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Allen, K. D., Thoma, L. M. & Golightly, Y. M. Epidemiology of osteoarthritis. Osteoarthr. Cartil.30, 184–195 (2022).
Loeser, R. F., Goldring, S. R., Scanzelllo, C. R. & Goldring, M. B. Osteoarthritis: a disease of the joint as an organ. Arthritis Rheum.64, 1697–1707 (2012).
Katz, J. N., Arant, K. R. & Loeser, R. F. Diagnosis and treatment of hip and knee osteoarthritis: a review. J. Am. Med. Assoc.325, 568–578 (2021).
Hunter, D. J. & Bierma-Zeinstra, S. Osteoarthritis. Lancet393, 1745–1759 (2019).
Safiri, S. et al. Global, regional and national burden of osteoarthritis 1990-2017: a systematic analysis of the Global Burden of Disease Study 2017. Ann. Rheum. Dis.79, 819–828 (2020).
Hunter, D. J. Pharmacologic therapy for osteoarthritis-the era of disease modification. Nat. Rev. Rheumatol.7, 13–22 (2011).
Kolasinski, S. L. et al. 2019 American College of Rheumatology/Arthritis Foundation guideline for the management of osteoarthritis of the hand, hip, and knee. Arthritis Rheumatol.72, 220–233 (2020).
Oo, W. M. & Hunter, D. J. Repurposed and investigational disease-modifying drugs in osteoarthritis (DMOADs). Ther. Adv. Musculoskelet. Dis.14, 1759720X221090297 (2022).
Lotz, M. & Loeser, R. F. Effects of aging on articular cartilage homeostasis. Bone51, 241–248 (2012).
Goldring, M. B. & Marcu, K. B. Cartilage homeostasis in health and rheumatic diseases. Arthritis Res. Ther.11, 224 (2009).
Lories, R. J. U. Joint homeostasis, restoration, and remodeling in osteoarthritis. Best Pract. Res. Clin. Rheumatol.22, 209–220 (2008).
Lotz, M. K. & Caramés, B. Autophagy and cartilage homeostasis mechanisms in joint health, aging and OA. Nat. Rev. Rheumatol.7, 579–587 (2011).
Goldring, M. B. The role of the chondrocyte in osteoarthritis. Arthritis Rheum.43, 1916–1926 (2000).
Saito, T. et al. Transcriptional regulation of endochondral ossification by HIF-2α during skeletal growth and osteoarthritis development. Nat. Med.16, 678–686 (2010).
Dreier, R. Hypertrophic differentiation of chondrocytes in osteoarthritis: the developmental aspect of degenerative joint disorders. Arthritis Res. Ther.12, 216 (2010).
Hosaka, Y. et al. Notch signaling in chondrocytes modulates endochondral ossification and osteoarthritis development. Proc. Natl Acad. Sci. USA110, 1875–1880 (2013).
Goldring, S. R. Role of bone in osteoarthritis pathogenesis. Med. Clin. North Am.93, 25–35 (2009).
Burr, D. B. & Gallant, M. A. Bone remodelling in osteoarthritis. Nat. Rev. Rheumatol.8, 665–673 (2012).
Goldring, S. R. & Goldring, M. B. Changes in the osteochondral unit during osteoarthritis: structure, function and cartilage bone crosstalk. Nat. Rev. Rheumatol.12, 632–644 (2016).
Ricard-Blum, S. & Salza, R. Matricryptins and matrikines: biologically active fragments of the extracellular matrix. Exp. Dermatol.23, 457–463 (2014).
Sanchez-Lopez, E., Coras, R., Torres, A., Lane, N. E. & Guma, M. Synovial inflammation in osteoarthritis progression. Nat. Rev. Rheumatol.18, 258–275 (2022).
Scanzello, C. R. & Goldring, S. R. The role of synovitis in osteoarthritis pathogenesis. Bone51, 249–257 (2012).
Guilak, F., Nims, R. J., Dicks, A., Wu, C. L. & Meulenbelt, I. Osteoarthritis as a disease of the cartilage pericellular matrix. Matrix Biol.71–72, 40–50 (2018).
Eyre, D. Articular cartilage and changes in arthritis: collagen of articular cartilage. Arthritis Res. Ther.4, 30–35 (2002).
Knudson, W., Ishizuka, S., Terabe, K., Askew, E. B. & Knudson, C. B. The pericellular hyaluronan of articular chondrocytes. Matrix Biol.78–79, 32–46 (2019).
Roughley, P. J. & Mort, J. S. The role of aggrecan in normal and osteoarthritic cartilage. J. Exp. Orthop.1, 8 (2014).
Kiani, C., Chen, L., Wu, Y. J., Yee, A. J. & Yang, B. B. Structure and function of aggrecan. Cell Res.12, 19–32 (2002).
Hodgkinson, T., Kelly, D. C., Curtin, C. M. & O’Brien, F. J. Mechanosignalling in cartilage: an emerging target for the treatment of osteoarthritis. Nat. Rev. Rheumatol.18, 67–84 (2022).
Alexopoulos, L. G., Haider, M. A., Vail, T. P. & Guilak, F. Alterations in the mechanical properties of the human chondrocyte pericellular matrix with osteoarthritis. J. Biomech. Eng.125, 323–333 (2003).
Peng, Z. et al. The regulation of cartilage extracellular matrix homeostasis in joint cartilage degeneration and regeneration. Biomaterials268, 120555 (2021).
Loeser, R. F. Integrins and chondrocyte–matrix interactions in articular cartilage. Matrix Biol.39, 11–16 (2014).
Bonnans, C., Chou, J. & Werb, Z. Remodelling the extracellular matrix in development and disease. Nat. Rev. Mol. Cell Biol.15, 786–801 (2014).
Larsen, M., Artym, V. V., Green, J. A. & Yamada, K. M. The matrix reorganized: extracellular matrix remodeling and integrin signaling. Curr. Opin. Cell Biol.18, 463–471 (2006).
Wu, W. et al. Sites of collagenase cleavage and denaturation of type II collagen in aging and osteoarthritic articular cartilage and their relationship to the distribution of matrix metalloproteinase 1 and matrix metalloproteinase 13. Arthritis Rheum.46, 2087–2094 (2002).
