Fibroblast-like Synoviocytes – Actors in Osteoimmunology

Abstract

Rheumatoid arthritis (RA) is an immune mediated inflammatory disease (IMID), characterized by chronic inflammation and irreversible bone loss. Studies have shown that fibroblast-like synoviocytes (FLS), a key cell population in the pathogenesis of RA, have an impact on balancing bone-forming osteoblasts and bone-destroying osteoclasts towards joint damage. Once activated, RA-FLS are able to destroy cartilage and subchondral bone through the release of RANKL, members of the metalloproteinase family and many more cytokines, chemokines and growth factors. Additionally, RA-FLS are responsible for the perpetuation and chronicity of the disease due the interaction with immune cells supporting the influx of T and B lymphocytes, monocytes, macrophages neutrophils and dendritic cells from the blood stream into the inflamed synovial tissue. In this review we highlight the direct and indirect impact of synovial fibroblasts in RA on joint damage and disease progression. Moreover, we describe mechanisms of synovitis and regulators of bone homeostasis in further inflammatory joint diseases such as ankylosing spondylitis (AS) and psoriatic arthritis (PsA) and compare them to RA.

Zusammenfassung

Die rheumatoide Arthritis (RA) ist eine immunvermittelte entzündliche Erkrankung (IMID), die durch chronische Entzündung und irreversiblen Knochenverlust gekennzeichnet ist. Studien haben gezeigt, dass Gelenkfibroblasten eine der Schlüsselrollen im Krankheitsverlauf der RA spielen, indem sie das Gleichgewicht zwischen knochenbildenden Osteoblasten und knochenzerstörenden Osteoklasten beeinflussen. Einmal aktiviert, sind die synovialen Fibroblasten in der Lage, Knorpel und Knochen durch die Freisetzung von RANKL, Mitgliedern der Metalloproteinase-Familie und vielen anderen Zytokinen, Chemokinen und Wachstumsfaktoren zu zerstören. Zudem sind Gelenkfibroblasten für die Perpetuierung und Chronifizierung der Erkrankung verantwortlich, indem sie mit Immunzellen interagieren, um den Einstrom von T- und B-Lymphozyten, Monozyten, Makrophagen, Neutrophilen und dendritischen Zellen aus der Blutbahn in das entzündete Synovialgewebe fördern. In dieser Übersichtsarbeit stellen wir den direkten und indirekten Einfluss der synovialen Fibroblasten bei RA auf die Gelenkschädigung und das Fortschreiten der Erkrankung dar. Darüber hinaus beschreiben wir Mechanismen der Synovitis und Regulatoren der Knochenhomöostase bei anderen entzündlichen Gelenkerkrankungen wie die ankylosierende Spondylitis (AS) und die Psoriasis-Arthritis (PsA) und vergleichen sie schließlich mit RA.

