Table Info

Table 1.

Overview of several genes related in the Wnt signaling pathway associated with diseases marked by bone overgrowth

Protein activity	Gene	Chr	Protein function in Wnt signaling	Disease (manifestation)	References
Transmembrane co-receptors	LRP5	11	Co-receptor that works with frizzled protein in the membrane	Endosteal hyperostosis (Worth disease; OMIM#144750) and steosclerosis (high bone mass)	[75, 102]
Transmembrane co-receptors	LRP4	11	Related to LRP5/6 in modulation of Wnt/β-catenin pathway. Bind to SOSTDC1, also known as WISE, a family of Wnt antagonists [103]	Sclerosteosis type 2 (OMIM#614305)	[97]
Inhibitors	DKK1	10	Inhibitor of Wnt signaling pathway	DISH (OMIM#106400), OPLL (OMIM%602475), AS (OMIM#106300), and OYL (low levels of DKK1 in humans)	[104]
	SOST	17	SOST by osteocytes is responsible for inhibiting bone formation	Sclerosteosis type 1 (OMIM#269500), Van Buchem disease (OMIM#239100), and Craniodiaphyseal dysplasia (OMIM#122860; high bone mass)	[94, 96, 105]
	SFRP4	7	Secreted protein which binds to Wnt ligands and inhibits Wnt signaling	Pyle’s disease (OMIM#265900)	[106–108]
	WTX/AMER1	X	Encodes an intracellular repressor of canonical Wnt signaling	Osteopathia striata (OMIM#300373; high bone mass)	[91]

Chr: chromosome; SOSTDC1: SOST domain-containing protein 1; DISH: diffuse idiopathic skeletal hyperostosis; OPLL: ossification of the posterior longitudinal ligament; AS: ankylosing spondylitis; OYL: ossification of yellow ligament

Declarations

Author contributions

BP: Conceptualization, Investigation, Writing—original draft, Writing—review & editing. ARC and LP: Writing—review & editing. JBA: Validation, Writing—review & editing, Supervision. All authors read and approved the submitted version.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

Not applicable.

Copyright

References

Pawlina W, Ross MH. Histology: a text and atlas: with correlated cell and molecular biology. 8th ed. Philadelphia: Wolters Kluwer; 2020.

Chan WCW, Tan Z, To MKT, Chan D. Regulation and role of transcription factors in osteogenesis. Int J Mol Sci. 2021;22:5445. [DOI] [PubMed] [PMC]

Office of the Surgeon General (US). The basics of bone in health and disease. Bone health and osteoporosis: a report of the surgeon general. Rockville: Office of the Surgeon General (US); 2004.

Langdahl B, Ferrari S, Dempster DW. Bone modeling and remodeling: potential as therapeutic targets for the treatment of osteoporosis. Ther Adv Musculoskelet Dis. 2016;8:225–35. [DOI] [PubMed] [PMC]

El Sayed SA, Nezwek TA, Varacallo M. Physiology, bone. Treasure Island (FL): StatPearls Publishing; 2023.

Boudin E, Van Hul W. MECHANISMS IN ENDOCRINOLOGY: genetics of human bone formation. Eur J Endocrinol. 2017;177:R69–83. [DOI] [PubMed]

Dwek JR. The periosteum: what is it, where is it, and what mimics it in its absence? Skeletal Radiol. 2010;39:319–23. [DOI] [PubMed] [PMC]

Rice DP, Rice R. Locate, condense, differentiate, grow and confront: developmental mechanisms controlling intramembranous bone and suture formation and function. Front Oral Biol. 2008;12:22–40. [DOI] [PubMed]

Junqueira LC, Carneiro J. Histologia Básica Texto & Atlas. 13th ed. Rio de Janeiro (RJ): Guanabara Koogan; 2017.

10.

Komori T, Yagi H, Nomura S, Yamaguchi A, Sasaki K, Deguchi K, et al. Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell. 1997;89:755–64. [DOI] [PubMed]

11.

Jaruga A, Hordyjewska E, Kandzierski G, Tylzanowski P. Cleidocranial dysplasia and RUNX2-clinical phenotype-genotype correlation. Clin Genet. 2016;90:393–402. [DOI] [PubMed]

12.

Levi G, Narboux-Nême N, Cohen-Solal M. DLX genes in the development and maintenance of the vertebrate skeleton: implications for human pathologies. Cells. 2022;11:3277. [DOI] [PubMed] [PMC]

13.

Gilbert SF. Development biology. 6th ed. Sunderland (MA): Sinauer Associates, Inc.; 2000.

14.

Mackie EJ, Ahmed YA, Tatarczuch L, Chen KS, Mirams M. Endochondral ossification: how cartilage is converted into bone in the developing skeleton. Int J Biochem Cell Biol. 2008;40:46–62. [DOI] [PubMed]

15.

Bi W, Deng JM, Zhang Z, Behringer RR, de Crombrugghe B. Sox9 is required for cartilage formation. Nat Genet. 1999;22:85–9. [DOI] [PubMed]

16.

Wright E, Hargrave MR, Christiansen J, Cooper L, Kun J, Evans T, et al. The Sry-related gene Sox9 is expressed during chondrogenesis in mouse embryos. Nat Genet. 1995;9:15–20. [DOI] [PubMed]

17.

Ikeda T, Kawaguchi H, Kamekura S, Ogata N, Mori Y, Nakamura K, et al. Distinct roles of Sox5, Sox6, and Sox9 in different stages of chondrogenic differentiation. J Bone Miner Metab. 2005;23:337–40. [DOI] [PubMed]

18.

Hallett SA, Ono W, Ono N. The hypertrophic chondrocyte: to be or not to be. Histol Histopathol. 2021;36:1021–36. [DOI] [PubMed] [PMC]

19.

Kirsch T, Nah HD, Shapiro IM, Pacifici M. Regulated production of mineralization-competent matrix vesicles in hypertrophic chondrocytes. J Cell Biol. 1997;137:1149–60. [DOI] [PubMed] [PMC]

20.

Kirsch T. Determinants of pathological mineralization. Curr Opin Rheumatol. 2006;18:174–80. [DOI] [PubMed]

21.

Anderson HC. Vesicles associated with calcification in the matrix of epiphyseal cartilage. J Cell Biol. 1969;41:59–72. [DOI] [PubMed] [PMC]

22.