Loeser, R. F. Aging and osteoarthritis: the role of chondrocyte senescence and aging changes in the cartilage matrix. Osteoarthr. Cartil.17, 971–979 (2009).
Patel, D. F. et al. An extracellular matrix fragment drives epithelial remodeling and airway hyperresponsiveness. Sci. Transl. Med.10, eaaq0693 (2018).
Hahn, C. S. et al. The matrikine N-α-PGP couples extracellular matrix fragmentation to endothelial permeability. Sci. Adv.1, e1500175 (2015).
Jariwala, N. et al. Matrikines as mediators of tissue remodelling. Adv. Drug Deliv. Rev.185, 114240 (2022).
Gaggar, A. & Weathington, N. Bioactive extracellular matrix fragments in lung health and disease. J. Clin. Invest.126, 3176–3184 (2016).
Miao, M. Z. et al. Redox-active endosomes mediate α5β1 integrin signaling and promote chondrocyte matrix metalloproteinase production in osteoarthritis. Sci. Signal.16, eadf8299 (2023).
Loeser, R. F., Collins, J. A. & Diekman, B. O. Ageing and the pathogenesis of osteoarthritis. Nat. Rev. Rheumatol.12, 412–420 (2016).
Heinegård, D. & Saxne, T. The role of the cartilage matrix in osteoarthritis. Nat. Rev. Rheumatol.7, 50–56 (2011).
Pap, T. & Korb-Pap, A. Cartilage damage in osteoarthritis and rheumatoid arthritis — two unequal siblings. Nat. Rev. Rheumatol.11, 606–615 (2015).
Gerwin, N. et al. Angiopoietin-like 3-derivative LNA043 for cartilage regeneration in osteoarthritis: a randomized phase 1 trial. Nat. Med.28, 2633–2645 (2022).
Hynes, R. O. Integrins: bidirectional, allosteric signaling machines. Cell110, 673–687 (2002).
Anthis, N. J. & Campbell, I. D. The tail of integrin activation. Trends Biochem. Sci.36, 191–198 (2011).
Giancotti, F. G. & Ruoslahti, E. Integrin signaling. Science285, 1028–1033 (1999).
Takagi, J., Petre, B. M., Walz, T. & Springer, T. A. Global conformational rearrangements in integrin extracellular domains in outside-in and inside-out signaling. Cell110, 599–611 (2002).
Shimaoka, M., Takagi, J. & Springer, T. A. Conformational regulation of integrin structure and function. Annu. Rev. Biophys. Biomol. Struct.31, 485–516 (2002).
Xiao, T., Takagi, J., Coller, B. S., Wang, J. H. & Springer, T. A. Structural basis for allostery in integrins and binding to fibrinogen-mimetic therapeutics. Nature432, 59–67 (2004).
Campbell, I. D. & Humphries, M. J. Integrin structure, activation, and interactions. Cold Spring Harb. Perspect. Biol.3, a004994 (2011).
Li, J. et al. Conformational equilibria and intrinsic affinities define integrin activation. EMBO J.36, 629–645 (2017).
Xiong, J.-P. et al. Crystal structure of the extracellular segment of integrin αVβ3. Science294, 339–345 (2001).
Xiong, J.-P. et al. Crystal structure of the extracellular segment of integrin αVβ3 in complex with an Arg-Gly-Asp ligand. Science296, 151–155 (2002).
Sun, Z., Costell, M. & Fässler, R. Integrin activation by talin, kindlin and mechanical forces. Nat. Cell Biol.21, 25–31 (2019).
Shattil, S. J., Kim, C. & Ginsberg, M. H. The final steps of integrin activation: the end game. Nat. Rev. Mol. Cell Biol.11, 288–300 (2010).
Calderwood, D. A., Campbell, I. D. & Critchley, D. R. Talins and kindlins: partners in integrin-mediated adhesion. Nat. Rev. Mol. Cell Biol.14, 503–517 (2013).
Miyamoto, S., Teramoto, H., Gutkind, J. S. & Yamada, K. M. Integrins can collaborate with growth factors for phosphorylation of receptor tyrosine kinases and MAP kinase activation: roles of integrin aggregation and occupancy of receptors. J. Cell Biol.135, 1633–1642 (1996).
Yamada, K. M. & Even-Ram, S. Integrin regulation of growth factor receptors. Nat. Cell Biol.4, E75–E76 (2002).
Hynes, R. O. Integrins: versatility, modulation, and signaling in cell adhesion. Cell69, 11–25 (1992).
Geiger, B., Bershadsky, A., Pankov, R. & Yamada, K. M. Transmembrane extracellular matrix — cytoskeleton crosstalk. Nat. Rev. Mol. Cell Biol.2, 793–805 (2001).
Emsley, J., Knight, C. G., Farndale, R. W., Barnes, M. J. & Liddington, R. C. Structural basis of collagen recognition by integrin α2β1. Cell101, 47–56 (2000).
Xu, Y. et al. Multiple binding sites in collagen type I for the integrins α1β1 and α2β1. J. Biol. Chem.275, 38981–38989 (2000).
Akiyama, S. K., Yamada, S. S., Yamada, K. M. & LaFlamme, S. E. Transmembrane signal transduction by integrin cytoplasmic domains expressed in single-subunit chimeras. J. Biol. Chem.269, 15961–15964 (1994).
Schaller, M. D. et al. Autophosphorylation of the focal adhesion kinase, pp125FAK, directs SH2-dependent binding of pp60src. Mol. Cell. Biol.14, 1680–1688 (1994).
Hughes, P. E. & Pfaff, M. Integrin affinity modulation. Trends Cell Biol.8, 359–364 (1998).
Ginsberg, M. H., Du, X. & Plow, E. F. Inside-out integrin signalling. Curr. Opin. Cell Biol.4, 766–771 (1992).
Lee, J. O., Bankston, L. A., Robert, C. & Liddington, M. A. A. Two conformations of the integrin A-domain (I-domain): a pathway for activation? Structure3, 1333–1340 (1995).
Lee, J. O., Rieu, P., Arnaout, M. A. & Liddington, R. Crystal structure of the A domain from the a subunit of integrin CR3 (CD11 b/CD18). Cell80, 631–638 (1995).
Burridge, K. & Connell, L. A new protein of adhesion plaques and ruffling membranes. J. Cell Biol.97, 359–367 (1983).
