An overview of molecular signaling pathways implicated in the progression of osteoarthritis
Keywords:
Osteoarthritis, angiogenesis, Matrix Metalloproteinases, Sclerostin, Fibroblast Growth Factors, TGF-β, Bone Morphogenetic Proteins, Notch signaling.Abstract
Background. Osteoarthritis (OA) is the most prevalent joint disease worldwide, causing chronic disability in older people. Various factors are associated with its pathogenesis, including aging, obesity, joint instability, and joint inflammation.
Objectives. Since the establishment of experimental murine models with surgically induced knee joint instability many studies have revealed the major molecules or signaling pathways responsible for OA. The aim of our study is to summarize the most important molecular pathways and the growth factors that are implicated in the pathophysiology of OA.
Results. Several in vitro and in vivo studies demonstrated that neovascularization, Matrix Metalloproteinases (MMPs) secretion, sclerostin as well as TGF-β -Bone Morphogenetic Proteins (BMPs), Fibroblast Growth Factors (FGFs) and Notch signaling pathways play important role in chondrocyte and osteochondral unit homeostasis and in the development and progression of OA.
Conclusions. However, more in vitro and in vivo studies focusing on the investigation of interactions between the growth factors and cytokines involved into the specific molecular networks that regulate the homeostasis of articular cartilage and OA pathogenesis is deemed necessary.
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References
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31. Hankenson KD, Sweetwyne MT, Shitaye H, Posey KL. Thrombospondins and novel TSR-containing proteins, R-spondins, regulate bone formation and remodeling. Curr Osteoporos Rep. 2010; 8(2):68-76
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2. Zang LZ, Zheng HA, Jiang Y, Tu YH, Jiang PH, Yang LA. Mechanical and biological link between cartilage and subchondral bone in osteoarthritis. Arthritis Care Res (Hoboken) 2012; 64: 960-967.
3. Vincent TL Peripheral pain mechanisms in osteoarthritis. Pain. 2020;161 Suppl 1(1): S138-S146.
4. Chen DY, Sun NH, Chen X, Gong JJ, Yuan ST, Hu ZZ, Lu NN, Körbelin J, Fukunaga K, Liu QH, Lu YM, Han F. Endothelium-derived semaphorin 3G attenuates ischemic retinopathy by coordinating β-catenin-dependent vascular remodeling. J Clin Invest. 2021;131(4): e135296
5. Jiang W, Jin Y, Zhang S, Ding Y, Huo K, Yang J, Zhao L, Nian B, Zhong TP, Lu W, Zhang H, Cao X, Shah KM, Wang N, Liu M, Luo J. PGE2 activates EP4 in subchondral bone osteoclasts to regulate osteoarthritis. Bone Res. 2022; 10(1): 27
6. Qin Q, Lee S, Patel N, Walden K, Gomez-Salazar M, Levi B, James AW. Neurovascular coupling in bone regeneration. Exp Mol Med. 2022;54 (11):1844-1849.
7. Van Bellinghen, X.; Idoux-Gillet, Y.; Pugliano, M.; Strub, M.; Bornert, F.; Clauss, F.; Schwinté, P.; Keller, L.; Benkirane-Jessel, N.; Kuchler-Bopp, S.; et al. Temporomandibular Joint Regenerative Medicine. Int. J. Mol. Sci. 2018, 19, 446.
8. Haigler, M.C.; Abdulrehman, E.; Siddappa, S.; Kishore, R.; Padilla, M.; Enciso, R. Use of platelet-rich plasma, platelet-rich growth factor with arthrocentesis or arthroscopy to treat temporomandibular joint osteoarthritis: Systematic review with meta-analyses. J. Am. Dent. Assoc. 2018, 149, 940–952.
9. Shi, Y.; Hu, X.; Cheng, J.; Zhang, X.; Zhao, F.; Shi, W.; Ren, B.; Yu, H.; Yang, P.; Li, Z.; et al. A Small Molecule Promotes Cartilage Extracellular Matrix Generation and Inhibits Osteoarthritis Development. Nat. Commun. 2019, 10, 1914.