Key words

osteoimmunology - bone remodelling - fibroblast-like synoviocytes - RA

Schlüsselwörter

Osteoimmunologie - Knochenhomöostase - synoviale Fibroblasten - RA

^* shared first authors

Publication History

Received: 22 July 2021

Accepted: 04 October 2021

Article published online:
18 November 2021

• References

• 1 Purdue PE, Crotti TN, Shen Z. et al Comprehensive profiling analysis of actively resorbing osteoclasts identifies critical signaling pathways regulated by bone substrate. Sci Rep 2014; 4: 7595
• 2 Pederson L, Ruan M, Westendorf JJ. et al Regulation of bone formation by osteoclasts involves Wnt/BMP signaling and the chemokine sphingosine-1-phosphate. Proc Natl Acad Sci U S A 2008; 105: 20764-20769
• 3 Negishi-Koga T, Shinohara M, Komatsu N. et al Suppression of bone formation by osteoclastic expression of semaphorin 4D. Nat Med 2011; 17: 1473-1480
• 4 Beno T, Yoon YJ, Cowin SC. et al Estimation of bone permeability using accurate microstructural measurements. J Biomech 2006; 39: 2378-2387
• 5 Bonewald LF. The Amazing Osteocyte. J Bone Miner Res 2011; 26: 229-238
• 6 Nakashima T, Hayashi M, Fukunaga T. et al Evidence for osteocyte regulation of bone homeostasis through RANKL expression. Nat Med 2011; 17: 1231-1234
• 7 Joeng KS, Lee YC, Lim J. et al Osteocyte-specific WNT1 regulates osteoblast function during bone homeostasis. J Clin Invest 2017; 127: 2678-2688
• 8 Li J, Sarosi I, Cattley RC. et al Dkk1-mediated inhibition of Wnt signaling in bone results in osteopenia. Bone 2006; 39: 754-766
• 9 Winkler DG, Sutherland MK, Geoghegan JC. et al Osteocyte control of bone formation via sclerostin, a novel BMP antagonist. Embo J 2003; 22: 6267-6276
• 10 Pathak JL, Bravenboer N, Luyten FP. et al Mechanical loading reduces inflammation-induced human osteocyte-to-osteoclast communication. Calcif Tissue Int 2015; 97: 169-178
• 11 Danks L, Komatsu N, Guerrini MM. et al RANKL expressed on synovial fibroblasts is primarily responsible for bone erosions during joint inflammation. Ann Rheum Dis 2016; 75: 1187-1195
• 12 Neumann E, Lefèvre S, Zimmermann B. et al Rheumatoid arthritis progression mediated by activated synovial fibroblasts. Trends Mol Med 2010; 16: 458-468
• 13 Bottini N, Firestein GS. Duality of fibroblast-like synoviocytes in RA: Passive responders and imprinted aggressors. Nat Rev Rheumatol 2013; 9: 24-33
• 14 Kiener HP, Stipp CS, Allen PG. et al The cadherin-11 cytoplasmic juxtamembrane domain promotes α-catenin turnover at adherens junctions and intercellular motility. Mol Biol Cell 2006; 17: 2366-2376
• 15 Miller MC, Manning HB, Jain A. et al Membrane type 1 matrix metalloproteinase is a crucial promoter of synovial invasion in human rheumatoid arthritis. Arthritis Rheum 2009; 60: 686-697
• 16 Beckmann D, Römer-Hillmann A, Krause A. et al Lasp1 regulates adherens junction dynamics and fibroblast transformation in destructive arthritis. Nat Commun 2021; 12: 3624. doi:10.1038/s41467-021-23706-8
• 17 Ospelt C, Gay S, Klein K. Epigenetics in the pathogenesis of RA. Semin Immunopathol 2017; 39: 409-419
• 18 Firestein GS, Yeo M, Zvaifler NJ. Apoptosis in rheumatoid arthritis synovium. J Clin Invest 1995; 96: 1631-1638
• 19 Croft AP, Campos J, Jansen K. et al Distinct fibroblast subsets drive inflammation and damage in arthritis. Nature 2019; 570: 246-251
• 20 Mizoguchi F, Slowikowski K, Wei K. et al Functionally distinct disease-associated fibroblast subsets in rheumatoid arthritis. Nat Commun 2018; 9: 1-11
• 21 Stephenson W, Donlin LT, Butler A. et al Single-cell RNA-seq of rheumatoid arthritis synovial tissue using low-cost microfluidic instrumentation. Nat Commun 2017 91 2018; 9: 1-10
• 22 Wei K, Korsunsky I, Marshall JL. et al Notch signalling drives synovial fibroblast identity and arthritis pathology. Nature 2020; 582 7811 259-264
• 23 Zhang F, Wei K, Slowikowski K. et al Defining inflammatory cell states in rheumatoid arthritis joint synovial tissues by integrating single-cell transcriptomics and mass cytometry. Nat Immunol 2019; 20: 928-942
• 24 Harris TJC, Tepass U. Adherens junctions: From molecules to morphogenesis. Nat Rev Mol Cell Biol 2010; 11: 502-514
• 25 Kiener HP, Brenner MB. Building the synovuim: Cadherin-11 mediates fibroblast-like synoviocyte cell-to-cell adhesion. Arthritis Res Ther 2005; 7: 49-54
• 26 Valencia X, Higgins JMG, Kiener HP. et al Cadherin-11 provides specific cellular adhesion between fibroblast-like synoviocytes. J Exp Med 2004; 200: 1673-1679
