Signalling interaction between β-catenin and other signalling molecules during osteoarthritis development

  • Jing Feng 1,2 ,
  • Qing Zhang 3 ,
  • Feifei Pu 1,2 ,
  • Zhenglin Zhu 4 ,
  • Ke Lu 5,6 ,
  • William W. Lu 5 ,
  • Liping Tong 6 ,
  • Huan Yu , 1,2 ,
  • Di Chen , 5,6
Expand
  • 1. Department of Orthopedics, Traditional Chinese and Western Medicine Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
  • 2. Department of Orthopedics, Wuhan No. 1 Hospital, Wuhan, Hubei, China
  • 3. Department of Emergency, Renmin Hospital, Wuhan University, Wuhan, Hubei, China
  • 4. Department of Orthopedic Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
  • 5. Faculty of Pharmaceutical Sciences, Shenzhen Institute of Advanced Technology, Shenzhen, China
  • 6. Research Center for Computer-aided Drug Discovery, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
yuhuanzq@gmail.com
di.chen@siat.ac.cn

Received date: 30 Sep 2023

Revised date: 29 Nov 2023

Accepted date: 29 Dec 2023

Copyright

2024 2024 The Authors. Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.

Abstract

Osteoarthritis (OA) is the most prevalent disorder of synovial joint affecting multiple joints. In the past decade, we have witnessed conceptual switch of OA pathogenesis from a ‘wear and tear’ disease to a disease affecting entire joint. Extensive studies have been conducted to understand the underlying mechanisms of OA using genetic mouse models and ex vivo joint tissues derived from individuals with OA. These studies revealed that multiple signalling pathways are involved in OA development, including the canonical Wnt/β-catenin signalling and its interaction with other signalling pathways, such as transforming growth factor β (TGF-β), bone morphogenic protein (BMP), Indian Hedgehog (Ihh), nuclear factor κB (NF-κB), fibroblast growth factor (FGF), and Notch. The identification of signalling interaction and underlying mechanisms are currently underway and the specific molecule(s) and key signalling pathway(s) playing a decisive role in OA development need to be evaluated. This review will focus on recent progresses in understanding of the critical role of Wnt/β-catenin signalling in OA pathogenesis and interaction of β-catenin with other pathways, such as TGF-β, BMP, Notch, Ihh, NF-κB, and FGF. Understanding of these novel insights into the interaction of β-catenin with other pathways and its integration into a complex gene regulatory network during OA development will help us identify the key signalling pathway of OA pathogenesis leading to the discovery of novel therapeutic strategies for OA intervention.

Cite this article

Jing Feng , Qing Zhang , Feifei Pu , Zhenglin Zhu , Ke Lu , William W. Lu , Liping Tong , Huan Yu , Di Chen . Signalling interaction between β-catenin and other signalling molecules during osteoarthritis development[J]. Cell Proliferation, 2024 , 57(6) : e13600 . DOI: 10.1111/cpr.13600

1
Yu H, Huang T, Lu WW, Tong L, Chen D. Osteoarthritis pain. Int J Mol Sci. 2022;23:9.

2
Tong L, Yu H, Huang X, et al. Current understanding of osteoarthritis pathogenesis and relevant new approaches. Bone Res. 2022;10(1):60.

3
Safiri S, Kolahi AA, Smith E, 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. 2020;79(6):819-828.

4
Long H, Liu Q, Yin H, et al. Prevalence trends of site-specific osteoarthritis from 1990 to 2019: findings from the global burden of disease study 2019. Arthritis Rheumatol. 2022;74(7):1172-1183.

5
Wu D, Wong P, Guo C, Tam LS, Gu J. Pattern and trend of five major musculoskeletal disorders in China from 1990 to 2017: findings from the global burden of disease study 2017. BMC Med. 2021;19(1):34.

6
Yao Q, Wu X, Tao C, et al. Osteoarthritis: pathogenic signaling pathways and therapeutic targets. Signal Transduct Target Ther. 2023;8(1):56.

7
Sun X, Zhen X, Hu X, et al. Osteoarthritis in the middle-aged and elderly in China: prevalence and influencing factors. Int J Environ Res Public Health. 2019;16(23):4701.

8
Zhang W, Zeng L, Yu H, et al. Injectable spontaneous hydrogen-releasing hydrogel for long-lasting alleviation of osteoarthritis. Acta Biomater. 2023;158:163-177.

9
Lu K, Wang Q, Hao L, et al. miR-204 ameliorates osteoarthritis pain by inhibiting SP1-LRP1 signaling and blocking neuro-cartilage interaction. Bioact Mater. 2023;26:425-436.

10
Chen D, Shen J, Zhao W, et al. Osteoarthritis: toward a comprehensive understanding of pathological mechanism. Bone Res. 2017;5:16044.

11
Teunissen M, Meij BP, Snel L, et al. The catabolic-to-anabolic shift seen in the canine osteoarthritic cartilage treated with knee joint distraction occurs after the distraction period. J Orthop Translat. 2023;38:44-55.