Zheng Q, Zhou G, Morello R, Chen Y, Garcia-Rojas X, Lee B. Type X collagen gene regulation by Runx2 contributes directly to its hypertrophic chondrocyte-specific expression in vivo. J Cell Biol. 2003;162:833–42. [DOI] [PubMed] [PMC]

23.

Wang C, Tan Z, Niu B, Tsang KY, Tai A, Chan WCW, et al. Inhibiting the integrated stress response pathway prevents aberrant chondrocyte differentiation thereby alleviating chondrodysplasia. Elife. 2018;7:e37673. [DOI] [PubMed] [PMC]

24.

Wang W, Lian N, Li L, Moss HE, Wang W, Perrien DS, et al. Atf4 regulates chondrocyte proliferation and differentiation during endochondral ossification by activating Ihh transcription. Development. 2009;136:4143–53. [DOI] [PubMed] [PMC]

25.

Kwan KM, Pang MK, Zhou S, Cowan SK, Kong RY, Pfordte T, et al. Abnormal compartmentalization of cartilage matrix components in mice lacking collagen X: implications for function. J Cell Biol. 1997;136:459–71. [DOI] [PubMed] [PMC]

26.

Thakker R, Whyte M, Eisman J, Igarashi T. Genetics of bone biology and skeletal disease. 2nd ed. Philadelphia: Elsevier Inc.; 2017.

27.

Hatori M, Klatte KJ, Teixeira CC, Shapiro IM. End labeling studies of fragmented DNA in the avian growth plate: evidence of apoptosis in terminally differentiated chondrocytes. J Bone Miner Res. 1995;10:1960–8. [DOI] [PubMed]

28.

Bruder SP, Caplan AI. Cellular and molecular events during embryonic bone development. Connect Tissue Res. 1989;20:65–71. [DOI] [PubMed]

29.

Florencio-Silva R, da Silva Sasso GR, Sasso-Cerri E, Simões MJ, Cerri PS. Biology of bone tissue: structure, function, and factors that influence bone cells. Biomed Res Int. 2015;2015:421746. [DOI] [PubMed] [PMC]

30.

Ortega N, Behonick DJ, Werb Z. Matrix remodeling during endochondral ossification. Trends Cell Biol. 2004;14:86–93. [DOI] [PubMed] [PMC]

31.

Teng Y, Li X, Chen Y, Cai H, Cao W, Chen X, et al. Extracellular matrix powder from cultured cartilage-like tissue as cell carrier for cartilage repair. J Mater Chem B. 2017;5:3283–92. [DOI] [PubMed]

32.

Chen X, Wang Z, Duan N, Zhu G, Schwarz EM, Xie C. Osteoblast–osteoclast interactions. Connect Tissue Res. 2018;59:99–107. [DOI] [PubMed] [PMC]

33.

Kahil K, Weiner S, Addadi L, Gal A. Ion pathways in biomineralization: perspectives on uptake, transport, and deposition of calcium, carbonate, and phosphate. J Am Chem Soc. 2021;143:21100–12. [DOI] [PubMed] [PMC]

34.

Cormick G, Belizán JM. Calcium intake and health. Nutrients. 2019;11:1606. [DOI] [PubMed] [PMC]

35.

Terkeltaub RA. Inorganic pyrophosphate generation and disposition in pathophysiology. Am J Physiol Cell Physiol. 2001;281:C1–11. [DOI] [PubMed]

36.

Caverzasio J, Bonjour JP. Characteristics and regulation of Pi transport in osteogenic cells for bone metabolism. Kidney Int. 1996;49:975–80. [DOI] [PubMed]

37.

Goding JW, Grobben B, Slegers H. Physiological and pathophysiological functions of the ecto-nucleotide pyrophosphatase/phosphodiesterase family. Biochim Biophys Acta. 2003;1638:1–19. [DOI] [PubMed]

38.

Johnson K, Goding J, Van Etten D, Sali A, Hu SI, Farley D, et al. Linked deficiencies in extracellular PP_i and osteopontin mediate pathologic calcification associated with defective PC-1 and ANK expression. J Bone Miner Res. 2003;18:994–1004. [DOI] [PubMed]

39.

Huang R, Rosenbach M, Vaughn R, Provvedini D, Rebbe N, Hickman S, et al. Expression of the murine plasma cell nucleotide pyrophosphohydrolase PC-1 is shared by human liver, bone, and cartilage cells. Regulation of PC-1 expression in osteosarcoma cells by transforming growth factor-beta. J Clin Invest. 1994;94:560–7. [DOI] [PubMed] [PMC]

40.

Fedde KN, Blair L, Silverstein J, Coburn SP, Ryan LM, Weinstein RS, et al. Alkaline phosphatase knock-out mice recapitulate the metabolic and skeletal defects of infantile hypophosphatasia. J Bone Miner Res. 1999;14:2015–26. [DOI]

41.

Pendleton A, Johnson MD, Hughes A, Gurley KA, Ho AM, Doherty M, et al. Mutations in ANKH cause chondrocalcinosis. Am J Hum Genet. 2002;71:933–40.

42.

Golub EE. Biomineralization and matrix vesicles in biology and pathology. Semin Immunopathol. 2011;33:409–17. [DOI] [PubMed] [PMC]

43.

Anderson HC, Garimella R, Tague SE. The role of matrix vesicles in growth plate development and biomineralization. Front Biosci. 2005;10:822–37. [DOI] [PubMed]

44.

Anderson HC. Molecular biology of matrix vesicles. Clin Orthop Relat Res. 1995;266–80. [PubMed]

45.

Ansari S, de Wildt BWM, Vis MAM, de Korte CE, Ito K, Hofmann S, Yuana Y. Matrix vesicles: role in bone mineralization and potential use as therapeutics. Pharmaceuticals (Basel). 2021;14:289. [DOI] [PubMed] [PMC]

46.

Ali SY, Sajdera SW, Anderson HC. Isolation and characterization of calcifying matrix vesicles from epiphyseal cartilage. Proc Natl Acad Sci U S A. 1970;67:1513–20. [DOI] [PubMed] [PMC]

47.

Cotmore JM, Nichols G Jr, Wuthier RE. Phospholipid—calcium phosphate complex: enhanced calcium migration in the presence of phosphate. Science. 1971;172:1339–41. [DOI] [PubMed]

48.

Wu LNY, Genge BR, Wuthier RE. Differential effects of zinc and magnesium ions on mineralization activity of phosphatidylserine calcium phosphate complexes. J Inorg Biochem. 2009;103:948–62. [DOI] [PubMed]

49.