Tadokoro, S. et al. Talin binding to integrin β tails: a final common step in integrin activation. Science302, 103–106 (2003).
Saltel, F. et al. New PI(4,5)P2- and membrane proximal integrin-binding motifs in the talin head control β3-integrin clustering. J. Cell Biol.187, 715–731 (2009).
Chinthalapudi, K., Rangarajan, E. S. & Izard, T. The interaction of talin with the cell membrane is essential for integrin activation and focal adhesion formation. Proc. Natl Acad. Sci. USA115, 10339–10344 (2018).
O’Toole, T. E. et al. Integrin cytoplasmic domains mediate inside-out signal transduction. J. Cell Biol.124, 1047–1059 (1994).
Anthis, N. J. et al. The structure of an integrin/talin complex reveals the basis of inside-out signal transduction. EMBO J.28, 3623–3632 (2009).
Wegener, K. L. et al. Structural basis of integrin activation by talin. Cell128, 171–182 (2007).
Kim, C., Ye, F., Hu, X. & Ginsberg, M. H. Talin activates integrins by altering the topology of the β transmembrane domain. J. Cell Biol.197, 605–611 (2012).
Kim, M., Carman, C. V. & Springer, T. A. Bidirectional transmembrane signaling by cytoplasmic domain separation in integrins. Science301, 1720–1725 (2003).
Aretz, J., Aziz, M., Strohmeyer, N., Sattler, M. & Fässler, R. Talin and kindlin use integrin tail allostery and direct binding to activate integrins. Nat. Struct. Mol. Biol.30, 1913–1924 (2023).
Winograd-Katz, S. E., Fässler, R., Geiger, B. & Legate, K. R. The integrin adhesome: from genes and proteins to human disease. Nat. Rev. Mol. Cell Biol.15, 273–288 (2014).
Kanchanawong, P. & Calderwood, D. A. Organization, dynamics and mechanoregulation of integrin-mediated cell–ECM adhesions. Nat. Rev. Mol. Cell Biol.24, 142–161 (2023).
Clark, E. A. & Brugge, J. S. Integrins and signal transduction pathways: the road taken. Science268, 233–239 (1995).
Zaidel-bar, R., Itzkovitz, S., Ma, A., Iyengar, R. & Geiger, B. Functional atlas of the integrin adhesome. Nat. Cell Biol.9, 858–867 (2007).
Horton, E. R. et al. Definition of a consensus integrin adhesome and its dynamics during adhesion complex assembly and disassembly. Nat. Cell Biol.17, 1577–1587 (2015).
Kanchanawong, P. et al. Nanoscale architecture of integrin-based cell adhesions. Nature468, 580–584 (2010).
Tan, S. J. et al. Regulation and dynamics of force transmission at individual cell-matrix adhesion bonds. Sci. Adv.6, eaax0317 (2020).
Liu, J. et al. Talin determines the nanoscale architecture of focal adhesions. Proc. Natl Acad. Sci. USA112, E4864–E4873 (2015).
Friedland, J. C., Lee, M. H. & Boettiger, D. Mechanically activated integrin switch controls α5β1 function. Science323, 642–644 (2009).
Liu, Y. J. et al. Differential transmission of actin motion within focal adhesions. Science315, 111–115 (2007).
Zhu, J. et al. Structure of a complete integrin ectodomain in a physiologic resting state and activation and deactivation by applied forces. Mol. Cell32, 849–861 (2008).
Kong, F. et al. Cyclic mechanical reinforcement of integrin-ligand interactions. Mol. Cell49, 1060–1068 (2013).
Geiger, B., Spatz, J. P. & Bershadsky, A. D. Environmental sensing through focal adhesions. Nat. Rev. Mol. Cell Biol.10, 21–33 (2009).
Miyamoto, S. et al. Integrin function: molecular hierarchies of cytoskeletal and signaling molecules. J. Cell Biol.131, 791–805 (1995).
Robertson, J. et al. Defining the phospho-adhesome through the phosphoproteomic analysis of integrin signalling. Nat. Commun.6, 6265 (2015).
Kong, F., García, A. J., Mould, A. P., Humphries, M. J. & Zhu, C. Demonstration of catch bonds between an integrin and its ligand. J. Cell Biol.185, 1275–1284 (2009).
Elosegui-Artola, A. et al. Mechanical regulation of a molecular clutch defines force transmission and transduction in response to matrix rigidity. Nat. Cell Biol.18, 540–548 (2016).
Jiang, G., Giannone, G., Critchley, D. R., Fukumoto, E. & Sheet, M. P. Two-piconewton slip bond between fibronectin and the cytoskeleton depends on talin. Nature424, 334–337 (2003).
Elosegui-Artola, A. et al. Force triggers YAP nuclear entry by regulating transport across nuclear pores. Cell171, 1397–1410.e14 (2017).
Ling, K., Doughman, R. L., Firestone, A. J., Bunce, M. W. & Anderson, R. A. Type Iγ phosphatidylinositol phosphate kinase targets and regulates focal adhesions. Nature420, 89–93 (2002).
Martel, V. et al. Conformation, localization, and integrin binding of talin depend on its interaction with phosphoinositides. J. Biol. Chem.276, 21217–21227 (2001).
Wills, R. C. & Hammond, G. R. V. PI(4,5)P2: signaling the plasma membrane. Biochem. J.479, 2311–2325 (2022).
Wood, S. T. et al. Cysteine-mediated redox regulation of cell signaling in chondrocytes stimulated with fibronectin fragments. Arthritis Rheumatol.68, 117–126 (2016).
Khan, I. M. et al. The development of synovial joints. Curr. Top. Dev. Biol.79, 1–36 (2007).
Gao, Y. et al. The ECM-cell interaction of cartilage extracellular matrix on chondrocytes. Biomed. Res. Int.2014, 648459 (2014).
Docheva, D., Popov, C., Alberton, P. & Aszodi, A. Integrin signaling in skeletal development and function. Birth Defects Res. C. Embryo Today102, 13–36 (2014).
Ostergaard, K. et al. Expression of α and β subunits of the integrin superfamily in articular cartilage from macroscopically normal and osteoarthritic human femoral heads. Ann. Rheum. Dis.57, 303–308 (1998).