12
Sun Y, Fang Y, Li X, et al. A static magnetic field enhances the repair of osteoarthritic cartilage by promoting the migration of stem cells and chondrogenesis. J Orthop Translat. 2023;39:43-54.

13
Brophy RH, Fillingham YA. AAOS clinical practice guideline summary: management of osteoarthritis of the knee (nonarthroplasty), third edition. J Am Acad Orthop Surg. 2022;30(9):e721-e729.

14
Huang J, Zhao L, Chen D. Growth factor signalling in osteoarthritis. Growth Factors. 2018;36(5–6):187-195.

15
Chen D, Kim DJ, Shen J, Zou Z, O'Keefe RJ. Runx2 plays a central role in osteoarthritis development. J Orthop Translat. 2020;23:132-139.

16
Chen D. Osteoarthritis: a complicated joint disease requiring extensive studies with multiple approaches. J Orthop Translat. 2022;32:130.

17
Gu Y, Hu Y, Zhang H, Wang S, Xu K, Su J. Single-cell RNA sequencing in osteoarthritis. Cell Prolif. 2023;56:e13517.

18
Tsutsumi N, Hwang S, Waghray D, et al. Structure of the Wnt-frizzled-LRP6 initiation complex reveals the basis for coreceptor discrimination. Proc Natl Acad Sci U S A. 2023;120(11):e2218238120.

19
Zhou Y, Wang T, Hamilton JL, Chen D. Wnt/beta-catenin signaling in osteoarthritis and in other forms of arthritis. Curr Rheumatol Rep. 2017;19(9):53.

20
Florio M, Kostenuik PJ, Stolina M, et al. Dual inhibition of the Wnt inhibitors DKK1 and Sclerostin promotes fracture healing and increases the density and strength of uninjured bone: an experimental study in nonhuman primates. J Bone Joint Surg Am. 2023;105:1145-1155.

21
Hsieh FL, Chang TH, Gabelli SB, Nathans J. Structure of WNT inhibitor adenomatosis polyposis coli down-regulated 1 (APCDD1), a cell-surface lipid-binding protein. Proc Natl Acad Sci U S A. 2023;120(20):e2217096120.

22
Jones SE, Jomary C. Secreted frizzled-related proteins: searching for relationships and patterns. Bioessays. 2002;24(9):811-820.

23
Yuasa T, Otani T, Koike T, Iwamoto M, Enomoto-Iwamoto M. Wnt/beta-catenin signaling stimulates matrix catabolic genes and activity in articular chondrocytes: its possible role in joint degeneration. Lab Invest. 2008;88(3):264-274.

24
Zhu Z, Huang Y, Li J, et al. AMPK activator decelerates osteoarthritis development by inhibition of beta-catenin signaling in chondrocytes. J Orthop Translat. 2023;38:158-166.

25
Tamamura Y, Otani T, Kanatani N, et al. Developmental regulation of Wnt/beta-catenin signals is required for growth plate assembly, cartilage integrity, and endochondral ossification. J Biol Chem. 2005;280(19):19185-19195.

26
Zhu M, Tang D, Wu Q, et al. Activation of beta-catenin signaling in articular chondrocytes leads to osteoarthritis-like phenotype in adult beta-catenin conditional activation mice. J Bone Miner Res. 2009;24(1):12-21.

27
Xia C, Wang P, Fang L, et al. Activation of beta-catenin in Col2-expressing chondrocytes leads to osteoarthritis-like defects in hip joint. J Cell Physiol. 2019;234(10):18535-18543.

28
Hui T, Zhou Y, Wang T, et al. Activation of beta-catenin signaling in aggrecan-expressing cells in temporomandibular joint causes osteoarthritis-like defects. Int J Oral Sci. 2018;10(2):13.

29
Wang M, Li S, Xie W, et al. Activation of beta-catenin signalling leads to temporomandibular joint defects. Eur Cell Mater. 2014;28:223-235.

30
Zhu M, Chen M, Zuscik M, et al. Inhibition of beta-catenin signaling in articular chondrocytes results in articular cartilage destruction. Arthritis Rheum. 2008;58(7):2053-2064.

31
Wang T, Li J, Zhou GQ, et al. Specific deletion of beta-catenin in Col2-expressing cells leads to defects in epiphyseal bone. Int J Biol Sci. 2017;13(12):1540-1546.

32
Tong W, Zeng Y, Chow DHK, et al. Wnt16 attenuates osteoarthritis progression through a PCP/JNK-mTORC1-PTHrP cascade. Ann Rheum Dis. 2019;78(4):551-561.

33
Chen YY, Chen Y, Wang WC, et al. Cyclin D1 regulates osteoarthritis chondrocyte apoptosis via WNT3/beta-catenin signalling. Artif Cells Nanomed Biotechnol. 2019;47(1):1971-1977.