10. East L, McCarthy A, Wienke D, Sturge J, Ashworth A, Isacke CM. A targeted deletion in the endocytic receptor gene Endo180 results in a defect in collagen uptake. EMBO Rep. 2003; 4(7): 710-6.
11. Engelholm LH, List K, Netzel-Arnett S, Cukierman E, Mitola DJ, Aaronson H, Kjøller L, Larsen JK, Yamada KM, Strickland DK, Holmbeck K, Danø K, Birkedal-Hansen H, Behrendt N, Bugge TH. uPARAP/Endo180 is essential for cellular uptake of collagen and promotes fibroblast collagen adhesion. J Cell Biol. 2003;160(7):1009-15
12. Lauer-Fields JL, Juska D, Fields GB. Matrix metalloproteinases and collagen catabolism. Biopolymers. 2002;66(1):19-32.
13. Paiva KBS, Granjeiro JM. Matrix Metalloproteinases in Bone Resorption, Remodeling, and Repair. Prog Mol Biol Transl Sci. 2017;148:203-303
14. Lian C, Wang X, Qiu X, Wu Z, Gao B, Liu L, Liang G, Zhou H, Yang X, Peng Y, Liang A, Xu C, Huang D, Su P. Collagen type II suppresses articular chondrocyte hypertrophy and osteoarthritis progression by promoting integrin β1-SMAD1 interaction. Bone Res. 2019;7:8
15. Yan JF, Qin WP, Xiao BC, Wan QQ, Tay FR, Niu LN, Jiao K. Pathological calcification in osteoarthritis: an outcome or a disease initiator? Biol Rev Camb Philos Soc. 2020 ;95(4):960-985
16. Jiao K, Zeng G, Niu LN, Yang HX, Ren GT, Xu XY, Li FF, Tay FR, Wang MQ. Activation of α2A-adrenergic signal transduction in chondrocytes promotes degenerative remodelling of temporomandibular joint. Sci Rep. 2016; 6:30085
17. Ge C, Mohamed F, Binrayes A, Kapila S, Franceschi RT. Selective Role of Discoidin Domain Receptor 2 in Murine Temporomandibular Joint Development and Aging. J Dent Res. 2018;97(3):321-328
18. Pesesse L, Sanchez C, Henrotin Y. Osteochondral plate angiogenesis: a new treatment target in osteoarthritis. Joint Bone Spine. 2011;78(2):144-9
19. Lehmann W, Edgar CM, Wang K, Cho TJ, Barnes GL, Kakar S, Graves DT, Rueger JM, Gerstenfeld LC, Einhorn TA. Tumor necrosis factor alpha (TNF-alpha) coordinately regulates the expression of specific matrix metalloproteinases (MMPS) and angiogenic factors during fracture healing.
20. Roberts S, Caterson B, Menage J, Evans EH, Jaffray DC, Eisenstein SM. Matrix metalloproteinases and aggrecanase: their role in disorders of the human intervertebral disc. Spine (Phila Pa 1976). 2000; 25(23): 3005-13
21. Kaspiris A, Khaldi L, Grivas TB, Vasiliadis E, Kouvaras I, Dagkas S, Chronopoulos E, Papadimitriou E. Subchondral cyst development and MMP-1 expression during progression of osteoarthritis: an immunohistochemical study. Orthop Traumatol Surg Res, 2013. 99(5): p. 523-9
22. Kaspiris A, Khaldi L, Chronopoulos E, Vasiliadis E, Grivas TB, Kouvaras I, Dagkas S, Papadimitriou E.Macrophage-specific metalloelastase (MMP-12) immunoexpression in the osteochondral unit in osteoarthritis correlates with BMI and disease severity. Pathophysiology, 2015. 22(3): p. 143-51.
23. Tetlow LC, Adlam DJ, Woolley DE. Matrix metalloproteinase and proinflammatory cytokine production by chondrocytes of human osteoarthritic cartilage: associations with degenerative changes. Arthritis Rheum. 2001; 44(3): 585-94
24. Feng Y, Ke J, Cao P, Deng M, Li J, Cai H, Meng Q, Li Y, Long X. HMGB1-induced angiogenesis in perforated disc cells of human temporomandibular joint. J Cell Mol Med. 2018;22(2):1283-1291
25. Jiang SJ, Li W, Li YJ, Fang W, Long X. Dickkopf related protein 1 induces angiogenesis by upregulating vascular endothelial growth factor in the synovial fibroblasts of patients with temporomandibular joint disorders. Mol Med Rep. 2015;12(4):4959-66
26. Xu J, Cai H, Meng Q, Li Y, Chen G, Fang W, Long X. IL-1β-regulating angiogenic factors expression in perforated temporomandibular disk cells via NF-κB pathway. J Oral Pathol Med. 2016; 45(8): 605-12
27. Tanaka E, Detamore MS, Mercuri LG. Degenerative disorders of the temporomandibular joint: etiology, diagnosis, and treatment. J Dent Res. 2008; 87(4):296-307.
28. Landes CA, Goral W, Mack MG, Sader R. 3-D sonography for diagnosis of osteoarthrosis and disk degeneration of the temporomandibular joint, compared with MRI. Ultrasound Med Biol. 2006;32(5):627-32
29. Mikelis, C., M. Koutsioumpa, E. Papadimitriou Pleiotrophin as a possible new target for angiogenesis-related diseases and cancer. Recent Pat Anticancer Drug Discov, 2007. 2(2): p. 175-86
30. Lamprou M, Kaspiris A, Panagiotopoulos E, Giannoudis PV, Papadimitriou E. The role of pleiotrophin in bone repair. Injury. 2014 ;45(12):1816-23.
31. Hankenson KD, Sweetwyne MT, Shitaye H, Posey KL. Thrombospondins and novel TSR-containing proteins, R-spondins, regulate bone formation and remodeling. Curr Osteoporos Rep. 2010; 8(2):68-76
32. Raulo E, Chernousov MA, Carey DJ, Nolo R, Rauvala H. Isolation of a neuronal cell surface receptor of heparin binding growth-associated molecule (HB-GAM). Identification as N-syndecan (syndecan-3). J Biol Chem. 1994; 269(17):12999-3004
33. Imai S, Kaksonen M, Raulo E, Kinnunen T, Fages C, Meng X, Lakso M, Rauvala H. Osteoblast recruitment and bone formation enhanced by cell matrix-associated heparin-binding growth-associated molecule (HB-GAM). J Cell Biol. 1998;143(4):1113-28.
34. Petersen W, Wildemann B, Pufe T, Raschke M, Schmidmaier G. The angiogenic peptide pleiotrophin (PTN/HB-GAM) is expressed in fracture healing: an immunohistochemical study in rats. Arch Orthop Trauma Surg. 2004;124(9):603-7
35. Bouderlique T, Henault E, Lebouvier A, Frescaline G, Bierling P, Rouard H, Courty J, Albanese P, Chevallier N. Pleiotrophin commits human bone marrow mesenchymal stromal cells towards hypertrophy during chondrogenesis. PLoS One. 2014; 9(2):e88287.
36. Kaspiris A, Mikelis C, Heroult M, Khaldi L, Grivas TB, Kouvaras I, Dangas S, Vasiliadis E, Lioté F, Courty J, Papadimitriou E. Expression of the growth factor pleiotrophin and its receptor protein tyrosine phosphatase beta/zeta in the serum, cartilage and subchondral bone of patients with osteoarthritis. Joint Bone Spine. 2013;80(4):407-13
37. Wang EA, Rosen V, D’Alessandro JS, Bauduy M, Cordes P, Harada T, Israel DI, Hewick RM, Kerns KM, LaPan P. Recombinant human bone morphogenetic protein induces bone formation. Proc Natl Acad Sci U S A. 1990;87(6):2220-4
38. Guo J, Wu G. The signaling and functions of heterodimeric bone morphogenetic proteins. Cytokine Growth Factor Rev, 2012. 23(1-2): p. 61-7.
39. Rosenzweig BL, Imamura T, Okadome T, Cox GN, Yamashita H, ten Dijke P, Heldin CH, Miyazono K. Cloning and characterization of a human type II receptor for bone morphogenetic proteins. Proc Natl Acad Sci U S A. 1995 ;92(17): 7632-6
40. Miyazono K, Kamiya Y, Morikawa M. Bone morphogenetic protein receptors and signal transduction. J Biochem, 2010. 147(1): p. 35-51.
41. Carreira AC, Lojudice FH, Halcsik E, Navarro RD, Sogayar MC, Granjeiro JM. Bone morphogenetic proteins: facts, challenges, and future perspectives. J Dent Res. 2014; 93(4):335-45.
42. Yi JJ, Barnes AP, Hand R, Polleux F, Ehlers MD. TGF-beta signaling specifies axons during brain development. Cell. 2010;142(1):144-57
43. Li W, Zhao S, Yang H, Zhang C, Kang Q, Deng J, Xu Y, Ding Y, Li S. Potential Novel Prediction of TMJ-OA: MiR-140-5p Regulates Inflammation Through Smad/TGF-β Signaling. Front Pharmacol. 2019;10:15.
44. Lu K, Ma F, Yi D, Yu H, Tong L, Chen D. Molecular signaling in temporomandibular joint osteoarthritis. J Orthop Translat. 2021; 32: 21-27.
45. Zhen G, Wen C, Jia X, Li Y, Crane JL, Mears SC, Askin FB, Frassica FJ, Chang W, Yao J, Carrino JA, Cosgarea A, Artemov D, Chen Q, Zhao Z, Zhou X, Riley L, Sponseller P, Wan M, Lu WW, Cao X. Inhibition of TGF-β signaling in mesenchymal stem cells of subchondral bone attenuates osteoarthritis. Nat Med. 2013;19(6):704-12.
46. Charoenlarp P, Rajendran AK, Iseki S. Role of fibroblast growth factors in bone regeneration. Inflamm Regen. 2017;37:10
47. Itoh N, Ornitz DM. Functional evolutionary history of the mouse Fgf gene family. Dev Dyn. 2008;237(1):18-27
48. Harada M, Murakami H, Okawa A, Okimoto N, Hiraoka S, Nakahara T, Akasaka R, Shiraishi Y, Futatsugi N, Mizutani-Koseki Y, Kuroiwa A, Shirouzu M, Yokoyama S, Taiji M, Iseki S, Ornitz DM, Koseki H. FGF9 monomer-dimer equilibrium regulates extracellular matrix affinity and tissue diffusion. Nat Genet. 2009 ;41(3):289-98.
49. Itoh N. The Fgf families in humans, mice, and zebrafish: their evolutional processes and roles in development, metabolism, and disease. Biol Pharm Bull. 2007; 30(10):1819-25.
50. Wang Z, Huang J, Zhou S, Luo F, Tan Q, Sun X, Ni Z, Chen H, Du X, Xie Y, Chen L. Loss of Fgfr1 in chondrocytes inhibits osteoarthritis by promoting autophagic activity in temporomandibular joint. J Biol Chem. 2018 ;293(23):8761-8774
51. Gerhardt H, Golding M, Fruttiger M, Ruhrberg C, Lundkvist A, Abramsson A, Jeltsch M, Mitchell C, Alitalo K, Shima D, Betsholtz C. VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia. J Cell Biol. 2003;161(6):1163-77
52. Hellström M, Phng LK, Hofmann JJ, Wallgard E, Coultas L, Lindblom P, Alva J, Nilsson AK, Karlsson L, Gaiano N, Yoon K, Rossant J, Iruela-Arispe ML, Kalén M, Gerhardt H, Betsholtz C. Nature. 2007;445(7129):776-80.
53. Potente M, Gerhardt H, Carmeliet P. Basic and therapeutic aspects of angiogenesis. Cell. 2011 Sep 16;146(6):873-87
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