Update on Wnt Signaling in Bone Cell Biology and Bone Disease

Overview

Journal Gene

Specialty Molecular Biology

Date 2011 Nov 15

PMID 22079544

Citations 178

Authors

David G Monroe

Meghan E McGee-Lawrence

Merry Jo Oursler

Jennifer J Westendorf

Affiliations

Soon will be listed here.

Abstract

For more than a decade, Wnt signaling pathways have been the focus of intense research activity in bone biology laboratories because of their importance in skeletal development, bone mass maintenance, and therapeutic potential for regenerative medicine. It is evident that even subtle alterations in the intensity, amplitude, location, and duration of Wnt signaling pathways affects skeletal development, as well as bone remodeling, regeneration, and repair during a lifespan. Here we review recent advances and discrepancies in how Wnt/Lrp5 signaling regulates osteoblasts and osteocytes, introduce new players in Wnt signaling pathways that have important roles in bone development, discuss emerging areas such as the role of Wnt signaling in osteoclastogenesis, and summarize progress made in translating basic studies to clinical therapeutics and diagnostics centered around inhibiting Wnt pathway antagonists, such as sclerostin, Dkk1 and Sfrp1. Emphasis is placed on the plethora of genetic studies in mouse models and genome wide association studies that reveal the requirement for and crucial roles of Wnt pathway components during skeletal development and disease.

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References

Ahn Y, Sanderson B, Klein O, Krumlauf R . Inhibition of Wnt signaling by Wise (Sostdc1) and negative feedback from Shh controls tooth number and patterning. Development. 2010; 137(19):3221-31. PMC: 6512258. DOI: 10.1242/dev.054668. View

Staehling-Hampton K, Proll S, Paeper B, Zhao L, Charmley P, Brown A . A 52-kb deletion in the SOST-MEOX1 intergenic region on 17q12-q21 is associated with van Buchem disease in the Dutch population. Am J Med Genet. 2002; 110(2):144-52. DOI: 10.1002/ajmg.10401. View

Roose J, Huls G, van Beest M, Moerer P, van der Horn K, Goldschmeding R . Synergy between tumor suppressor APC and the beta-catenin-Tcf4 target Tcf1. Science. 1999; 285(5435):1923-6. DOI: 10.1126/science.285.5435.1923. View

Hoeppner L, Secreto F, Razidlo D, Whitney T, Westendorf J . Lef1DeltaN binds beta-catenin and increases osteoblast activity and trabecular bone mass. J Biol Chem. 2011; 286(13):10950-9. PMC: 3064150. DOI: 10.1074/jbc.M110.165100. View

Liu T, Liu X, Wang H, Moon R, Malbon C . Activation of rat frizzled-1 promotes Wnt signaling and differentiation of mouse F9 teratocarcinoma cells via pathways that require Galpha(q) and Galpha(o) function. J Biol Chem. 1999; 274(47):33539-44. DOI: 10.1074/jbc.274.47.33539. View

Saxon L, Jackson B, Sugiyama T, Lanyon L, Price J . Analysis of multiple bone responses to graded strains above functional levels, and to disuse, in mice in vivo show that the human Lrp5 G171V High Bone Mass mutation increases the osteogenic response to loading but that lack of Lrp5 activity reduces.... Bone. 2011; 49(2):184-93. PMC: 3121951. DOI: 10.1016/j.bone.2011.03.683. View

Boland G, Perkins G, Hall D, Tuan R . Wnt 3a promotes proliferation and suppresses osteogenic differentiation of adult human mesenchymal stem cells. J Cell Biochem. 2004; 93(6):1210-30. DOI: 10.1002/jcb.20284. View

Fujino T, Asaba H, Kang M, Ikeda Y, Sone H, Takada S . Low-density lipoprotein receptor-related protein 5 (LRP5) is essential for normal cholesterol metabolism and glucose-induced insulin secretion. Proc Natl Acad Sci U S A. 2003; 100(1):229-34. PMC: 140935. DOI: 10.1073/pnas.0133792100. View

Case N, Ma M, Sen B, Xie Z, Gross T, Rubin J . Beta-catenin levels influence rapid mechanical responses in osteoblasts. J Biol Chem. 2008; 283(43):29196-205. PMC: 2570859. DOI: 10.1074/jbc.M801907200. View

10.

Kugimiya F, Kawaguchi H, Ohba S, Kawamura N, Hirata M, Chikuda H . GSK-3beta controls osteogenesis through regulating Runx2 activity. PLoS One. 2007; 2(9):e837. PMC: 1950686. DOI: 10.1371/journal.pone.0000837. View

11.

Yoon J, Ng A, Kim B, Bianco A, Xavier R, Elledge S . Wnt signaling regulates mitochondrial physiology and insulin sensitivity. Genes Dev. 2010; 24(14):1507-18. PMC: 2904941. DOI: 10.1101/gad.1924910. View

12.

Luo J, Zhou W, Zhou X, Li D, Weng J, Yi Z . Regulation of bone formation and remodeling by G-protein-coupled receptor 48. Development. 2009; 136(16):2747-56. PMC: 2730404. DOI: 10.1242/dev.033571. View

13.

Chan B, Fuller E, Russell A, Smith S, Smith M, Jackson M . Increased chondrocyte sclerostin may protect against cartilage degradation in osteoarthritis. Osteoarthritis Cartilage. 2011; 19(7):874-85. DOI: 10.1016/j.joca.2011.04.014. View

14.

Rivadeneira F, Styrkarsdottir U, Estrada K, Halldorsson B, Hsu Y, Richards J . Twenty bone-mineral-density loci identified by large-scale meta-analysis of genome-wide association studies. Nat Genet. 2009; 41(11):1199-206. PMC: 2783489. DOI: 10.1038/ng.446. View

15.

Tian E, Zhan F, Walker R, Rasmussen E, Ma Y, Barlogie B . The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. N Engl J Med. 2003; 349(26):2483-94. DOI: 10.1056/NEJMoa030847. View

16.

Mak W, Shao X, Dunstan C, Seibel M, Zhou H . Biphasic glucocorticoid-dependent regulation of Wnt expression and its inhibitors in mature osteoblastic cells. Calcif Tissue Int. 2009; 85(6):538-45. DOI: 10.1007/s00223-009-9303-1. View

17.

Wilting I, de Vries F, Thio B, Cooper C, Heerdink E, Leufkens H . Lithium use and the risk of fractures. Bone. 2007; 40(5):1252-8. DOI: 10.1016/j.bone.2006.12.055. View

18.

Itasaki N, Jones C, Mercurio S, Rowe A, Domingos P, Smith J . Wise, a context-dependent activator and inhibitor of Wnt signalling. Development. 2003; 130(18):4295-305. DOI: 10.1242/dev.00674. View

19.

Niehrs C, Shen J . Regulation of Lrp6 phosphorylation. Cell Mol Life Sci. 2010; 67(15):2551-62. PMC: 11115861. DOI: 10.1007/s00018-010-0329-3. View

20.

He J, Yue H, Hu W, Hu Y, Zhang Z . Contribution of the sclerostin domain-containing protein 1 (SOSTDC1) gene to normal variation of peak bone mineral density in Chinese women and men. J Bone Miner Metab. 2011; 29(5):571-81. DOI: 10.1007/s00774-010-0253-5. View