34
Xuan F, Yano F, Mori D, et al. Wnt/beta-catenin signaling contributes to articular cartilage homeostasis through lubricin induction in the superficial zone. Arthritis Res Ther. 2019;21(1):247.

35
Bai R, Miao MZ, Li H, et al. Increased Wnt/beta-catenin signaling contributes to autophagy inhibition resulting from a dietary magnesium deficiency in injury-induced osteoarthritis. Arthritis Res Ther. 2022;24(1):165.

36
Wu J, Pan Y, Yu Y, et al. Axial compressive loading attenuates early osteoarthritis by reducing subchondral bone remodeling. Am J Sports Med. 2023;51(7):1752-1764.

37
Lin C, Chen Z, Guo D, et al. Increased expression of osteopontin in subchondral bone promotes bone turnover and remodeling, and accelerates the progression of OA in a mouse model. Aging (Albany NY). 2022;14(1):253-271.

38
Huang K, Cai S, Fu T, et al. Wnt10b regulates osteogenesis of adipose-derived stem cells through Wnt/beta-catenin signalling pathway in osteoporosis. Cell Prolif. 2023:e13522.

39
Little RD, Carulli JP, Del Mastro RG, et al. A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait. Am J Hum Genet. 2002;70(1):11-19.

40
Gong Y, Slee RB, Fukai N, et al. LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell. 2001;107(4):513-523.

41
Boyden LM, Mao J, Belsky J, et al. High bone density due to a mutation in LDL-receptor-related protein 5. N Engl J Med. 2002;346(20):1513-1521.

42
Loots GG, Kneissel M, Keller H, et al. Genomic deletion of a long-range bone enhancer misregulates sclerostin in Van Buchem disease. Genome Res. 2005;15(7):928-935.

43
Brunkow ME, Gardner JC, Van Ness J, et al. Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein. Am J Hum Genet. 2001;68(3):577-589.

44
Balemans W, Patel N, Ebeling M, et al. Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease. J Med Genet. 2002;39(2):91-97.

45
Richards JB, Rivadeneira F, Inouye M, et al. Bone mineral density, osteoporosis, and osteoporotic fractures: a genome-wide association study. Lancet. 2008;371(9623):1505-1512.

46
Garcia-Ibarbia C, Perez-Nunez MI, Olmos JM, et al. Missense polymorphisms of the WNT16 gene are associated with bone mass, hip geometry and fractures. Osteoporos Int. 2013;24(9):2449-2454.

47
Estrada K, Styrkarsdottir U, Evangelou E, et al. Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture. Nat Genet. 2012;44(5):491-501.

48
Funck-Brentano T, Bouaziz W, Marty C, Geoffroy V, Hay E, Cohen-Solal M. Dkk-1-mediated inhibition of Wnt signaling in bone ameliorates osteoarthritis in mice. Arthritis Rheumatol. 2014;66(11):3028-3039.

49
Li F, Tan Q, Li F, et al. Hypoxia-induced Wnt/beta-catenin signaling activation in subchondral bone osteoblasts leads to an osteoarthritis-like phenotype of chondrocytes in articular cartilage. Front Mol Biosci. 2023;10:1057154.

50
Zhu X, Chan YT, Yung PSH, Tuan RS, Jiang Y. Subchondral bone remodeling: a therapeutic target for osteoarthritis. Front Cell Dev Biol. 2020;8:607764.

51
Zhao X, Ma L, Guo H, et al. Osteoclasts secrete leukemia inhibitory factor to promote abnormal bone remodeling of subchondral bone in osteoarthritis. BMC Musculoskelet Disord. 2022;23(1):87.

52
Goldring SR. Alterations in periarticular bone and cross talk between subchondral bone and articular cartilage in osteoarthritis. Ther Adv Musculoskelet Dis. 2012;4(4):249-258.

53
Li G, Liu S, Chen Y, et al. Teriparatide ameliorates articular cartilage degradation and aberrant subchondral bone remodeling in DMM mice. J Orthop Translat. 2023;38:241-255.

54
Bruyere O, Delferriere D, Roux C, et al. Effects of strontium ranelate on spinal osteoarthritis progression. Ann Rheum Dis. 2008;67(3):335-339.

55
Laslett LL, Dore DA, Quinn SJ, et al. Zoledronic acid reduces knee pain and bone marrow lesions over 1 year: a randomised controlled trial. Ann Rheum Dis. 2012;71(8):1322-1328.

56
Reginster JY, Badurski J, Bellamy N, et al. Efficacy and safety of strontium ranelate in the treatment of knee osteoarthritis: results of a double-blind, randomised placebo-controlled trial. Ann Rheum Dis. 2013;72(2):179-186.

57
Ozden FO, Demir E, Lutfioglu M, Acarel EE, Bilgici B, Atmaca A. Effects of periodontal and bisphosphonate treatment on the gingival crevicular levels of sclerostin and dickkopf-1 in postmenopausal osteoporosis with and without periodontitis. J Periodontal Res. 2022;57(4):849-858.

