Regulation of Bone Metabolism by Wnt Signals

Overview

Journal J Biochem

Publisher Oxford University Press

Specialty Biochemistry

Date 2015 Dec 30

PMID 26711238

Citations 96

Authors

Yasuhiro Kobayashi

Shunsuke Uehara

Nobuyuki Udagawa

Naoyuki Takahashi

Affiliations

Soon will be listed here.

Abstract

Wnt ligands play a central role in the development and homeostasis of various organs through β-catenin-dependent and -independent signalling. The crucial roles of Wnt/β-catenin signals in bone mass have been established by a large number of studies since the discovery of a causal link between mutations in the low-density lipoprotein receptor-related protein 5 (Lrp5) gene and alternations in human bone mass. The activation of Wnt/β-catenin signalling induces the expression of osterix, a transcription factor, which promotes osteoblast differentiation. Furthermore, this signalling induces the expression of osteoprotegerin, an osteoclast inhibitory factor in osteoblast-lineage cells to prevent bone resorption. Recent studies have also shown that Wnt5a, a typical non-canonical Wnt ligand, enhanced osteoclast formation. In contrast, Wnt16 inhibited osteoclast formation through β-catenin-independent signalling. In this review, we discussed the current understanding of the Wnt signalling molecules involved in bone formation and resorption.

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References

Chang M, Kramer I, Huber T, Kinzel B, Guth-Gundel S, Leupin O . Disruption of Lrp4 function by genetic deletion or pharmacological blockade increases bone mass and serum sclerostin levels. Proc Natl Acad Sci U S A. 2014; 111(48):E5187-95. PMC: 4260537. DOI: 10.1073/pnas.1413828111. View

Kramer I, Loots G, Studer A, Keller H, Kneissel M . Parathyroid hormone (PTH)-induced bone gain is blunted in SOST overexpressing and deficient mice. J Bone Miner Res. 2009; 25(2):178-89. PMC: 3153379. DOI: 10.1359/jbmr.090730. View

Yamane T, Kunisada T, Tsukamoto H, Yamazaki H, Niwa H, Takada S . Wnt signaling regulates hemopoiesis through stromal cells. J Immunol. 2001; 167(2):765-72. DOI: 10.4049/jimmunol.167.2.765. View

Enomoto M, Hayakawa S, Itsukushima S, Ren D, Matsuo M, Tamada K . Autonomous regulation of osteosarcoma cell invasiveness by Wnt5a/Ror2 signaling. Oncogene. 2009; 28(36):3197-208. DOI: 10.1038/onc.2009.175. View

Okamoto M, Udagawa N, Uehara S, Maeda K, Yamashita T, Nakamichi Y . Noncanonical Wnt5a enhances Wnt/β-catenin signaling during osteoblastogenesis. Sci Rep. 2014; 4:4493. PMC: 3967152. DOI: 10.1038/srep04493. View

OBrien C, Plotkin L, Galli C, Goellner J, Gortazar A, Allen M . Control of bone mass and remodeling by PTH receptor signaling in osteocytes. PLoS One. 2008; 3(8):e2942. PMC: 2491588. DOI: 10.1371/journal.pone.0002942. View

Brunkow M, Gardner J, Van Ness J, Paeper B, Kovacevich B, Proll S . Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein. Am J Hum Genet. 2001; 68(3):577-89. PMC: 1274471. DOI: 10.1086/318811. View

Gong Y, Slee R, Fukai N, Rawadi G, Roman-Roman S, Reginato A . LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell. 2001; 107(4):513-23. DOI: 10.1016/s0092-8674(01)00571-2. View

Takayanagi H, Kim S, Koga T, Nishina H, Isshiki M, Yoshida H . Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. Dev Cell. 2002; 3(6):889-901. DOI: 10.1016/s1534-5807(02)00369-6. View

10.

Collette N, Genetos D, Economides A, Xie L, Shahnazari M, Yao W . Targeted deletion of Sost distal enhancer increases bone formation and bone mass. Proc Natl Acad Sci U S A. 2012; 109(35):14092-7. PMC: 3435175. DOI: 10.1073/pnas.1207188109. View

11.

Kukita T, Wada N, Kukita A, Kakimoto T, Sandra F, Toh K . RANKL-induced DC-STAMP is essential for osteoclastogenesis. J Exp Med. 2004; 200(7):941-6. PMC: 2213286. DOI: 10.1084/jem.20040518. View

12.

Glass 2nd D, Bialek P, Ahn J, Starbuck M, Patel M, Clevers H . Canonical Wnt signaling in differentiated osteoblasts controls osteoclast differentiation. Dev Cell. 2005; 8(5):751-64. DOI: 10.1016/j.devcel.2005.02.017. View

13.

Kobayashi Y, Thirukonda G, Nakamura Y, Koide M, Yamashita T, Uehara S . Wnt16 regulates osteoclast differentiation in conjunction with Wnt5a. Biochem Biophys Res Commun. 2015; 463(4):1278-83. DOI: 10.1016/j.bbrc.2015.06.102. View

14.

Miller J . The Wnts. Genome Biol. 2002; 3(1):REVIEWS3001. PMC: 150458. DOI: 10.1186/gb-2001-3-1-reviews3001. View

15.

Oishi I, Suzuki H, Onishi N, Takada R, Kani S, Ohkawara B . The receptor tyrosine kinase Ror2 is involved in non-canonical Wnt5a/JNK signalling pathway. Genes Cells. 2003; 8(7):645-54. DOI: 10.1046/j.1365-2443.2003.00662.x. View

16.

Simonet W, Lacey D, Dunstan C, Kelley M, Chang M, Luthy R . Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell. 1997; 89(2):309-19. DOI: 10.1016/s0092-8674(00)80209-3. View

17.

Powell Jr W, Barry K, Tulum I, Kobayashi T, Harris S, Bringhurst F . Targeted ablation of the PTH/PTHrP receptor in osteocytes impairs bone structure and homeostatic calcemic responses. J Endocrinol. 2011; 209(1):21-32. PMC: 3783949. DOI: 10.1530/JOE-10-0308. View

18.

Nakashima T, Hayashi M, Fukunaga T, Kurata K, Oh-Hora M, Feng J . Evidence for osteocyte regulation of bone homeostasis through RANKL expression. Nat Med. 2011; 17(10):1231-4. DOI: 10.1038/nm.2452. View

19.

van Bezooijen R, Roelen B, Visser A, van der Wee-Pals L, de Wilt E, Karperien M . Sclerostin is an osteocyte-expressed negative regulator of bone formation, but not a classical BMP antagonist. J Exp Med. 2004; 199(6):805-14. PMC: 2212719. DOI: 10.1084/jem.20031454. View

20.

Baron R, Kneissel M . WNT signaling in bone homeostasis and disease: from human mutations to treatments. Nat Med. 2013; 19(2):179-92. DOI: 10.1038/nm.3074. View