Millán JL. The role of phosphatases in the initiation of skeletal mineralization. Calcif Tissue Int. 2013;93:299–306. [DOI] [PubMed] [PMC]

50.

Yadav MC, Simao AM, Narisawa S, Huesa C, McKee MD, Farquharson C, et al. Loss of skeletal mineralization by the simultaneous ablation of PHOSPHO1 and alkaline phosphatase function: a unified model of the mechanisms of initiation of skeletal calcification. J Bone Miner Res. 2011;26:286–97. [DOI] [PubMed] [PMC]

51.

Addison WN, Azari F, Sorensen ES, Kaartinen MT, McKee MD. Pyrophosphate inhibits mineralization of osteoblast cultures by binding to mineral, up-regulating osteopontin, and inhibiting alkaline phosphatase activity. J Biol Chem. 2007;282:15872–83. [DOI] [PubMed]

52.

Fisher LW, Fedarko NS. Six genes expressed in bones and teeth encode the current members of the SIBLING family of proteins. Connect Tissue Res. 2003;44:33–40. [PubMed]

53.

Rowe PSN. Regulation of bone-renal mineral and energy metabolism: the PHEX, FGF23, DMP1, MEPE ASARM pathway. Crit Rev Eukaryot Gene Expr. 2012;22:61–86. [DOI] [PubMed] [PMC]

54.

Palmer G, Zhao J, Bonjour J, Hofstetter W, Caverzasio J. In vivo expression of transcripts encoding the glvr-1 phosphate transporter/retrovirus receptor during bone development. Bone. 1999;24:1–7. [DOI] [PubMed]

55.

Houston B, Stewart AJ, Farquharson C. PHOSPHO1—a novel phosphatase specifically expressed at sites of mineralisation in bone and cartilage. Bone. 2004;34:629–37. [DOI] [PubMed]

56.

Stewart AJ, Roberts SJ, Seawright E, Davey MG, Fleming RH, Farquharson C. The presence of PHOSPHO1 in matrix vesicles and its developmental expression prior to skeletal mineralization. Bone. 2006;39:1000–7. [DOI] [PubMed]

57.

Yadav MC, Bottini M, Cory E, Bhattacharya K, Kuss P, Narisawa S, et al. Skeletal mineralization deficits and impaired biogenesis and function of chondrocyte-derived matrix vesicles in Phospho1^-/- and Phospho1/P_it1 double-knockout mice. J Bone Miner Res. 2016;31:1275–86. [DOI] [PubMed] [PMC]

58.

Chaturvedi P, Chen NX, O’Neill K, McClintick JN, Moe SM, Janga SC. Differential miRNA expression in cells and matrix vesicles in vascular smooth muscle cells from rats with kidney disease. PLoS One. 2015;10:e0131589. [DOI] [PubMed] [PMC]

59.

Tanaka Y, Nakayamada S, Okada Y. Osteoblasts and osteoclasts in bone remodeling and inflammation. Curr Drug Targets Inflamm Allergy. 2005;4:325–8. [DOI] [PubMed]

60.

Guasto A, Cormier-Daire V. Signaling pathways in bone development and their related skeletal dysplasia. Int J Mol Sci. 2021;22:4321. [DOI] [PubMed] [PMC]

61.

Boudin E, Fijalkowski I, Piters E, Van Hul W. The role of extracellular modulators of canonical Wnt signaling in bone metabolism and diseases. Semin Arthritis Rheum. 2013;43:220–40. [DOI] [PubMed]

62.

Kan C, Chen L, Hu Y, Ding N, Lu H, Li Y, et al. Conserved signaling pathways underlying heterotopic ossification. Bone. 2018;109:43–8. [DOI] [PubMed] [PMC]

63.

Monroe DG, McGee-Lawrence ME, Oursler MJ, Westendorf JJ. Update on Wnt signaling in bone cell biology and bone disease. Gene. 2012;492:1–18. [DOI] [PubMed] [PMC]

64.

Nusse R. Wnt signaling in disease and in development. Cell Res. 2005;15:28–32. [DOI] [PubMed]

65.

Tu X, Joeng KS, Nakayama KI, Nakayama K, Rajagopal J, Carroll TJ, et al. Noncanonical Wnt signaling through G protein-linked PKCδ activation promotes bone formation. Dev Cell. 2007;12:113–27. [DOI] [PubMed] [PMC]

66.

Maeda K, Kobayashi Y, Udagawa N, Uehara S, Ishihara A, Mizoguchi T, et al. Wnt5a-Ror2 signaling between osteoblast-lineage cells and osteoclast precursors enhances osteoclastogenesis. Nat Med. 2012;18:405–12. [DOI] [PubMed]

67.

Moverare-Skrtic S, Henning P, Liu X, Nagano K, Saito H, Borjesson AE, et al. Osteoblast-derived WNT16 represses osteoclastogenesis and prevents cortical bone fragility fractures. Nat Med. 2014;20:1279–88. [DOI] [PubMed] [PMC]

68.

Tan Z, Ding N, Lu H, Kessler JA, Kan L. Wnt signaling in physiological and pathological bone formation. Histol Histopathol. 2019;34:303–12. [DOI] [PubMed]

69.

Rao TP, Kuhl M. An updated overview on Wnt signaling pathways: a prelude for more. Circ Res. 2010;106:1798–806. [DOI] [PubMed]

70.

MacDonald BT, Tamai K, He X. Wnt/β-catenin signaling: components, mechanisms, and diseases. Dev Cell. 2009;17:9–26. [DOI] [PubMed] [PMC]

71.

Logan CY, Nusse R. The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol. 2004;20:781–810. [DOI] [PubMed]

72.

Kim JH, Liu X, Wang J, Chen X, Zhang H, Kim SH, et al. Wnt signaling in bone formation and its therapeutic potential for bone diseases. Ther Adv Musculoskelet Dis. 2013;5:13–31. [DOI] [PubMed] [PMC]

73.

Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS, Luthy R, et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell. 1997;89:309–19. [DOI] [PubMed]

74.

Munasinghe A, Lin P, Colina CM. Unraveling binding interactions between human RANKL and its decoy receptor osteoprotegerin. J Phys Chem B. 2017;121:9141–8. [DOI] [PubMed]

75.

Kobayashi Y, Uehara S, Koide M, Takahashi N. The regulation of osteoclast differentiation by Wnt signals. Bonekey Rep. 2015;4:713. [DOI] [PubMed] [PMC]

76.

Bafico A, Liu G, Yaniv A, Gazit A, Aaronson SA. Novel mechanism of Wnt signalling inhibition mediated by Dickkopf-1 interaction with LRP6/Arrow. Nat Cell Biol. 2001;3:683–6. [DOI] [PubMed]

77.

Mao B, Wu W, Davidson G, Marhold J, Li M, Mechler BM, et al. Kremen proteins are Dickkopf receptors that regulate Wnt/beta-catenin signalling. Nature. 2002;417:664–7. [DOI] [PubMed]

78.

Li X, Zhang Y, Kang H, Liu W, Liu P, Zhang J, et al. Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling. J Biol Chem. 2005;280:19883–7. [DOI] [PubMed]

79.

SemënovM, Tamai K, He X. SOST is a ligand for LRP5/LRP6 and a Wnt signaling inhibitor. J Biol Chem. 2005;280:26770–5. [DOI] [PubMed]

80.

Hsieh JC, Kodjabachian L, Rebbert ML, Rattner A, Smallwood PM, Samos CH, et al. A new secreted protein that binds to Wnt proteins and inhibits their activities. Nature. 1999;398:431–6. [DOI] [PubMed]

81.

Kawano Y, Kypta R. Secreted antagonists of the Wnt signalling pathway. J Cell Sci. 2003;116:2627–34. [DOI] [PubMed]

82.

Major MB, Camp ND, Berndt JD, Yi X, Goldenberg SJ, Hubbert C, et al. Wilms tumor suppressor WTX negatively regulates WNT/β-catenin signaling. Science. 2007;316:1043–6. [DOI] [PubMed]

83.

Takemaru KI, Yamaguchi S, Lee YS, Zhang Y, Carthew RW, Moon RT. Chibby, a nuclear β-catenin-associated antagonist of the Wnt/Wingless pathway. Nature. 2003;422:905–9. [DOI] [PubMed]

84.

Lerner UH, Ohlsson C. The WNT system: background and its role in bone. J Intern Med. 2015;277:630–49. [DOI] [PubMed]

85.

Sugimura R, Li L. Noncanonical Wnt signaling in vertebrate development, stem cells, and diseases. Birth Defects Res C Embryo Today. 2010;90:243–56. [DOI] [PubMed]

86.

De A. Wnt/Ca²⁺ signaling pathway: a brief overview. Acta Biochim Biophys Sin (Shanghai). 2011;43:745–56. [DOI] [PubMed]

87.

Kühl M. The WNT/calcium pathway: biochemical mediators, tools and future requirements. Front Biosci. 2004;9:967–74. [DOI] [PubMed]

88.

Gong Y, Slee RB, Fukai N, Rawadi G, Roman-Roman S, Reginato AM, et al.; The Osteoporosis-Pseudoglioma Syndrome Collaborative Group3. LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell. 2001;107:513–23. [DOI] [PubMed]

89.

Little RD, Carulli JP, Del Mastro RG, Dupuis J, Osborne M, Folz C, 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;70:11–9. [DOI] [PubMed] [PMC]

90.

Leupin O, Piters E, Halleux C, Hu S, Kramer I, Morvan F, et al. Bone overgrowth-associated mutations in the LRP4 gene impair sclerostin facilitator function. J Biol Chem. 2011;286:19489–500. [DOI] [PubMed] [PMC]

91.

Perdu B, de Freitas F, Frints SG, Schouten M, Schrander-Stumpel C, Barbosa M, et al. Osteopathia striata with cranial sclerosis owing to WTX gene defect. J Bone Miner Res. 2010;25:82–90. [DOI] [PubMed]

92.

Hartikka H, Makitie O, Mannikko M, Doria AS, Daneman A, Cole WG, et al. Heterozygous mutations in the LDL receptor-related protein 5 (LRP5) gene are associated with primary osteoporosis in children. J Bone Miner Res. 2005;20:783–9. [DOI] [PubMed]

93.

Levasseur R, Lacombe D, de Vernejoul MC. LRP5 mutations in osteoporosis-pseudoglioma syndrome and high-bone-mass disorders. Joint Bone Spine. 2005;72:207–14. [DOI] [PubMed]

94.

Balemans W, Ebeling M, Patel N, Van Hul E, Olson P, Dioszegi M, et al. Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST). Hum Mol Genet. 2001;10:537–43. [DOI] [PubMed]

95.

Ekhzaimy AA, Alyusuf EY, Alswailem M, Alzahrani AS. A novel mutation in a gene causes sclerosteosis in a family of mediterranean origin. Medicina (Kaunas). 2022;58:202. [DOI] [PubMed] [PMC]

96.

Balemans W, Patel N, Ebeling M, Van Hul E, Wuyts W, Lacza C, et al. Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease. J Med Genet. 2002;39:91–7. [DOI] [PubMed] [PMC]

97.

Fijalkowski I, Geets E, Steenackers E, Van Hoof V, Ramos FJ, Mortier G, et al. A novel domain-specific mutation in a sclerosteosis patient suggests a role of LRP4 as an anchor for sclerostin in human bone. J Bone Miner Res. 2016;31:874–81. [DOI] [PubMed]

98.

Jenkins ZA, van Kogelenberg M, Morgan T, Jeffs A, Fukuzawa R, Pearl E, et al. Germline mutations in WTX cause a sclerosing skeletal dysplasia but do not predispose to tumorigenesis. Nat Genet. 2009;41:95–100. [DOI] [PubMed]

99.

Baron R, Kneissel M. WNT signaling in bone homeostasis and disease: from human mutations to treatments. Nat Med. 2013;19:179–92. [DOI] [PubMed]

100.

Boyden LM, Mao J, Belsky J, Mitzner L, Farhi A, Mitnick MA, et al. High bone density due to a mutation in LDL-receptor–related protein 5. N Engl J Med. 2002;346:1513–21. [DOI] [PubMed]

101.

Balemans W, Piters E, Cleiren E, Ai M, Van Wesenbeeck L, Warman ML, et al. The binding between sclerostin and LRP5 is altered by DKK1 and by high-bone mass LRP5 mutations. Calcif Tissue Int. 2008;82:445–53. [DOI] [PubMed]

102.

Van Wesenbeeck L, Cleiren E, Gram J, Beals RK, Benichou O, Scopelliti D, et al. Six novel missense mutations in the LDL receptor-related protein 5 (LRP5) gene in different conditions with an increased bone density. Am J Hum Genet. 2003;72:763–71. [DOI] [PubMed] [PMC]

103.

Ahn Y, Sims C, Murray MJ, Kuhlmann PK, Fuentes-Antras J, Weatherbee SD, et al. Multiple modes of Lrp4 function in modulation of Wnt/β-catenin signaling during tooth development. Development. 2017;144:2824–36. [DOI] [PubMed] [PMC]

104.

Niu CC, Lin SS, Yuan LJ, Chen LH, Yang CY, Chung AN, et al. Correlation of blood bone turnover biomarkers and Wnt signaling antagonists with AS, DISH, OPLL, and OYL. BMC Musculoskelet Disord. 2017;18:61. [DOI] [PubMed] [PMC]

105.

Kim SJ, Bieganski T, Sohn YB, Kozlowski K, Semenov M, Okamoto N, et al. Identification of signal peptide domain SOST mutations in autosomal dominant craniodiaphyseal dysplasia. Hum Genet. 2011;129:497–502. [DOI] [PubMed]

106.

Chatron N, Lesca G, Labalme A, Rollat-Farnier PA, Monin P, Pichot E, et al. A novel homozygous truncating mutation of the SFRP4 gene in Pyle’s disease. Clin Genet. 2017;92:112–4. [DOI] [PubMed]

107.

Galada C, Shah H, Shukla A, Girisha KM. A novel sequence variant in SFRP4 causing Pyle disease. J Hum Genet. 2017;62:575–6. [DOI] [PubMed]

108.

Kiper POS, Saito H, Gori F, Unger S, Hesse E, Yamana K, et al. Cortical-bone fragility—insights from sFRP4 deficiency in Pyle’s disease. N Engl J Med. 2016;374:2553–62. [DOI] [PubMed] [PMC]

109.

Uderhardt S, Diarra D, Katzenbeisser J, David JP, Zwerina J, Richards W, et al. Blockade of Dickkopf (DKK)-1 induces fusion of sacroiliac joints. Ann Rheum Dis. 2010;69:592–7. [DOI] [PubMed]

110.

Haynes KR, Pettit AR, Duan R, Tseng HW, Glant TT, Brown MA, et al. Excessive bone formation in a mouse model of ankylosing spondylitis is associated with decreases in Wnt pathway inhibitors. Arthritis Res Ther. 2012;14:R253. [DOI] [PubMed] [PMC]

111.

Senolt L, Hulejova H, Krystufkova O, Forejtova S, Andres Cerezo L, Gatterova J, et al. Low circulating Dickkopf-1 and its link with severity of spinal involvement in diffuse idiopathic skeletal hyperostosis. Ann Rheum Dis. 2012;71:71–4. [DOI] [PubMed]

112.

Diarra D, Stolina M, Polzer K, Zwerina J, Ominsky MS, Dwyer D, et al. Dickkopf-1 is a master regulator of joint remodeling. Nat Med. 2007;13:156–63. [DOI] [PubMed]

113.

Klavdianou K, Kanellou A, Daoussis D. Molecular mechanisms of new bone formation in axial spondyloarthritis. Mediterr J Rheumatol. 2022;33:115–25. [DOI] [PubMed] [PMC]

114.

Daoussis D, Liossis SN, Solomou EE, Tsanaktsi A, Bounia K, Karampetsou M, et al. Evidence that Dkk-1 is dysfunctional in ankylosing spondylitis. Arthritis Rheum. 2010;62:150–8. [DOI] [PubMed]

115.

Kobayashi Y, Uehara S, Udagawa N, Takahashi N. Regulation of bone metabolism by Wnt signals. J Biochem. 2016;159:387–92. [DOI] [PubMed] [PMC]

116.

Sebastian A, Loots GG. Genetics of Sost/SOST in sclerosteosis and van Buchem disease animal models. Metabolism. 2018;80:38–47. [DOI] [PubMed]

117.

Pflanz D, Birkhold AI, Albiol L, Thiele T, Julien C, Seliger A, et al. Sost deficiency led to a greater cortical bone formation response to mechanical loading and altered gene expression. Sci Rep. 2017;7:9435. [DOI] [PubMed] [PMC]

118.

van Lierop AH, Moester MJ, Hamdy NA, Papapoulos SE. Serum Dickkopf 1 levels in sclerostin deficiency. J Clin Endocrinol Metab. 2014;99:E252–6. [DOI] [PubMed]

119.

De Maré A, D’Haese PC, Verhulst A. The role of sclerostin in bone and ectopic calcification. Int J Mol Sci. 2020;21:3199. [DOI] [PubMed] [PMC]

120.

Kapinas K, Kessler C, Ricks T, Gronowicz G, Delany AM. miR-29 modulates Wnt signaling in human osteoblasts through a positive feedback loop. J Biol Chem. 2010;285:25221–31. [DOI] [PubMed] [PMC]

121.

Zhang F, Cao K, Du G, Zhang Q, Yin Z. miR-29a promotes osteoblast proliferation by downregulating DKK-1 expression and activating Wnt/β-catenin signaling pathway. Adv Clin Exp Med. 2019;28:1293–300. [DOI] [PubMed]

122.

Zhang J, Tu Q, Bonewald LF, He X, Stein G, Lian J, et al. Effects of miR-335-5p in modulating osteogenic differentiation by specifically downregulating Wnt antagonist DKK1. J Bone Miner Res. 2011;26:1953–63. [DOI] [PubMed] [PMC]

123.

Ma S, Wang DD, Ma CY, Zhang YD. microRNA-96 promotes osteoblast differentiation and bone formation in ankylosing spondylitis mice through activating the Wnt signaling pathway by binding to SOST. J Cell Biochem. 2019;120:15429–42. [DOI] [PubMed]

124.

Wang T, Xu Z. miR-27 promotes osteoblast differentiation by modulating Wnt signaling. Biochem Biophys Res Commun. 2010;402:186–9. [DOI] [PubMed]

125.

Shi Y, Fu Y, Tong W, Geng Y, Lui PP, Tang T, et al. Uniaxial mechanical tension promoted osteogenic differentiation of rat tendon-derived stem cells (rTDSCs) via the Wnt5a-RhoA pathway. J Cell Biochem. 2012;113:3133–42. [DOI] [PubMed]

126.