58
van den Bosch MH, Blom AB, Sloetjes AW, et al. Induction of canonical Wnt signaling by synovial overexpression of selected Wnts leads to protease activity and early osteoarthritis-like cartilage damage. Am J Pathol. 2015;185(7):1970-1980.

59
van den Bosch MH, Blom AB, van de Loo FA, et al. Brief report: induction of matrix metalloproteinase expression by synovial Wnt signaling and association with disease progression in early symptomatic osteoarthritis. Arthritis Rheumatol. 2017;69(10):1978-1983.

60
Lietman C, Wu B, Lechner S, et al. Inhibition of Wnt/beta-catenin signaling ameliorates osteoarthritis in a murine model of experimental osteoarthritis. JCI Insight. 2018;3(3):e96308.

61
Knights AJ, Farrell EC, Ellis OM, et al. Synovial fibroblasts assume distinct functional identities and secrete R-spondin 2 in osteoarthritis. Ann Rheum Dis. 2023;82(2):272-282.

62
Liao B, Guan M, Tan Q, et al. Low-intensity pulsed ultrasound inhibits fibroblast-like synoviocyte proliferation and reduces synovial fibrosis by regulating Wnt/beta-catenin signaling. J Orthop Translat. 2021;30:41-50.

63
Ye C, Chen J, Qu Y, et al. Naringin in the repair of knee cartilage injury via the TGF-beta/ALK5/Smad2/3 signal transduction pathway combined with an acellular dermal matrix. J Orthop Translat. 2022;32:1-11.

64
Shen J, Li S, Chen D. TGF-beta signaling and the development of osteoarthritis. Bone Res. 2014;2:14002.

65
Wu Q, Kim KO, Sampson ER, et al. Induction of an osteoarthritis-like phenotype and degradation of phosphorylated Smad3 by Smurf2 in transgenic mice. Arthritis Rheum. 2008;58(10):3132-3144.

66
Scharstuhl A, Diepens R, Lensen J, et al. Adenoviral overexpression of Smad-7 and Smad-6 differentially regulates TGF-beta-mediated chondrocyte proliferation and proteoglycan synthesis. Osteoarthr Cartil. 2003;11(11):773-782.

67
Xia C, Ge Q, Fang L, et al. TGF-beta/Smad2 signalling regulates enchondral bone formation of Gli1(+) periosteal cells during fracture healing. Cell Prolif. 2020;53(11):e12904.

68
Li X, Xie R, Luo Y, et al. Cooperation of TGF-beta and FGF signalling pathways in skin development. Cell Prolif. 2023;56:e13489.

69
Shen J, Li J, Wang B, et al. Deletion of the transforming growth factor beta receptor type II gene in articular chondrocytes leads to a progressive osteoarthritis-like phenotype in mice. Arthritis Rheum. 2013;65(12):3107-3119.

70
Zhu M, Chen M, Lichtler AC, O'Keefe RJ, Chen D. Tamoxifen-inducible Cre-recombination in articular chondrocytes of adult Col2a1-CreER(T2) transgenic mice. Osteoarthr Cartil. 2008;16(1):129-130.

71
Wang M, Sampson ER, Jin H, et al. MMP13 is a critical target gene during the progression of osteoarthritis. Arthritis Res Ther. 2013;15(1):R5.

72
Dao DY, Yang X, Chen D, Zuscik M, O'Keefe RJ. Axin1 and Axin2 are regulated by TGF- and mediate cross-talk between TGF- and Wnt signaling pathways. Ann N Y Acad Sci. 2007;1116:82-99.

73
Zhou S, Eid K, Glowacki J. Cooperation between TGF-beta and Wnt pathways during chondrocyte and adipocyte differentiation of human marrow stromal cells. J Bone Miner Res. 2004;19(3):463-470.

74
Kim P, Park J, Lee DJ, et al. Mast4 determines the cell fate of MSCs for bone and cartilage development. Nat Commun. 2022;13(1):3960.

75
van den Bosch MH, Blom AB, van Lent PL, et al. Canonical Wnt signaling skews TGF-beta signaling in chondrocytes towards signaling via ALK1 and Smad 1/5/8. Cell Signal. 2014;26(5):951-958.

76
Sun K, Guo J, Yao X, Guo Z, Guo F. Growth differentiation factor 5 in cartilage and osteoarthritis: a possible therapeutic candidate. Cell Prolif. 2021;54(3):e12998.

77
Frohlich J, Kovacovicova K, Raffaele M, et al. GDF11 inhibits adipogenesis and improves mature adipocytes metabolic function via WNT/beta-catenin and ALK5/SMAD2/3 pathways. Cell Prolif. 2022;55(10):e13310.

78
Bordukalo-Niksic T, Kufner V, Vukicevic S. The role of BMPs in the regulation of osteoclasts resorption and bone remodeling: from experimental models to clinical applications. Front Immunol. 2022;13:869422.

