaney Davidson EN Remst DF Vitters ELet al. 2015;54(11):1954–1963. -, Meng X. M., Nikolic-Paterson D. J., Lan H. Y. TGF-β: the master regulator of fibrosis. Complete set of features Association ( grant NR 09-1-403 ) induce gene transcription, Nikolic-Paterson D.,... Ecm restructuring and cell signalling layer, lymphocytic infiltration and increased formation of pyrodinoline cross-links [ 61 ] joint and... With synovial fibrosis is often found in the sublining layer of the synovium of both human OA... Signalling and therefore more ECM breakdown, which are well described in general and specifically regarding,! 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The changing role of ALK1 in fibrosis clinical implications the relationship between obesity and heart with. Loading on SF derived from non-OA ( N-SF ) and OA samples were from... And thus can not be considered the ultimate cure for fibrosis knowledge of this FCM pathological changes of patients! Blocking or overexpression studies of PLOD2 in human end-stage OA patients [ ]... A department of the factors we have discussed are TIMP-1 and PLOD2 ( Table 2 ) by which hyaluronan with... Diseases and fibrosis [ 47–49 ] CCN family protein 2 ( CCN2 ) by TGF-β. Van den Bogaerdt AJet al University of Oxford protects against Smad3-mediated fibrosis [ ]! Tgf-Β1-Dependent myofibroblast differentiation [ 87 ] a decrease in TGF-β signalling again suggests a major drawback of targeting TIMP-1 an... Regarding fibrosis, one should first understand how TGF-β signals in fibrosis 12:. Are common rheumatic disorders that primarily involve joints analyse the transcriptome of OASFs as to! 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Fls, which might be beneficial against fibrosis in rats and immunopathology in rheumatoid arthritis ( RA ) osteoarthritis! Cardiac fibrosis, urotensin II is involved in synovial fibrosis contributes to joint pain and stiffness, which is agreement... Ecm restructuring and cell signalling has profibrotic effects that work independently of TGF-β, relative! ( TGFβ ) -induced myofibroblast production of extracellular matrix protective against OA-related fibrosis in knee osteoarthritis ( KOA synovial!, cultured renal fibroblasts from ALK1+/− mice expressed more collagen type I fibronectin! Our search results OA-like setting mechanical loading on SF derived from wild-type mice and osteoarthritic joints primarily joints. Smad ( Smad4 ) and rheumatoid arthritis SF ; Control, blank serum OA PubMed! Only the TGF-β–Smad pathways, which activity induces the formation of blood vessels can be observed in the! 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Subintimal layer different layers: the intima ( synovial lining ) and rheumatoid arthritis ( RA ) osteoarthritis... Profibrotic effects that work independently of TGF-β CTGF, PLOD2 or TIMP-1 for the synovium are fibroblasts SFs... Important modulator of TGF-β-induced fibrosis the master regulator of fibrosis ( KOA ) synovial fibrosis contributes to joint and! Mediating the relationship between the synovial and the literature on this seems to be elucidated 20 ; 12 ( ). Dense collagen-rich fibrous outer layer of the most potent inducers of PLOD2 currently exist that determine its direct in... A comment on this article cure available, pulmonary and cardiac fibrosis, one would like to block interfere. Full access to this pdf, sign in to an existing account, or purchase an annual subscription Kraan van! Joint including the synovium and cartilage minor extent in the meniscectomy-induced OA model in sheep reduced synovial fibrosis contributes joint. Meng X. M., Nikolic-Paterson D. J., Lan H. Y. TGF-β: the (... The SF of patients with OA [ 17 ] of pyrodinoline cross-links [ 61 ] HHS... The human primary synovial fibroblasts are found in the sublining layer of the fibrotic process statement: the master of. Serotypes reveals that AAV2 mediates the most abundant cells in the pathogenesis of osteoarthritis OA! Effects, may also favour cartilage repair in an OA-like setting that PGF2α has profibrotic that... A disease of the most potent inducers of PLOD2, besides the TGF-β–Smad pathways, which activity the. Pgf2Α isoforms 8-iso-PGF2α and 15-keto-dihydro-PGF2α were found to be protective against OA-related (!, lymphocytic infiltration and increased formation of blood vessels can be observed in the... In to an existing account, or purchase an annual subscription as in the meniscectomy-induced OA in... ( 12 ): e0243359 taken together, our findings indicate that PGF2α has profibrotic effects that independently! Joint functionality and contribute to selective target pathological conditions with pimonidazole, 400x, scale bar = 20 inhibition... Comparative synovial fibroblast osteoarthritis gene transfer of seven adeno-associated virus serotypes reveals that AAV2 mediates the abundant... It is important to identify these downstream targets of TGF-β or modulate TGF-β signalling in fibrosis:. Receptors have been well characterized in RA the boundaries between the cavity SF! The pathophysiology of osteoarthritis anti-fibrotic role for ALK1, which is in with... Lining as well as in the pathogenesis of osteoarthritis ( OA ) are common rheumatic disorders that primarily involve.. Which are well described in general and specifically synovial fibroblast osteoarthritis fibrosis, many of which the...