Loeser, R. F., Carlson, C. S. & McGee, M. P. Expression of β1 integrins by cultured articular chondrocytes and in osteoarthritic cartilage. Exp. Cell Res.217, 248–257 (1995).
Zemmyo, M., Meharra, E. J., Kühn, K., Creighton-Achermann, L. & Lotz, M. Accelerated, aging-dependent development of osteoarthritis in α1 integrin-deficient mice. Arthritis Rheum.48, 2873–2880 (2003).
Hughes, D. E., Salter, D. M., Dedhar, S. & Simpson, R. Integrin expression in human bone. J. Bone Miner. Res.8, 527–533 (1993).
Shekaran, A. & García, A. J. Extracellular matrix-mimetic adhesive biomaterials for bone repair. J. Biomed. Mater. Res. A96, 261–272 (2011).
Gronthos, S., Stewart, K., Graves, S. E., Hay, S. & Simmons, P. J. Integrin expression and function on human osteoblast-like cells. J. Bone Miner. Res.12, 1189–1197 (1997).
Duong, L. T., Lakkakorpi, P., Nakamura, I. & Rodan, G. A. Integrins and signaling in osteoclast function. Matrix Biol.19, 97–105 (2000).
Prasadam, I. et al. Impact of extracellular matrix derived from osteoarthritis subchondral bone osteoblasts on osteocytes: role of integrin β1 and focal adhesion kinase signaling cues. Arthritis Res. Ther.15, R150 (2013).
Robinson, W. H. et al. Low-grade inflammation as a key mediator of the pathogenesis of osteoarthritis. Nat. Rev. Rheumatol.12, 580–592 (2016).
Konttinen, Y. T. et al. Expression of laminins and their integrin receptors in different conditions of synovial membrane and synovial membrane-like interface tissue. Ann. Rheum. Dis.58, 683–690 (1999).
Korkusuz, P., Dagdeviren, A., Eksioglu, F. & Ors, U. Immunohistological analysis of normal and osteoarthritic human synovial tissue. Bull. Hosp. Jt Dis.63, 63–69 (2005).
Rinaldi, N. et al. Increased expression of integrins on fibroblast-like synoviocytes from rheumatoid arthritis in vitro correlates with enhanced binding to extracellular matrix proteins. Ann. Rheum. Dis.56, 45–51 (1997).
Shahrara, S., Castro-Rueda, H. P., Haines, G. K. & Koch, A. E. Differential expression of the FAK family kinases in rheumatoid arthritis and osteoarthritis synovial tissues. Arthritis Res. Ther.9, R112 (2007).
Schedel, J. et al. Differential adherence of osteoarthritis and rheumatoid arthritis synovial fibroblasts to cartilage and bone matrix proteins and its implication for osteoarthritis pathogenesis. Scand. J. Immunol.60, 514–523 (2004).
Daley, W. P. & Yamada, K. M. ECM-modulated cellular dynamics as a driving force for tissue morphogenesis. Curr. Opin. Genet. Dev.23, 408–414 (2013).
Cruz Walma, D. A. & Yamada, K. M. The extracellular matrix in development. Development147, dev175596 (2020).
Soul, J., Barter, M. J., Little, C. B. & Young, D. A. OATargets: a knowledge base of genes associated with osteoarthritis joint damage in animals. Ann. Rheum. Dis.80, 376–383 (2021).
Fang, H. & Beier, F. Mouse models of osteoarthritis: modelling risk factors and assessing outcomes. Nat. Rev. Rheumatol.10, 413–421 (2014).
Candela, M. E. et al. Alpha 5 integrin mediates osteoarthritic changes in mouse knee joints. PLoS ONE11, e0156783 (2016).
Bengtsson, T. et al. Loss of α10β1 integrin expression leads to moderate dysfunction of growth plate chondrocytes. J. Cell Sci.118, 929–936 (2005).
Aszodi, A., Hunziker, E. B., Brakebusch, C. & Fässler, R. β1 integrins regulate chondrocyte rotation, G1 progression, and cytokinesis. Genes Dev.17, 2465–2479 (2003).
Raducanu, A., Hunziker, E. B., Drosse, I. & Aszédi, A. β1 integrin deficiency results in multiple abnormalities of the knee joint. J. Biol. Chem.284, 23780–23792 (2009).
Grashoff, C., Aszódi, A., Sakai, T., Hunziker, E. B. & Fässler, R. Integrin-linked kinase regulates chondrocyte shape and proliferation. EMBO Rep.4, 432–438 (2003).
Terpstra, L. et al. Reduced chondrocyte proliferation and chondrodysplasia in mice lacking the integrin-linked kinase in chondrocytes. J. Cell Biol.162, 139–148 (2003).
Qu, M. et al. Pip5k1c loss in chondrocytes causes spontaneous osteoarthritic lesions in aged mice. Aging Dis.14, 502–514 (2023).
Wu, X. et al. Kindlin-2 preserves integrity of the articular cartilage to protect against osteoarthritis. Nat. Aging2, 332–347 (2022).
Lai, Y. et al. Kindlin-2 loss in condylar chondrocytes causes spontaneous osteoarthritic lesions in the temporomandibular joint in mice. Int. J. Oral. Sci.14, 33 (2022).
Wu, C. et al. Kindlin-2 controls TGF-β signalling and Sox9 expression to regulate chondrogenesis. Nat. Commun.6, 7531 (2015).
Swingler, T. E. et al. Degradome expression profiling in human articular cartilage. Arthritis Res. Ther.11, R96 (2009).
Rydén, M. et al. Identification and quantification of degradome components in human synovial fluid reveals an increased proteolytic activity in knee osteoarthritis patients vs controls. Proteomics23, e2300040 (2023).
Bhutada, S. et al. Forward and reverse degradomics defines the proteolytic landscape of human knee osteoarthritic cartilage and the role of the serine protease HtrA1. Osteoarthr. Cartil.30, 1091–1102 (2022).
Rapp, A. E. & Zaucke, F. Cartilage extracellular matrix-derived matrikines in osteoarthritis. Am. J. Physiol. Cell Physiol.324, C377–C394 (2023).
Ricard-Blum, S. & Vallet, S. D. Fragments generated upon extracellular matrix remodeling: biological regulators and potential drugs. Matrix Biol.75–76, 170–189 (2019).