79
Whitty C, Pernstich C, Marris C, McCaskie A, Jones M, Henson F. Sustained delivery of the bone morphogenetic proteins BMP-2 and BMP-7 for cartilage repair and regeneration in osteoarthritis. Osteoarthr Cartil Open. 2022;4(1):100240.

80
Luyten FP, Chen P, Paralkar V, Reddi AH. Recombinant bone morphogenetic protein-4, transforming growth factor-beta 1, and activin a enhance the cartilage phenotype of articular chondrocytes in vitro. Exp Cell Res. 1994;210(2):224-229.

81
Chubinskaya S, Segalite D, Pikovsky D, Hakimiyan AA, Rueger DC. Effects induced by BMPS in cultures of human articular chondrocytes: comparative studies. Growth Factors. 2008;26(5):275-283.

82
Perez-Lozano ML, Sudre L, van Eegher S, et al. Gremlin-1 and BMP-4 overexpressed in osteoarthritis drive an Osteochondral-remodeling program in osteoblasts and hypertrophic chondrocytes. Int J Mol Sci. 2022;23(4):2084.

83
Bobacz K, Gruber R, Soleiman A, Erlacher L, Smolen JS, Graninger WB. Expression of bone morphogenetic protein 6 in healthy and osteoarthritic human articular chondrocytes and stimulation of matrix synthesis in vitro. Arthritis Rheum. 2003;48(9):2501-2508.

84
Ito H, Akiyama H, Shigeno C, Nakamura T. Bone morphogenetic protein-6 and parathyroid hormone-related protein coordinately regulate the hypertrophic conversion in mouse clonal chondrogenic EC cells, ATDC5. Biochim Biophys Acta. 1999;1451(2–3):263-270.

85
Blunk T, Sieminski AL, Appel B, et al. Bone morphogenetic protein 9: a potent modulator of cartilage development in vitro. Growth Factors. 2003;21(2):71-77.

86
Luu HH, Song WX, Luo X, et al. Distinct roles of bone morphogenetic proteins in osteogenic differentiation of mesenchymal stem cells. J Orthop Res. 2007;25(5):665-677.

87
van Caam A, Blaney Davidson E, Garcia de Vinuesa A, et al. The high affinity ALK1-ligand BMP9 induces a hypertrophy-like state in chondrocytes that is antagonized by TGFbeta1. Osteoarthr Cartil. 2015;23(6):985-995.

88
Boer CG, Hatzikotoulas K, Southam L, et al. Deciphering osteoarthritis genetics across 826,690 individuals from 9 populations. Cell. 2021;184(18):4784-4818.e4717.

89
Takahata Y, Hagino H, Kimura A, et al. Regulatory mechanisms of Prg4 and Gdf5 expression in articular cartilage and functions in osteoarthritis. Int J Mol Sci. 2022;23(9):4672.

90
Garciadiego-Cazares D, Aguirre-Sanchez HI, Abarca-Buis RF, Kouri JB, Velasquillo C, Ibarra C. Regulation of alpha5 and alphaV integrin expression by GDF-5 and BMP-7 in chondrocyte differentiation and osteoarthritis. PLoS One. 2015;10(5):e0127166.

91
McHugh J. Osteoarthritis: GDF5 modifies disease in OA rat model. Nat Rev Rheumatol. 2017;13(1):3.

92
Enochson L, Stenberg J, Brittberg M, Lindahl A. GDF5 reduces MMP13 expression in human chondrocytes via DKK1 mediated canonical Wnt signaling inhibition. Osteoarthr Cartil. 2014;22(4):566-577.

93
Zhang R, Oyajobi BO, Harris SE, et al. Wnt/beta-catenin signaling activates bone morphogenetic protein 2 expression in osteoblasts. Bone. 2013;52(1):145-156.

94
Zhang M, Yan Y, Lim YB, et al. BMP-2 modulates beta-catenin signaling through stimulation of Lrp5 expression and inhibition of beta-TrCP expression in osteoblasts. J Cell Biochem. 2009;108(4):896-905.

95
Rawadi G, Vayssiere B, Dunn F, Baron R, Roman-Roman S. BMP-2 controls alkaline phosphatase expression and osteoblast mineralization by a Wnt autocrine loop. J Bone Miner Res. 2003;18(10):1842-1853.

96
Kamiya N, Kobayashi T, Mochida Y, et al. Wnt inhibitors Dkk1 and Sost are downstream targets of BMP signaling through the type IA receptor (BMPRIA) in osteoblasts. J Bone Miner Res. 2010;25(2):200-210.

97
Salazar VS, Zarkadis N, Huang L, et al. Postnatal ablation of osteoblast Smad4 enhances proliferative responses to canonical Wnt signaling through interactions with beta-catenin. J Cell Sci. 2013;126(Pt 24):5598-5609.

98
Papathanasiou I, Malizos KN, Tsezou A. Bone morphogenetic protein-2-induced Wnt/beta-catenin signaling pathway activation through enhanced low-density-lipoprotein receptor-related protein 5 catabolic activity contributes to hypertrophy in osteoarthritic chondrocytes. Arthritis Res Ther. 2012;14(2):R82.

99
Sachan N, Sharma V, Mutsuddi M, Mukherjee A. Notch signalling: multifaceted role in development and disease. FEBS J. 2023.

100
Yang Y, Zhang D, Guo D, et al. Osteoblasts impair cholesterol synthesis in chondrocytes via Notch1 signalling. Cell Prolif. 2021;54(12):e13156.

101
Gozlan O, Sprinzak D. Notch signaling in development and homeostasis. Development. 2023;150(4):dev201138.

102
Kwak M, Southard KM, Kim WR, et al. Adherens junctions organize size-selective proteolytic hotspots critical for notch signalling. Nat Cell Biol. 2022;24(12):1739-1753.

103
Hosaka Y, Saito T, Sugita S, et al. Notch signaling in chondrocytes modulates endochondral ossification and osteoarthritis development. Proc Natl Acad Sci U S A. 2013;110(5):1875-1880.

104
Liu Z, Ren Y, Mirando AJ, et al. Notch signaling in postnatal joint chondrocytes, but not subchondral osteoblasts, is required for articular cartilage and joint maintenance. Osteoarthr Cartil. 2016;24(4):740-751.

105
Liu Z, Chen J, Mirando AJ, et al. A dual role for NOTCH signaling in joint cartilage maintenance and osteoarthritis. Sci Signal. 2015;8(386):ra71.

106
Gopalakrishnan N, Saravanakumar M, Madankumar P, Thiyagu M, Devaraj H. Colocalization of beta-catenin with notch intracellular domain in colon cancer: a possible role of Notch1 signaling in activation of CyclinD1-mediated cell proliferation. Mol Cell Biochem. 2014;396(1–2):281-293.

107
Shi Y, Shu B, Yang R, et al. Wnt and notch signaling pathway involved in wound healing by targeting c-Myc and Hes1 separately. Stem Cell Res Ther. 2015;6(1):120.

108
Li CT, Liu JX, Yu B, Liu R, Dong C, Li SJ. Notch signaling represses hypoxia-inducible factor-1alpha-induced activation of Wnt/beta-catenin signaling in osteoblasts under cobalt-mimicked hypoxia. Mol Med Rep. 2016;14(1):689-696.

109
Choi HK, Yuan H, Fang F, et al. Tsc1 regulates the balance between osteoblast and adipocyte differentiation through autophagy/Notch1/beta-catenin Cascade. J Bone Miner Res. 2018;33(11):2021-2034.

110
Deregowski V, Gazzerro E, Priest L, Rydziel S, Canalis E. Notch 1 overexpression inhibits osteoblastogenesis by suppressing Wnt/beta-catenin but not bone morphogenetic protein signaling. J Biol Chem. 2006;281(10):6203-6210.

111
Sciaudone M, Gazzerro E, Priest L, Delany AM, Canalis E. Notch 1 impairs osteoblastic cell differentiation. Endocrinology. 2003;144(12):5631-5639.

112
Shao J, Zhou Y, Xiao Y. The regulatory roles of notch in osteocyte differentiation via the crosstalk with canonical Wnt pathways during the transition of osteoblasts to osteocytes. Bone. 2018;108:165-178.

113
Xiao WF, Li YS, Deng A, Yang YT, He M. Functional role of hedgehog pathway in osteoarthritis. Cell Biochem Funct. 2020;38(2):122-129.

114
Rockel JS, Yu C, Whetstone H, et al. Hedgehog inhibits beta-catenin activity in synovial joint development and osteoarthritis. J Clin Invest. 2016;126(5):1649-1663.

115
Lin AC, Seeto BL, Bartoszko JM, et al. Modulating hedgehog signaling can attenuate the severity of osteoarthritis. Nat Med. 2009;15(12):1421-1425.

116
Weber AE, Jalali O, Limfat S, et al. Modulation of hedgehog signaling by kappa opioids to attenuate osteoarthritis. Arthritis Rheumatol. 2020;72(8):1278-1288.

117
Smith AE, Sigurbjornsdottir ES, Steingrimsson E, Sigurbjornsdottir S. Hedgehog signalling in bone and osteoarthritis: the role of smoothened and cholesterol. FEBS J. 2022;290:3059-3075.

118
Zhou J, Chen Q, Lanske B, et al. Disrupting the Indian hedgehog signaling pathway in vivo attenuates surgically induced osteoarthritis progression in Col2a1-CreERT2; Ihhfl/fl mice. Arthritis Res Ther. 2014;16(1):R11.

119
Tachmazidou I, Hatzikotoulas K, Southam L, et al. Identification of new therapeutic targets for osteoarthritis through genome-wide analyses of UK biobank data. Nat Genet. 2019;51(2):230-236.

