Regulation of bone formation and remodeling by G-protein-coupled receptor 48.
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.
Luo
Jian
J
The Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
Zhou
Wei
W
Zhou
Xin
X
Li
Dali
D
Weng
Jinsheng
J
Yi
Zhengfang
Z
Cho
Sung Gook
SG
Li
Chenghai
C
Yi
Tingfang
T
Wu
Xiushan
X
Li
Xiao-Ying
XY
de Crombrugghe
Benoit
B
Höök
Magnus
M
Liu
Mingyao
M
D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015519:Bone Density; D016723:Bone Remodeling / Q000502:physiology*; D001842:Bone and Bones / Q000166:cytology / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D019902:Chondrocytes / Q000166:cytology / Q000378:metabolism; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004622:Embryo, Mammalian / Q000033:anatomy & histology / Q000502:physiology; D018507:Gene Expression Regulation, Developmental; D058574:Integrin-Binding Sialoprotein; D051379:Mice; D018345:Mice, Knockout; D010006:Osteoblasts / Q000166:cytology / Q000502:physiology; D015675:Osteocalcin / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism; D010012:Osteogenesis / Q000502:physiology*; D010024:Osteoporosis / Q000503:physiopathology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D012795:Sialoglycoproteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
C081452:Atf4 protein, mouse; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; C546872:Ibsp protein, mouse; D058574:Integrin-Binding Sialoprotein; C496200:LGR4 protein, mouse; D020033:Protein Isoforms; D043562:Receptors, G-Protein-Coupled; D012795:Sialoglycoproteins; D015675:Osteocalcin; D051701:Activating Transcription Factor 4; D003094:Collagen; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases