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First published online 15 July 2009
doi: 10.1242/dev.033571

Development 136, 2747-2756 (2009)
Published by The Company of Biologists 2009
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Regulation of bone formation and remodeling by G-protein-coupled receptor 48

Jian Luo1,2,4, Wei Zhou2, Xin Zhou3, Dali Li1,2, Jinsheng Weng2, Zhengfang Yi1, Sung Gook Cho2, Chenghai Li1, Tingfang Yi2, Xiushan Wu4, Xiao-Ying Li5, Benoit de Crombrugghe3, Magnus Höök2 and Mingyao Liu1,2,*

1 The Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
2 Alkek Institute of Biosciences and Technology, Texas A&M University System Health Science Center, Houston, TX 77030, USA.
3 University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
4 College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, China.
5 Shanghai Institute of Endocrinology and Metabolism, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.

* Author for correspondence (mliu{at}ibt.tamhsc.edu)

Accepted 11 June 2009

G-protein-coupled receptor (GPCR) 48 (Gpr48; Lgr4), a newly discovered member of the glycoprotein hormone receptor subfamily of GPCRs, is an orphan GPCR of unknown function. Using a knockout mouse model, we have characterized the essential roles of Gpr48 in bone formation and remodeling. Deletion of Gpr48 in mice results in a dramatic delay in osteoblast differentiation and mineralization, but not in chondrocyte proliferation and maturation, during embryonic bone formation. Postnatal bone remodeling is also significantly affected in Gpr48-/- mice, including the kinetic indices of bone formation rate, bone mineral density and osteoid formation, whereas the activity and number of osteoclasts are increased as assessed by tartrate-resistant acid phosphatase staining. Examination of the molecular mechanism of Gpr48 action in bone formation revealed that Gpr48 can activate the cAMP-PKA-CREB signaling pathway to regulate the expression level of Atf4 in osteoblasts. Furthermore, we show that Gpr48 significantly downregulates the expression levels of Atf4 target genes/proteins, such as osteocalcin (Ocn; Bglap2), bone sialoprotein (Bsp; Ibsp) and collagen. Together, our data demonstrate that Gpr48 regulates bone formation and remodeling through the cAMP-PKA-Atf4 signaling pathway.

Key words: Gpr48 (Lgr4), Atf4, Bone formation, Bone remodeling, Mouse


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