120
Mak KK, Kronenberg HM, Chuang PT, Mackem S, Yang Y. Indian hedgehog signals independently of PTHrP to promote chondrocyte hypertrophy. Development. 2008;135(11):1947-1956.

121
Deng Q, Li P, Che M, et al. Activation of hedgehog signaling in mesenchymal stem cells induces cartilage and bone tumor formation via Wnt/beta-catenin. Elife. 2019;8:e50208.

122
Mak KK, Chen MH, Day TF, Chuang PT, Yang Y. Wnt/beta-catenin signaling interacts differentially with Ihh signaling in controlling endochondral bone and synovial joint formation. Development. 2006;133(18):3695-3707.

123
Zhang P, Jin Y, Xia W, Wang X, Zhou Z. Phillygenin inhibits inflammation in chondrocytes via the Nrf2/NF-kappaB axis and ameliorates osteoarthritis in mice. J Orthop Translat. 2023;41:1-11.

124
Yu H, Yao S, Zhou C, et al. Morroniside attenuates apoptosis and pyroptosis of chondrocytes and ameliorates osteoarthritic development by inhibiting NF-kappaB signaling. J Ethnopharmacol. 2021;266:113447.

125
Lamberti C, Lin KM, Yamamoto Y, et al. Regulation of beta-catenin function by the IkappaB kinases. J Biol Chem. 2001;276(45):42276-42286.

126
Carayol N, Wang CY. IKKalpha stabilizes cytosolic beta-catenin by inhibiting both canonical and non-canonical degradation pathways. Cell Signal. 2006;18(11):1941-1946.

127
Albanese C, Wu K, D'Amico M, et al. IKKalpha regulates mitogenic signaling through transcriptional induction of cyclin D1 via Tcf. Mol Biol Cell. 2003;14(2):585-599.

128
Park KJ, Krishnan V, O'Malley BW, Yamamoto Y, Gaynor RB. Formation of an IKKalpha-dependent transcription complex is required for estrogen receptor-mediated gene activation. Mol Cell. 2005;18(1):71-82.

129
Song L, Dong W, Gao M, et al. A novel role of IKKalpha in the mediation of UVB-induced G0/G1 cell cycle arrest response by suppressing cyclin D1 expression. Biochim Biophys Acta. 2010;1803(2):323-332.

130
Kwak YT, Li R, Becerra CR, Tripathy D, Frenkel EP, Verma UN. IkappaB kinase alpha regulates subcellular distribution and turnover of cyclin D1 by phosphorylation. J Biol Chem. 2005;280(40):33945-33952.

131
Kwak YT, Radaideh SM, Ding L, et al. Cells lacking IKKalpha show nuclear cyclin D1 overexpression and a neoplastic phenotype: role of IKKalpha as a tumor suppressor. Mol Cancer Res. 2011;9(3):341-349.

132
Ma B, van Blitterswijk CA, Karperien M. A Wnt/beta-catenin negative feedback loop inhibits interleukin-1-induced matrix metalloproteinase expression in human articular chondrocytes. Arthritis Rheum. 2012;64(8):2589-2600.

133
Tang Y, Yang P, Jin M, et al. Fgfr1 deficiency in osteocytes leads to increased bone mass by enhancing Wnt/beta-catenin signaling. Bone. 2023;174:116817.

134
Meo Burt P, Xiao L, Hurley MM. FGF23 regulates Wnt/beta-catenin signaling-mediated osteoarthritis in mice overexpressing high-molecular-weight FGF2. Endocrinology. 2018;159(6):2386-2396.

135
Chen H, Cui Y, Zhang D, Xie J, Zhou X. The role of fibroblast growth factor 8 in cartilage development and disease. J Cell Mol Med. 2022;26(4):990-999.

136
Chen TM, Chen YH, Sun HS, Tsai SJ. Fibroblast growth factors: potential novel targets for regenerative therapy of osteoarthritis. Chin J Physiol. 2019;62(1):2-10.

137
Orfanidou T, Iliopoulos D, Malizos KN, Tsezou A. Involvement of SOX-9 and FGF-23 in RUNX-2 regulation in osteoarthritic chondrocytes. J Cell Mol Med. 2009;13(9B):3186-3194.

138
Bianchi A, Guibert M, Cailotto F, et al. Fibroblast growth factor 23 drives MMP13 expression in human osteoarthritic chondrocytes in a klotho-independent manner. Osteoarthr Cartil. 2016;24(11):1961-1969.

139
Guibert M, Gasser A, Kempf H, Bianchi A. Fibroblast-growth factor 23 promotes terminal differentiation of ATDC5 cells. PLoS One. 2017;12(4):e0174969.

140
Liu S, Tang W, Fang J, et al. Novel regulators of Fgf23 expression and mineralization in Hyp bone. Mol Endocrinol. 2009;23(9):1505-1518.

141
Jeon SH, Yoon JY, Park YN, et al. Axin inhibits extracellular signal-regulated kinase pathway by Ras degradation via beta-catenin. J Biol Chem. 2007;282(19):14482-14492.

142
Buchtova M, Oralova V, Aklian A, et al. Fibroblast growth factor and canonical WNT/beta-catenin signaling cooperate in suppression of chondrocyte differentiation in experimental models of FGFR signaling in cartilage. Biochim Biophys Acta. 2015;1852(5):839-850.

143
Zhou Y, Shu B, Xie R, et al. Deletion of Axin1 in condylar chondrocytes leads to osteoarthritis-like phenotype in temporomandibular joint via activation of beta-catenin and FGF signaling. J Cell Physiol. 2019;234(2):1720-1729.

144
Komori T. Runx2, an inducer of osteoblast and chondrocyte differentiation. Histochem Cell Biol. 2018;149(4):313-323.

145
Li F, Xu Z, Xie Z, et al. Adipose mesenchymal stem cells-derived exosomes alleviate osteoarthritis by transporting microRNA-376c-3p and targeting the WNT-beta-catenin signaling axis. Apoptosis. 2023;28(3–4):362-378.

146
Kamekura S, Kawasaki Y, Hoshi K, et al. Contribution of runt-related transcription factor 2 to the pathogenesis of osteoarthritis in mice after induction of knee joint instability. Arthritis Rheum. 2006;54(8):2462-2470.

147
Liao L, Zhang S, Gu J, et al. Deletion of Runx2 in articular chondrocytes decelerates the progression of DMM-induced osteoarthritis in adult mice. Sci Rep. 2017;7(1):2371.

148
Catheline SE, Hoak D, Chang M, et al. Chondrocyte-specific RUNX2 overexpression accelerates post-traumatic osteoarthritis progression in adult mice. J Bone Miner Res. 2019;34(9):1676-1689.

149
Komori T. Molecular mechanism of Runx2-dependent bone development. Mol Cells. 2020;43(2):168-175.

150
Komori T. Regulation of proliferation, differentiation and functions of osteoblasts by Runx2. Int J Mol Sci. 2019;20(7):1694.

151
Hussein SM, Duff EK, Sirard C. Smad4 and beta-catenin co-activators functionally interact with lymphoid-enhancing factor to regulate graded expression of Msx2. J Biol Chem. 2003;278(49):48805-48814.

152
Liu TM, Lee EH. Transcriptional regulatory cascades in Runx2-dependent bone development. Tissue Eng Part B Rev. 2013;19(3):254-263.

153
Cai T, Sun D, Duan Y, et al. WNT/beta-catenin signaling promotes VSMCs to osteogenic transdifferentiation and calcification through directly modulating Runx2 gene expression. Exp Cell Res. 2016;345(2):206-217.

154
Jayasuriya CT, Hu N, Li J, et al. Molecular characterization of mesenchymal stem cells in human osteoarthritis cartilage reveals contribution to the OA phenotype. Sci Rep. 2018;8(1):7044.

155
Wu Q, Zhu M, Rosier RN, Zuscik MJ, O'Keefe RJ, Chen D. Beta-catenin, cartilage, and osteoarthritis. Ann N Y Acad Sci. 2010;1192(1):344-350.

156
Wu Q, Chen D, Zuscik MJ, O'Keefe RJ, Rosier RN. Overexpression of Smurf2 stimulates endochondral ossification through upregulation of beta-catenin. J Bone Miner Res. 2008;23(4):552-563.

157
Lu K, Wang Q, Jiang H, et al. Upregulation of beta-catenin signaling represents a single common pathway leading to the various phenotypes of spinal degeneration and pain. Bone Res. 2023;11(1):18.

158
Madan B, McDonald MJ, Foxa GE, Diegel CR, Williams BO, Virshup DM. Bone loss from Wnt inhibition mitigated by concurrent alendronate therapy. Bone Res. 2018;6:17.

159
Jimeno A, Gordon M, Chugh R, et al. A first-in-human phase I study of the anticancer stem cell agent Ipafricept (OMP-54F28), a decoy receptor for Wnt ligands, in patients with advanced solid tumors. Clin Cancer Res. 2017;23(24):7490-7497.

160
Fischer MM, Cancilla B, Yeung VP, et al. WNT antagonists exhibit unique combinatorial antitumor activity with taxanes by potentiating mitotic cell death. Sci Adv. 2017;3(6):e1700090.

161
Zimmerli D, Hausmann G, Cantu C, Basler K. Pharmacological interventions in the Wnt pathway: inhibition of Wnt secretion versus disrupting the protein-protein interfaces of nuclear factors. Br J Pharmacol. 2017;174(24):4600-4610.

162
Jung YS, Park JI. Wnt signaling in cancer: therapeutic targeting of Wnt signaling beyond beta-catenin and the destruction complex. Exp Mol Med. 2020;52(2):183-191.

Options
Outlines

/