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First published online 16 October 2008
doi: 10.1242/dev.025825
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1 Laboratory of Reproductive and Developmental Toxicology, NIEHS/NIH, Research
Triangle Park, NC 27709, USA.
2 School of Dentistry, University Michigan, Ann Arbor, MI 48109, USA.
3 School of Dentistry, University of Missouri-Kansas City, Kansas City, MO
64108, USA.
4 Endocrine Unit, Massachusetts General Hospital and Harvard Medical School,
Boston, MA 02114, USA.
5 Dental Research Center, University of North Carolina, Chapel Hill, NC 27599,
USA.
* Author for correspondence (e-mail: mishina{at}umich.edu)
Accepted 24 September 2008
Bone morphogenetic proteins (BMPs) are known to induce ectopic bone. However, it is largely unknown how BMP signaling in osteoblasts directly regulates endogenous bone. This study investigated the mechanism by which BMP signaling through the type IA receptor (BMPR1A) regulates endogenous bone mass using an inducible Cre-loxP system. When BMPR1A in osteoblasts was conditionally disrupted during embryonic bone development, bone mass surprisingly was increased with upregulation of canonical Wnt signaling. Although levels of bone formation markers were modestly reduced, levels of resorption markers representing osteoclastogenesis were severely reduced, resulting in a net increase in bone mass. The reduction of osteoclastogenesis was primarily caused by Bmpr1a-deficiency in osteoblasts, at least through the RANKL-OPG pathway. Sclerostin (Sost) expression was downregulated by about 90% and SOST protein was undetectable in osteoblasts and osteocytes, whereas the Wnt signaling was upregulated. Treatment of Bmpr1a-deficient calvariae with sclerostin repressed the Wnt signaling and restored normal bone morphology. By gain of Smad-dependent BMPR1A signaling in mice, Sost expression was upregulated and osteoclastogenesis was increased. Finally, the Bmpr1a-deficient bone phenotype was rescued by enhancing BMPR1A signaling, with restoration of osteoclastogenesis. These findings demonstrate that BMPR1A signaling in osteoblasts restrain endogenous bone mass directly by upregulating osteoclastogenesis through the RANKL-OPG pathway, or indirectly by downregulating canonical Wnt signaling through sclerostin, a Wnt inhibitor and a bone mass mediator.
Key words: BMP receptor IA, Bone mass, Canonical Wnt signaling, Osteoblast, Osteoclastogenesis, Sclerostin, Mouse
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