Regulation of bone formation and remodeling by G-protein-coupled receptor 48
Author:
Luo Jian123, Zhou Wei2, Zhou Xin4, Li Dali12, Weng Jinsheng2, Yi Zhengfang1, Cho Sung Gook2, Li Chenghai1, Yi Tingfang2, Wu Xiushan3, Li Xiao-Ying5, de Crombrugghe Benoit4, Höök Magnus2, Liu Mingyao12
Affiliation:
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. College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081,China. 4. University of Texas M. D. Anderson Cancer Center, Houston, TX 77030,USA. 5. Shanghai Institute of Endocrinology and Metabolism, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Abstract
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.
Publisher
The Company of Biologists
Subject
Developmental Biology,Molecular Biology
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