Strachan T, Read A. Human molecular genetics. 4th ed. New York: Garland Science; 2011.

127.

Delgado-Calle J, Sañudo C, Bolado A, Fernandez AF, Arozamena J, Pascual-Carra MA, et al. DNA methylation contributes to the regulation of sclerostin expression in human osteocytes. J Bone Miner Res. 2012;27:926–37. [DOI] [PubMed]

128.

Reppe S, Noer A, Grimholt RM, Halldorsson BV, Medina-Gomez C, Gautvik VT, et al. Methylation of bone SOST, its mRNA, and serum sclerostin levels correlate strongly with fracture risk in postmenopausal women. J Bone Miner Res. 2015;30:249–56. [DOI] [PubMed]

129.

Day TF, Yang Y. Wnt and hedgehog signaling pathways in bone development. J Bone Joint Surg Am. 2008;90:19–24. [DOI] [PubMed]

130.

Alman BA. The role of hedgehog signalling in skeletal health and disease. Nat Rev Rheumatol. 2015;11:552–60. [DOI] [PubMed]

131.

Briscoe J, Therond PP. The mechanisms of hedgehog signalling and its roles in development and disease. Nat Rev Mol Cell Biol. 2013;14:416–29. [DOI] [PubMed]

132.

Bangs F, Anderson KV. Primary cilia and mammalian hedgehog signaling. Cold Spring Harb Perspect Biol. 2017;9:a028175. [DOI] [PubMed] [PMC]

133.

Kim J, Kato M, Beachy PA. Gli2 trafficking links hedgehog-dependent activation of smoothened in the primary cilium to transcriptional activation in the nucleus. Proc Natl Acad Sci U S A. 2009;106:21666–71. [DOI] [PubMed] [PMC]

134.

Humke EW, Dorn KV, Milenkovic L, Scott MP, Rohatgi R. The output of hedgehog signaling is controlled by the dynamic association between suppressor of fused and the Gli proteins. Genes Dev. 2010;24:670–82. [DOI] [PubMed] [PMC]

135.

Li ZJ, Nieuwenhuis E, Nien W, Zhang X, Zhang J, Puviindran V, et al. Kif7 regulates Gli2 through Sufu-dependent and -independent functions during skin development and tumorigenesis. Development. 2012;139:4152–61. [DOI] [PubMed]

136.

Vortkamp A, Lee K, Lanske B, Segre GV, Kronenberg HM, Tabin CJ. Regulation of rate of cartilage differentiation by Indian hedgehog and PTH-related protein. Science. 1996;273:613–22. [DOI] [PubMed]

137.

Zhou M, Jiang J. Gli Phosphorylation code in hedgehog signal transduction. Front Cell Dev Biol. 2022;10:846927. [DOI] [PubMed] [PMC]

138.

Pan Y, Bai CB, Joyner AL, Wang B. Sonic hedgehog signaling regulates Gli2 transcriptional activity by suppressing its processing and degradation. Mol Cell Biol. 2006;26:3365–77. [DOI] [PubMed] [PMC]

139.

Feng H, Xing W, Han Y, Sun J, Kong M, Gao B, et al. Tendon-derived cathepsin K-expressing progenitor cells activate Hedgehog signaling to drive heterotopic ossification. J Clin Invest. 2020;130:6354–65. [DOI] [PubMed] [PMC]

140.

Kan C, Chen L, Hu Y, Ding N, Li Y, McGuire TL, et al. Gli1-labeled adult mesenchymal stem/progenitor cells and hedgehog signaling contribute to endochondral heterotopic ossification. Bone. 2018;109:71–9. [DOI] [PubMed] [PMC]

141.

Lin AC, Seeto BL, Bartoszko JM, Khoury MA, Whetstone H, Ho L, et al. Modulating hedgehog signaling can attenuate the severity of osteoarthritis. Nat Med. 2009;15:1421–5. [DOI] [PubMed]

142.

Ruiz-Heiland G, Horn A, Zerr P, Hofstetter W, Baum W, Stock M, et al. Blockade of the hedgehog pathway inhibits osteophyte formation in arthritis. Ann Rheum Dis. 2012;71:400–7. [DOI] [PubMed]

143.

Dittmann K, Wuelling M, Uhmann A, Dullin C, Hahn H, Schweyer S, et al. Inactivation of Patched1 in murine chondrocytes causes spinal fusion without inflammation. Arthritis Rheumatol. 2014;66:831–40. [DOI] [PubMed]

144.

Daoussis D, Filippopoulou A, Liossis SN, Sirinian C, Klavdianou K, Bouris P, et al. Anti-TNFα treatment decreases the previously increased serum Indian Hedgehog levels in patients with ankylosing spondylitis and affects the expression of functional Hedgehog pathway target genes. Semin Arthritis Rheum. 2015;44:646–51. [DOI] [PubMed]

145.

Sugita D, Yayama T, Uchida K, Kokubo Y, Nakajima H, Yamagishi A, et al. Indian hedgehog signaling promotes chondrocyte differentiation in enchondral ossification in human cervical ossification of the posterior longitudinal ligament. Spine (Phila Pa 1976). 2013;38:E1388–96. [DOI] [PubMed]

146.

Pignolo RJ, Ramaswamy G, Fong JT, Shore EM, Kaplan FS. Progressive osseous heteroplasia: diagnosis, treatment, and prognosis. Appl Clin Genet. 2015;8:37–48. [DOI] [PubMed] [PMC]

147.

Cairns DM, Pignolo RJ, Uchimura T, Brennan TA, Lindborg CM, Xu M, et al. Somitic disruption of GNAS in chick embryos mimics progressive osseous heteroplasia. J Clin Invest. 2013;123:3624–33. [DOI] [PubMed] [PMC]

148.

Regard JB, Malhotra D, Gvozdenovic-Jeremic J, Josey M, Chen M, Weinstein LS, et al. Activation of Hedgehog signaling by loss of GNAS causes heterotopic ossification. Nat Med. 2013;19:1505–12. [DOI] [PubMed] [PMC]

149.

Regard JB, Cherman N, Palmer D, Kuznetsov SA, Celi FS, Guettier JM, et al. Wnt/β-catenin signaling is differentially regulated by Gα proteins and contributes to fibrous dysplasia. Proc Natl Acad Sci U S A. 2011;108:20101–6. [DOI] [PubMed] [PMC]

150.

Yang J, Andre P, Ye L, Yang YZ. The Hedgehog signalling pathway in bone formation. Int J Oral Sci. 2015;7:73–9. [DOI] [PubMed] [PMC]

151.

Johnson RL, Rothman AL, Xie J, Goodrich LV, Bare JW, Bonifas JM, et al. Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science. 1996;272:1668–71. [DOI] [PubMed]

152.

Bale SJ, Amos CI, Parry DM, Bale AE. Relationship between head circumference and height in normal adults and in the nevoid basal cell carcinoma syndrome and neurofibromatosis type I. Am J Med Genet. 1991;40:206–10. [DOI] [PubMed]

153.

Gorlin RJ. Nevoid basal cell carcinoma syndrome. Dermatol Clin. 1995;13:113–25. [PubMed]

154.

Kimonis VE, Goldstein AM, Pastakia B, Yang ML, Kase R, DiGiovanna JJ, et al. Clinical manifestations in 105 persons with nevoid basal cell carcinoma syndrome. Am J Med Genet. 1997;69:299–308. [PubMed]

155.

Ohba S, Kawaguchi H, Kugimiya F, Ogasawara T, Kawamura N, Saito T, et al. Patched1 haploinsufficiency increases adult bone mass and modulates Gli3 repressor activity. Dev Cell. 2008;14:689–99. [DOI] [PubMed]

156.

Huang M, Qing Y, Shi Q, Cao Y, Song K. miR-342-3p elevates osteogenic differentiation of umbilical cord mesenchymal stem cells via inhibiting Sufu in vitro. Biochem Biophys Res Commun. 2017;491:571–7. [DOI] [PubMed]

157.

Qing Y, Huang M, Cao Y, Du T, Song K. Effects of miRNA-342-3p in modulating Hedgehog signaling pathway of human umbilical cord mesenchymal stem cells by down-regulating Sufu. Oral Dis. 2019;25:1147–57. [DOI] [PubMed]

158.

Kureel J, John AA, Dixit M, Singh D. MicroRNA-467g inhibits new bone regeneration by targeting Ihh/Runx-2 signaling. Int J Biochem Cell Biol. 2017;85:35–43. [DOI] [PubMed]

159.

Wu M, Chen G, Li YP. TGF-β and BMP signaling in osteoblast, skeletal development, and bone formation, homeostasis and disease. Bone Res. 2016;4:16009. [DOI] [PubMed] [PMC]

160.

Crane JL, Xian L, Cao X. Role of TGF-β signaling in coupling bone remodeling. Methods Mol Biol. 2016;1344:287–300. [DOI] [PubMed]

161.

Tzavlaki K, Moustakas A. TGF-β signaling. Biomolecules. 2020;10:487. [DOI] [PubMed] [PMC]

162.

Crane JL, Cao X. Bone marrow mesenchymal stem cells and TGF-β signaling in bone remodeling. J Clin Invest. 2014;124:466–72. [DOI] [PubMed] [PMC]

163.

Heldin CH, Moustakas A. Signaling receptors for TGF-β family members. Cold Spring Harb Perspect Biol. 2016;8:a022053. [DOI] [PubMed] [PMC]

164.

Derynck R, Budi EH. Specificity, versatility, and control of TGF-β family signaling. Sci Signal. 2019;12:eaav5183. [DOI] [PubMed] [PMC]

165.

Shi S, de Gorter DJJ, Hoogaars WMH, ’t Hoen PAC, ten Dijke P. Overactive bone morphogenetic protein signaling in heterotopic ossification and Duchenne muscular dystrophy. Cell Mol Life Sci. 2013;70:407–23. [DOI] [PubMed] [PMC]

166.

Marcellini S, Henriquez JP, Bertin A. Control of osteogenesis by the canonical Wnt and BMP pathways in vivo: cooperation and antagonism between the canonical Wnt and BMP pathways as cells differentiate from osteochondroprogenitors to osteoblasts and osteocytes. Bioessays. 2012;34:953–62. [DOI] [PubMed]

167.

de Ceuninck van Capelle C, Spit M, ten Dijke P. Current perspectives on inhibitory SMAD7 in health and disease. Crit Rev Biochem Mol Biol. 2020;55:691–715. [DOI] [PubMed]

168.

Kavsak P, Rasmussen RK, Causing CG, Bonni S, Zhu H, Thomsen GH, et al. Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGFβ receptor for degradation. Mol Cell. 2000;6:1365–75. [DOI] [PubMed]

169.

Hanyu A, Ishidou Y, Ebisawa T, Shimanuki T, Imamura T, Miyazono K. The N domain of Smad7 is essential for specific inhibition of transforming growth factor-β signaling. J Cell Biol. 2001;155:1017–27. [DOI] [PubMed] [PMC]

170.

Ebisawa T, Fukuchi M, Murakami G, Chiba T, Tanaka K, Imamura T, et al. Smurf1 interacts with transforming growth factor-β type I receptor through Smad7 and induces receptor degradation. J Biol Chem. 2001;276:12477–80. [DOI] [PubMed]

171.

Onichtchouk D, Chen YG, Dosch R, Gawantka V, Delius H, Massague J, et al. Silencing of TGF-β signalling by the pseudoreceptor BAMBI. Nature. 1999;401:480–5. [PubMed]

172.

Martinez-Hackert E, Sundan A, Holien T. Receptor binding competition: a paradigm for regulating TGF-β family action. Cytokine Growth Factor Rev. 2021;57:39–54. [DOI] [PubMed] [PMC]

173.

Blaney Davidson EN, van der Kraan PM, van den Berg WB. TGF-β and osteoarthritis. Osteoarthritis Cartilage. 2007;15:597–604. [DOI] [PubMed]

174.

Zhang W, Zhou M, Liu C, Liu C, Qiao T, Huang D, et al. A novel mutation of SMAD3 identified in a Chinese family with aneurysms-osteoarthritis syndrome. Biomed Res Int. 2015;2015:968135. [DOI] [PubMed] [PMC]

175.

Qu X, Chen Z, Fan D, Xiang S, Sun C, Zeng Y, et al. Two novel BMP-2 variants identified in patients with thoracic ossification of the ligamentum flavum. Eur J Hum Genet. 2017;25:565–71. [DOI] [PubMed] [PMC]

176.