Tuckwell, D. S., Ayad, S., Grant, M. E., Takigawa, M. & Humphries, M. J. Conformation dependence of integrin-type II collagen binding Inability of collagen peptides to support α2β1 binding, and mediation of adhesion to denatured collagen by a novel α5β1-fibronectin bridge. J. Cell Sci.107, 993–1005 (1994).
Guilak, F. et al. The pericellular matrix as a transducer of biomechanical and biochemical signals in articular cartilage. Ann. N. Y. Acad. Sci.1068, 498–512 (2006).
Wilusz, R. E., Sanchez-Adams, J. & Guilak, F. The structure and function of the pericellular matrix of articular cartilage. Matrix Biol.39, 25–32 (2014).
Sparding, N. et al. Endotrophin, a collagen type VI-derived matrikine, reflects the degree of renal fibrosis in patients with IgA nephropathy and in patients with ANCA-associated vasculitis. Nephrol. Dial. Transplant.37, 1099–1108 (2022).
Park, J. & Scherer, P. E. Adipocyte-derived endotrophin promotes malignant tumor progression. J. Clin. Invest.122, 4243–4256 (2012).
Pankov, R. & Yamada, K. M. Fibronectin at a glance. J. Cell Sci.115, 3861–3863 (2002).
Xie, D., Meyers, R. & Homandberg, G. A. Fibronectin fragments in osteoarthritic synovial fluid. J. Rheumatol.19, 1448–1452 (1992).
Homandberg, G. A., Wen, C. & Hui, F. Cartilage damaging activities of fibronectin fragments derived from cartilage and synovial fluid. Osteoarthr. Cartil.6, 231–244 (1998).
Barilla, M. L. & Carsons, S. E. Fibronectin fragments and their role in inflammatory arthritis. Semin. Arthritis Rheum.29, 252–265 (2000).
Zack, M. D. et al. Identification of fibronectin neoepitopes present in human osteoarthritic cartilage. Arthritis Rheum.54, 2912–2922 (2006).
Zhang, X., Chen, C. T., Bhargava, M. & Torzilli, P. A. A comparative study of fibronectin cleavage by MMP-1, -3, -13, and -14. Cartilage3, 267–277 (2012).
Zack, M. D. et al. ADAM-8 isolated from human osteoarthritic chondrocytes cleaves fibronectin at Ala271. Arthritis Rheum.60, 2704–2713 (2009).
Sofat, N. Analysing the role of endogenous matrix molecules in the development of osteoarthritis. Int. J. Exp. Pathol.90, 463–479 (2009).
Pérez-García, S. et al. Profile of matrix-remodeling proteinases in osteoarthritis: impact of fibronectin. Cells9, 40 (2020).
Homandberg, G. A., Costa, V. & Wen, C. Fibronectin fragments active in chondrocytic chondrolysis can be chemically cross-linked to the alpha5 integrin receptor subunit. Osteoarthr. Cartil.10, 938–949 (2002).
Midwood, K. S., Chiquet, M., Tucker, R. P. & Orend, G. Tenascin-C at a glance. J. Cell Sci.129, 4321–4327 (2016).
Tucker, R. P. & Chiquet-Ehrismann, R. Tenascin-C: its functions as an integrin ligand. Int. J. Biochem. Cell Biol.65, 165–168 (2015).
Chiquet-Ehrismann, R. & Tucker, R. P. Tenascins and the importance of adhesion modulation. Cold Spring Harb. Perspect. Biol.3, a004960 (2011).
Patel, L. et al. Tenascin-C induces inflammatory mediators and matrix degradation in osteoarthritic cartilage. BMC Musculoskelet. Disord.12, 164 (2011).
Sofat, N. et al. Tenascin-C fragments are endogenous inducers of cartilage matrix degradation. Rheumatol. Int.32, 2809–2817 (2012).
Hasegawa, M., Yoshida, T. & Sudo, A. Tenascin-C in osteoarthritis and rheumatoid arthritis. Front. Immunol.11, 577015 (2020).
Hasegawa M et al. Tenascin-C concentration in synovial fluid correlates with radiographic progression of knee osteoarthritis. J. Rheumatol.31, 2021–2026 (2004).
Iozzo, R. V. & Schaefer, L. Proteoglycan form and function: a comprehensive nomenclature of proteoglycans. Matrix Biol.42, 11–55 (2015).
Barreto, G. et al. Soluble biglycan: a potential mediator of cartilage degradation in osteoarthritis. Arthritis Res. Ther.17, 379 (2015).
Monfort, J. et al. Degradation of small leucine-rich repeat proteoglycans by matrix metalloprotease-13: identification of a new biglycan cleavage site. Arthritis Res. Ther.8, R26 (2006).
Zhen, E. Y. et al. Characterization of metalloprotease cleavage products of human articular cartilage. Arthritis Rheum.58, 2420–2431 (2008).
Haglund, L. et al. Identification and characterization of the integrin α2β1 binding motif in chondroadherin mediating cell attachment. J. Biol. Chem.286, 3925–3934 (2011).
Camper, L., Heinegård, D. & Lundgren-Åkerlund, E. Integrin α2β1 is a receptor for the cartilage matrix protein chondroadherin. J. Cell Biol.138, 1159–1167 (1997).
Akhatib, B. et al. Chondroadherin fragmentation mediated by the protease HTRA1 distinguishes human intervertebral disc degeneration from normal aging. J. Biol. Chem.288, 19280–19287 (2013).
Sengupta, S. et al. Differentiated glioma cell-derived fibromodulin activates integrin-dependent Notch signaling in endothelial cells to promote tumor angiogenesis and growth. eLife11, e78972 (2022).
Acharya, C. et al. Cartilage oligomeric matrix protein and its binding partners in the cartilage extracellular matrix: interaction, regulation and role in chondrogenesis. Matrix Biol.37, 102–111 (2014).
Lohmander, L. S., Saxne, T. & Heinegard, D. K. Release of cartilage oligomeric matrix protein (COMP) into joint fluid after knee injury and in osteoarthritis. Ann. Rheum. Dis.53, 8–13 (1994).
Åhrman, E. et al. Novel cartilage oligomeric matrix protein (COMP) neoepitopes identified in synovial fluids from patients with joint diseases using affinity chromatography and mass spectrometry. J. Biol. Chem.289, 20908–20916 (2014).
Neidhart, M. et al. Small fragments of cartilage oligomeric matrix protein in synovial fluid and serum as markers for cartilage degradation. Br. J. Rheumatol.36, 1151–1160 (1997).
Di Cesare, P. E. et al. Increased degradation and altered tissue distribution of cartilage oligomeric matrix protein in human rheumatoid and osteoarthritic cartilage. J. Orthop. Res.14, 946–955 (1996).
Chen, F. H., Thomas, A. O., Hecht, J. T., Goldring, M. B. & Lawler, J. Cartilage oligomeric matrix protein/thrombospondin 5 supports chondrocyte attachment through interaction with integrins. J. Biol. Chem.280, 32655–32661 (2005).
Kvansakul, M., Adams, J. C. & Hohenester, E. Structure of a thrombospondin C-terminal fragment reveals a novel calcium core in the type 3 repeats. EMBO J.23, 1223–1233 (2004).
Ciregia, F. et al. Modulation of αVβ6 integrin in osteoarthritis-related synovitis and the interaction with VTN(381–397 a.a.) competing for TGF-β1 activation. Exp. Mol. Med.53, 210–222 (2021).
Carsons, S. E. & Wolf, J. Interaction between synoviocytes and extracellular matrix in vitro. Ann. Rheum. Dis.54, 413–416 (1995).
Forsyth, C. B., Pulai, J. & Loeser, R. F. Fibronectin fragments and blocking antibodies to α2β1 and α5β1 integrins stimulate mitogen-activated protein kinase signaling and increase collagenase 3 (matrix metalloproteinase 13) production by human articular chondrocytes. Arthritis Rheum.46, 2368–2376 (2002).
Del Carlo, M., Schwartz, D., Erickson, E. A. & Loeser, R. F. Endogenous production of reactive oxygen species is required for stimulation of human articular chondrocyte matrix metalloproteinase production by fibronectin fragments. Free. Radic. Biol. Med.42, 1350–1358 (2007).
Pulai, J. I. et al. NF-κB mediates the stimulation of cytokine and chemokine expression by human articular chondrocytes in response to fibronectin fragments. J. Immunol.174, 5781–5788 (2005).
Long, D. L., Willey, J. S. & Loeser, R. F. Rac1 is required for matrix metalloproteinase 13 production by chondrocytes in response to fibronectin fragments. Arthritis Rheum.65, 1561–1568 (2013).
Loeser, R. F., Forsyth, C. B., Samarel, A. M. & Im, H. J. Fibronectin fragment activation of proline-rich tyrosine kinase PYK2 mediates integrin signals regulating collagenase-3 expression by human chondrocytes through a protein kinase C-dependent pathway. J. Biol. Chem.278, 24577–24585 (2003).
Obara, M., Kang, M. S. & Yamada, K. M. Site-directed mutagenesis of the cell-binding domain of human fibronectin: separable, synergistic sites mediate adhesive function. Cell53, 649–657 (1988).
Aota, S. I., Nomizu, M. & Yamada, K. M. The short amino acid sequence Pro-His-Ser-Arg-Asn in human fibronectin enhances cell-adhesive function. J. Biol. Chem.269, 24756–24761 (1994).
Schumacher, S. et al. Structural insights into integrin α5β1 opening by fibronectin ligand. Sci. Adv.7, eabe9716 (2021).
Reed, K. S. M. et al. Transcriptional response of human articular chondrocytes treated with fibronectin fragments: an in vitro model of the osteoarthritis phenotype. Osteoarthr. Cartil.29, 235–247 (2021).
Thulson, E. et al. 3D chromatin structure in chondrocytes identifies putative osteoarthritis risk genes. Genetics222, iyac141 (2022).
Sorkin, A. & Von Zastrow, M. Signal transduction and endocytosis: close encounters of many kinds. Nat. Rev. Mol. Cell Biol.3, 600–614 (2002).
Sorkin, A. & Von Zastrow, M. Endocytosis and signalling: intertwining molecular networks. Nat. Rev. Mol. Cell Biol.10, 609–622 (2009).
Willette, B. K. A., Zhang, J. F., Zhang, J. & Tsvetanova, N. G. Endosome positioning coordinates spatially selective GPCR signaling. Nat. Chem. Biol.20, 151–161 (2023).
Chen, Y. G. Endocytic regulation of TGF-β signaling. Cell Res.19, 58–70 (2009).
Alanko, J. et al. Integrin endosomal signalling suppresses anoikis. Nat. Cell Biol.17, 1412–1421 (2015).
Nader, G. P. F., Ezratty, E. J. & Gundersen, G. G. FAK, talin and PIPKIγ regulate endocytosed integrin activation to polarize focal adhesion assembly. Nat. Cell Biol.18, 491–503 (2016).
Kechagia, J. Z., Ivaska, J. & Roca-Cusachs, P. Integrins as biomechanical sensors of the microenvironment. Nat. Rev. Mol. Cell Biol.20, 457–473 (2019).
Caswell, P. T., Vadrevu, S. & Norman, J. C. Integrins: masters and slaves of endocytic transport. Nat. Rev. Mol. Cell Biol.10, 843–853 (2009).
Sies, H. et al. Defining roles of specific reactive oxygen species (ROS) in cell biology and physiology. Nat. Rev. Mol. Cell Biol.23, 499–515 (2022).
Sies, H. Hydrogen peroxide as a central redox signaling molecule in physiological oxidative stress: oxidative eustress. Redox Biol.11, 613–619 (2017).
Sies, H. & Jones, D. P. Reactive oxygen species (ROS) as pleiotropic physiological signalling agents. Nat. Rev. Mol. Cell Biol.21, 363–383 (2020).
Oakley, F. D., Abbott, D., Li, Q. & Engelhardt, J. F. Signaling components of redox active endosomes: the redoxosomes. Antioxid. Redox Signal.11, 1313–1333 (2009).
Withofs, N. et al. 18F-FPRGD2 PET/CT imaging of musculoskeletal disorders. Ann. Nucl. Med.29, 839–847 (2015).