• 27 Piedra J, Miravet S, Castaño J. et al p120 Catenin-Associated Fer and Fyn Tyrosine Kinases Regulate β-Catenin Tyr-142 Phosphorylation and β-Catenin-α-Catenin Interaction. Mol Cell Biol 2003; 23: 2287-2297
• 28 Bartok B, Firestein GS. Fibroblast-like synoviocytes: Key effector cells in rheumatoid arthritis. Immunol Rev 2010; 233: 233-255
• 29 Tonks NK. Protein tyrosine phosphatases: From genes, to function, to disease. Nat Rev Mol Cell Biol 2006; 7: 833-846
• 30 Svensson MND, Zoccheddu M, Yang S. et al Synoviocyte-targeted therapy synergizes with TNF inhibition in arthritis reversal. Sci Adv 2020; 6: eaba4353. doi: 10.1126/sciadv.aba4353
• 31 Mustelin T, Bottini N, Stanford SM. The Contribution of PTPN22 to Rheumatic Disease. Arthritis Rheumatol 2019; 71: 486-495
• 32 Naylor AJ, Filer A, Buckley CD. The role of stromal cells in the persistence of chronic inflammation. Clin Exp Immunol 2013; 171: 30-35
• 33 Wehmeyer C, Frank S, Beckmann D. et al Sclerostin inhibition promotes TNF-dependent inflammatory joint destruction. Sci Transl Med 2016; 8: 330ra35-330ra35
• 34 Weyand CM, Goronzy JJ, Takemura S, Kurtin PJ. Cell-cell interactions in synovitis Interactions between T cells and B cells in rheumatoid arthritis. Arthritis Res 2000; 2: 457-463
• 35 McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med 2011; 365: 2205-2219
• 36 Wang L, Ding Y, Guo X. et al Role and mechanism of vascular cell adhesion molecule-1 in the development of rheumatoid arthritis. Exp Ther Med 2015; 10: 1229-1233
• 37 Tikhonova AN, Dolgalev I, Hu H. et al The bone marrow microenvironment at single-cell resolution. Nature 2019; 569: 222-228
• 38 Takayanagi H, Ogasawara K, Hida S. et al T-cell-mediated regulation of osteoclastogenesis by signalling cross-talk between RANKL and IFN-γ. Nature 2000; 408: 600-605
• 39 Kollet O, Dar A, Shivtiel S. et al Osteoclasts degrade endosteal components and promote mobilization of hematopoietic progenitor cells. Nat Med Vol 2006; 12. doi: 10.1038/nm1417
• 40 Batsivari A, Haltalli MLR, Passaro D. et al Dynamic responses of the haematopoietic stem cell niche to diverse stresses. Nat Cell Biol 2020; 22: 7-17
• 41 Lefèvre S, Knedla A, Tennie C. et al Synovial fibroblasts spread rheumatoid arthritis to unaffected joints. Nat Med 2009; 15: 1414-1420
• 42 Hillen J, Geyer C, Heitzmann M. et al Structural cartilage damage attracts circulating rheumatoid arthritis synovial fibroblasts into affected joints. Arthritis Res Ther 2017; 19: 40
• 43 Baccin C, Al-Sabah J, Velten L. et al Combined single-cell and spatial transcriptomics reveal the molecular, cellular and spatial bone marrow niche organization. Nat Cell Biol 2020; 22: 38-48
• 44 Tuckermann J, Adams RH. The endothelium–bone axis in development, homeostasis and bone and joint disease. Nat Rev Rheumatol 2021; 17: 608-620
• 45 Koenen M, Culemann S, Vettorazzi S. et al Glucocorticoid receptor in stromal cells is essential for glucocorticoid-mediated suppression of inflammation in arthritis. Ann Rheum Dis. 2018; 77: 1610-1618
• 46 Jimenez-Boj E, Redlich K, Türk B. et al Interaction between Synovial Inflammatory Tissue and Bone Marrow in Rheumatoid Arthritis. J Immunol 2005; 175: 2579-2588
• 47 Park SJ, Kim KJ, Kim WU. et al Interaction of mesenchymal stem cells with fibroblast-like synoviocytes via cadherin-11 promotes angiogenesis by enhanced secretion of placental growth factor. J Immunol 2014; 1 192 3003-3010
• 48 Iaremenko O, Shynkaruk I, Fedkov D. et al Bone turnover biomarkers, disease activity, and MRI changes of sacroiliac joints in patients with spondyloarthritis. Rheumatol Int 2020; 40: 2057-2063
• 49 Ikeuchi H, Kuroiwa T, Hiramatsu N. et al Expression of interleukin-22 in rheumatoid arthritis: potential role as a proinflammatory cytokine. Arthritis Rheum. 2005; 52: 1037-1046
• 50 Resende GG, Machado CRL, Rocha MA. et al Il-22 increases the production of sfrp3 by fls in inflammatory joint diseases. Brazilian J Med Biol Res 2020; 53: 1-5
• 51 Fennen M, Weinhage T, Kracke V. et al A myostatin-CCL20–CCR6 axis regulates Th17 cell recruitment to inflamed joints in experimental arthritis. Sci Rep 2021; 11: 14145
• 52 Xu X, Davelaar N, Mus A-M. et al Interleukin-17A Is Produced by CD4+but Not CD8+T Cells in Synovial Fluid Following T Cell Receptor Activation and Regulates Different Inflammatory Mediators Compared to Tumor Necrosis Factor in a Model of Psoriatic Arthritis Synovitis. Arthritis Rheumatol 2020; 72: 1303-1313
• 53 Sepriano A, Miossec P, Robert M. IL-17 in Rheumatoid Arthritis and Precision Medicine: From Synovitis Expression to Circulating Bioactive Levels. Front Med | www.frontiersin.org 2019; 1: 364