Kaplan FS, Al Mukaddam M, Stanley A, Towler OW, Shore EM. Fibrodysplasia ossificans progressiva (FOP): a disorder of osteochondrogenesis. Bone. 2020;140:115539. [DOI] [PubMed] [PMC]

177.

Shore EM, Xu M, Feldman GJ, Fenstermacher DA, Cho TJ, Choi IH, et al. A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva. Nat Genet. 2006;38:525–7. [DOI] [PubMed]

178.

Yayama T, Uchida K, Kobayashi S, Kokubo Y, Sato R, Nakajima H, et al. Thoracic ossification of the human ligamentum flavum: histopathological and immunohistochemical findings around the ossified lesion. J Neurosurg Spine. 2007;7:184–93. [DOI] [PubMed]

179.

Yan L, Gao R, Liu Y, He B, Lv S, Hao D. The pathogenesis of ossification of the posterior longitudinal ligament. Aging Dis. 2017;8:570–82. [DOI] [PubMed] [PMC]

180.

Kinoshita A, Saito T, Tomita HA, Makita Y, Yoshida K, Ghadami M, et al. Domain-specific mutations in TGFB1 result in Camurati-Engelmann disease. Nat Genet. 2000;26:19–20. [DOI] [PubMed]

181.

Janssens K, Gershoni-Baruch R, Guañabens N, Migone N, Ralston S, Bonduelle M, et al. Mutations in the gene encoding the latency-associated peptide of TGF-β1 cause Camurati-Engelmann disease. Nat Genet. 2000;26:273–5. [DOI] [PubMed]

182.

Kawaguchi H, Kurokawa T, Hoshino Y, Kawahara H, Ogata E, Matsumoto T. Immunohistochemical demonstration of bone morphogenetic protein-2 and transforming growth factor-β in the ossification of the posterior longitudinal ligament of the cervical spine. Spine (Phila Pa 1976). 1992;17:33–6. [DOI]

183.

Kamiya M, Harada A, Mizuno M, Iwata H, Yamada Y. Association between a polymorphism of the transforming growth factor-β1 gene and genetic susceptibility to ossification of the posterior longitudinal ligament in Japanese patients. Spine (Phila Pa 1976). 2001;26:1264–6; discussion 1266. [DOI] [PubMed]

184.

Horikoshi T, Maeda K, Kawaguchi Y, Chiba K, Mori K, Koshizuka Y, et al. A large-scale genetic association study of ossification of the posterior longitudinal ligament of the spine. Hum Genet. 2006;119:611–6. [DOI] [PubMed]

185.

Kawaguchi Y, Furushima K, Sugimori K, Inoue I, Kimura T. Association between polymorphism of the transforming growth factor-β1 gene with the radiologic characteristic and ossification of the posterior longitudinal ligament. Spine (Phila Pa 1976). 2003;28:1424–6. [DOI] [PubMed]

186.

Jekarl DW, Paek CM, An YJ, Kim YJ, Kim M, Kim Y, et al. TGFBR2 gene polymorphism is associated with ossification of the posterior longitudinal ligament. J Clin Neurosci. 2013;20:453–6. [DOI] [PubMed]

187.

Lagier R, Mbakop A, Bigler A. Osteopoikilosis: a radiological and pathological study. Skeletal Radiol. 1984;11:161–8. [DOI] [PubMed]

188.

Couto AR, Parreira B, Thomson R, Soares M, Power DM, Stankovich J, et al. Combined approach for finding susceptibility genes in DISH/chondrocalcinosis families: whole-genome-wide linkage and IBS/IBD studies. Hum Genome Var. 2017;4:17041. [DOI] [PubMed] [PMC]

189.

Katagiri T, Watabe T. Bone morphogenetic proteins. Cold Spring Harb Perspect Biol. 2016;8:a021899. [DOI] [PubMed] [PMC]

190.

Hellemans J, Preobrazhenska O, Willaert A, Debeer P, Verdonk PC, Costa T, et al. Loss-of-function mutations in LEMD3 result in osteopoikilosis, Buschke-Ollendorff syndrome and melorheostosis. Nat Genet. 2004;36:1213–8. [DOI] [PubMed]

191.

Li Z, Hassan MQ, Volinia S, van Wijnen AJ, Stein JL, Croce CM, et al. A microRNA signature for a BMP2-induced osteoblast lineage commitment program. Proc Natl Acad Sci U S A. 2008;105:13906–11. [DOI] [PubMed] [PMC]

192.

Wu T, Zhou H, Hong Y, Li J, Jiang X, Huang H. miR-30 family members negatively regulate osteoblast differentiation. J Biol Chem. 2012;287:7503–11. [DOI] [PubMed] [PMC]

193.

Kureel J, Dixit M, Tyagi AM, Mansoori MN, Srivastava K, Raghuvanshi A, et al. miR-542-3p suppresses osteoblast cell proliferation and differentiation, targets BMP-7 signaling and inhibits bone formation. Cell Death Dis. 2014;5:e1050. [DOI] [PubMed] [PMC]

194.

Zhang JF, Fu WM, He ML, Xie WD, Lv Q, Wan G, et al. MiRNA-20a promotes osteogenic differentiation of human mesenchymal stem cells by co-regulating BMP signaling. RNA Biol. 2011;8:829–38. [DOI] [PubMed]

195.

Mak KK, Chen MH, Day TF, Chuang PT, Yang Y. Wnt/β-catenin signaling interacts differentially with Ihh signaling in controlling endochondral bone and synovial joint formation. Development. 2006;133:3695–707. [DOI] [PubMed]

196.

Zhang R, Oyajobi BO, Harris SE, Chen D, Tsao C, Deng HW, et al. Wnt/β-catenin signaling activates bone morphogenetic protein 2 expression in osteoblasts. Bone. 2013;52:145–56. [DOI] [PubMed] [PMC]

197.

Papathanasiou I, Malizos KN, Tsezou A. Bone morphogenetic protein-2-induced Wnt/β-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:R82. [DOI] [PubMed] [PMC]

198.

Shi Y, Liao X, Long JY, Yao L, Chen J, Yin B, et al. Gli1⁺ progenitors mediate bone anabolic function of teriparatide via Hh and Igf signaling. Cell Rep. 2021;36:109542. [DOI] [PubMed] [PMC]

199.

Thomas S, Jaganathan BG. Signaling network regulating osteogenesis in mesenchymal stem cells. J Cell Commun Signal. 2022;16:47–61. [DOI] [PubMed] [PMC]