Charlier, E. et al. Toward diagnostic relevance of the αVβ5, αVβ3, and αVβ6 integrins in OA: expression within human cartilage and spinal osteophytes. Bone Res.8, 35 (2020).
Hua, Q., Knudson, C. B. & Knudson, W. Internalization of hyaluronan by chondrocytes occurs via receptor-mediated endocytosis. J. Cell Sci.106, 365–375 (1993).
Embry, J. J. & Knudson, W. G1 domain of aggrecan cointernalizes with hyaluronan via a CD44-mediated mechanism in bovine articular chondrocytes. Arthritis Rheum.48, 3431–3441 (2003).
Silverstein, A. M. et al. Toward understanding the role of cartilage particulates in synovial inflammation. Osteoarthr. Cartil.25, 1353–1361 (2017).
Zhen, G. et al. Mechanical stress determines the configuration of TGFβ activation in articular cartilage. Nat. Commun.12, 1–16 (2021).
Wang, Q. et al. Dysregulated integrin aVβ3 and CD47 signaling promotes joint inflammation, cartilage breakdown, and progression of osteoarthritis. JCI Insight4, 1706 (2019).
Li, K. et al. Tyrosine kinase Fyn promotes osteoarthritis by activating the β-catenin pathway. Ann. Rheum. Dis.77, 935–943 (2018).
Sumsuzzman, D. M., Khan, Z. A., Choi, J. & Hong, Y. Assessment of functional roles and therapeutic potential of integrin receptors in osteoarthritis: a systematic review and meta-analysis of preclinical studies. Ageing Res. Rev.81, 101729 (2022).
Maylin, A. B. et al. Genetic abrogation of the fibronectin-α5β1 integrin interaction in articular cartilage aggravates osteoarthritis in mice. PLoS ONE13, e0198559 (2018).
Song, F. et al. Integrin αVβ3 signaling in the progression of osteoarthritis induced by excessive mechanical stress. Inflammation46, 739–751 (2023).
Lian, C. et al. Collagen type II suppresses articular chondrocyte hypertrophy and osteoarthritis progression by promoting integrin β1−SMAD1 interaction. Bone Res7, 8 (2019).
St Amant, J. et al. Depleting transforming growth factor beta receptor 2 signalling in the cartilage of itga1-null mice attenuates spontaneous knee osteoarthritis. Osteoarthr. Cartil. Open.5, 100399 (2023).
Shin, S. Y., Pozzi, A., Boyd, S. K. & Clark, A. L. Integrin α1β1 protects against signs of post-traumatic osteoarthritis in the female murine knee partially via regulation of epidermal growth factor receptor signalling. Osteoarthr. Cartil.24, 1795–1806 (2016).
Cui, Z. et al. Endothelial PDGF-BB/PDGFR-β signaling promotes osteoarthritis by enhancing angiogenesis-dependent abnormal subchondral bone formation. Bone Res10, 58 (2022).
Li, T. et al. TGF-β type 2 receptor-mediated modulation of the IL-36 family can be therapeutically targeted in osteoarthritis. Sci. Transl. Med.11, eaan2585 (2019).
Tetsunaga, T. et al. Mechanical stretch stimulates integrin αVβ3-mediated collagen expression in human anterior cruciate ligament cells. J. Biomech.42, 2097–2103 (2009).
Mousavizadeh, R. et al. β1 integrin, ILK and mTOR regulate collagen synthesis in mechanically loaded tendon cells. Sci. Rep.10, 12644 (2020).
Wang, D. et al. Tendon-derived extracellular matrix induces mesenchymal stem cell tenogenesis via an integrin/transforming growth factor-β crosstalk-mediated mechanism. FASEB J.34, 8172–8186 (2020).
Moffat, K. L. et al. Characterization of the structure-function relationship at the ligament-to-bone interface. Proc. Natl Acad. Sci. USA105, 7947–7952 (2008).
Fleming, B. C., Hulstyn, M. J., Oksendahl, H. L. & Fadale, P. D. Ligament injury, reconstruction and osteoarthritis. Curr. Opin. Orthop.16, 354–362 (2005).
Dai, B. et al. Blockage of osteopontin-integrin β3 signaling in infrapatellar fat pad attenuates osteoarthritis in mice. Adv. Sci.10, e2300897 (2023).
Song, E. K. et al. ITGBL1 modulates integrin activity to promote cartilage formation and protect against arthritis. Sci. Transl. Med.10, eaam7486 (2018).
Delco, M. L. et al. Integrin α10β1-selected mesenchymal stem cells mitigate the progression of osteoarthritis in an equine talar impact model. Am. J. Sports Med.48, 612–623 (2020).
Andersen, C. et al. Human integrin α10β1-selected mesenchymal stem cells home to cartilage defects in the rabbit knee and assume a chondrocyte-like phenotype. Stem Cell Res. Ther.13, 206 (2022).
Coller, B. S. et al. Monoclonal antibodies to platelet glycoprotein IIb/IIIa as antithrombotic agents. Ann. N. Y. Acad. Sci.614, 193–213 (1991).
De Luca, G. et al. Abciximab as adjunctive therapy to reperfusion in acute ST-segment elevation myocardial infarction: a meta-analysis of randomized trials. J. Am. Med. Assoc.293, 1759–1765 (2005).
Slack, R. J., Macdonald, S. J. F., Roper, J. A., Jenkins, R. G. & Hatley, R. J. D. Emerging therapeutic opportunities for integrin inhibitors. Nat. Rev. Drug Discov.21, 60–78 (2022).
Pang, X. et al. Targeting integrin pathways: mechanisms and advances in therapy. Signal Transduct. Target. Ther.8, 1 (2023).
Desgrosellier, J. S. & Cheresh, D. A. Integrins in cancer: biological implications and therapeutic opportunities. Nat. Rev. Cancer10, 9–22 (2010).
Stupp, R. et al. Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with methylated MGMT promoter (CENTRIC EORTC 26071-22072 study): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol.15, 1100–1108 (2014).
Cox, D., Brennan, M. & Moran, N. Integrins as therapeutic targets: lessons and opportunities. Nat. Rev. Drug Discov.9, 804–820 (2010).
Cox, D. How not to discover a drug - integrins. Expert Opin. Drug Discov.16, 197–211 (2021).
Saraswathibhatla, A., Indana, D. & Chaudhuri, O. Cell–extracellular matrix mechanotransduction in 3D. Nat. Rev. Mol. Cell Biol.24, 495–516 (2023).
Schäfer, N. & Grässel, S. Targeted therapy for osteoarthritis: progress and pitfalls. Nat. Med.28, 2473–2475 (2022).
Chevalier, X. Fibronectin, cartilage, and osteoarthritis. Semin. Arthritis Rheum.22, 307–318 (1993).
Johnson, K. et al. A stem cell-based approach to cartilage repair. Science336, 717–721 (2012).
Karsdal, M. A. et al. Reflections from the OARSI 2022 clinical trials symposium: the pain of OA — deconstruction of pain and patient-reported outcome measures for the benefit of patients and clinical trial design. Osteoarthr. Cartil.31, 1293–1302 (2023).
Syx, D., Tran, P. B., Miller, R. E. & Malfait, A. M. Peripheral mechanisms contributing to osteoarthritis pain. Curr. Rheumatol. Rep.20, 9 (2018).
Zhu, S. et al. Subchondral bone osteoclasts induce sensory innervation and osteoarthritis pain. J. Clin. Invest.129, 1076–1093 (2019).
Sroka, I. C. et al. The laminin binding integrin α6β1 in prostate cancer perineural invasion. J. Cell. Physiol.224, 283–288 (2010).
Lefèvre, S. et al. Synovial fibroblasts spread rheumatoid arthritis to unaffected joints. Nat. Med.15, 1414–1420 (2009).
Lowin, T. & Straub, R. H. Integrins and their ligands in rheumatoid arthritis. Arthritis Res. Ther.13, 244 (2011).
Sharma, L. Osteoarthritis of the knee. N. Engl. J. Med.384, 51–59 (2021).
Deveza, L. A. et al. Phenotypes of osteoarthritis - current state and future implications. Clin. Exp. Rheumatol.37, 64–72 (2019).
Hamidi, H. & Ivaska, J. Every step of the way: integrins in cancer progression and metastasis. Nat. Rev. Cancer18, 533–548 (2018).
Boer, C. G. et al. Deciphering osteoarthritis genetics across 826,690 individuals from 9 populations. Cell184, 4784–4818.e17 (2021).
Zengini, E. et al. Genome-wide analyses using UK Biobank data provide insights into the genetic architecture of osteoarthritis. Nat. Genet.50, 549–558 (2018).
Nelson, M. R. et al. The support of human genetic evidence for approved drug indications. Nat. Genet.47, 856–860 (2015).
Namba, S., Konuma, T., Wu, K. H., Zhou, W. & Okada, Y. A practical guideline of genomics-driven drug discovery in the era of global biobank meta-analysis. Cell Genomics2, 100190 (2022).
Reay, W. R. & Cairns, M. J. Advancing the use of genome-wide association studies for drug repurposing. Nat. Rev. Genet.22, 658–671 (2021).
Kang, H. et al. PharmGWAS: a GWAS-based knowledgebase for drug repurposing. Nucleic Acids Res.52, D972–D979 (2024).
Giacomini, K. M. et al. Genome-wide association studies of drug response and toxicity: an opportunity for genome medicine. Nat. Rev. Drug Discov.16, 1 (2016).
Moffat, J. G., Vincent, F., Lee, J. A., Eder, J. & Prunotto, M. Opportunities and challenges in phenotypic drug discovery: an industry perspective. Nat. Rev. Drug Discov.16, 531–543 (2017).
Schermelleh, L. et al. Super-resolution microscopy demystified. Nat. Cell Biol.21, 72–84 (2019).
Balzarotti, F. et al. Nanometer resolution imaging and tracking of fluorescent molecules with minimal photon fluxes. Science355, 606–612 (2017).
Huet-Calderwood, C. et al. Novel ecto-tagged integrins reveal their trafficking in live cells. Nat. Commun.8, 570 (2017).
Tsunoyama, T. A. et al. Super-long single-molecule tracking reveals dynamic-anchorage-induced integrin function. Nat. Chem. Biol.14, 497–506 (2018).
Branon, T. C. et al. Efficient proximity labeling in living cells and organisms with TurboID. Nat. Biotechnol.36, 880–898 (2018).
Liu, X., Salokas, K., Weldatsadik, R. G., Gawriyski, L. & Varjosalo, M. Combined proximity labeling and affinity purification−mass spectrometry workflow for mapping and visualizing protein interaction networks. Nat. Protoc.15, 3182–3211 (2020).
Witze, E. S., Old, W. M., Resing, K. A. & Ahn, N. G. Mapping protein post-translational modifications with mass spectrometry. Nat. Methods4, 798–806 (2007).
Smith, L. M. et al. The human proteoform project: defining the human proteome. Sci. Adv.7, eabk0734 (2021).
Cukierman, E., Pankov, R., Stevens, D. R. & Yamada, K. M. Taking cell-matrix adhesions to the third dimension. Science294, 1708–1712 (2001).
Paggi, C. A., Teixeira, L. M., Le Gac, S. & Karperien, M. Joint-on-chip platforms: entering a new era of in vitro models for arthritis. Nat. Rev. Rheumatol.18, 217–231 (2022).
Li, Z. A. et al. Synovial joint-on-a-chip for modeling arthritis: progress, pitfalls, and potential. Trends Biotechnol.41, 511–527 (2023).
Smith, M. H. et al. Drivers of heterogeneity in synovial fibroblasts in rheumatoid arthritis. Nat. Immunol.24, 1200–1210 (2023).
Griffith, L. G. & Swartz, M. A. Capturing complex 3D tissue physiology in vitro. Nat. Rev. Mol. Cell Biol.7, 211–224 (2006).
Kholodenko, B. N. Cell-signalling dynamics in time and space. Nat. Rev. Mol. Cell Biol.7, 165–176 (2006).
Dwivedi-Agnihotri, H. et al. Distinct phosphorylation sites in a prototypical GPCR differently orchestrate β-arrestin interaction, trafficking, and signaling. Sci. Adv.6, eabb8368 (2020).
Moreno-Layseca, P. et al. Cargo-specific recruitment in clathrin- and dynamin-independent endocytosis. Nat. Cell Biol.23, 1073–1084 (2021).
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