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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Activating Transcription Factor 4 / genetics
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Activating Transcription Factor 4 / metabolism
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Animals
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Bone Density
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Bone Remodeling / physiology*
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Bone and Bones / cytology
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Bone and Bones / physiology
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Cell Differentiation / physiology
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Cells, Cultured
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Chondrocytes / cytology
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Chondrocytes / metabolism
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Collagen / genetics
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Collagen / metabolism
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Cyclic AMP / metabolism
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Cyclic AMP Response Element-Binding Protein / metabolism
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Cyclic AMP-Dependent Protein Kinases / metabolism
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Embryo, Mammalian / anatomy & histology
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Embryo, Mammalian / physiology
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Gene Expression Regulation, Developmental
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Integrin-Binding Sialoprotein
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Mice
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Mice, Knockout
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Osteoblasts / cytology
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Osteoblasts / physiology
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Osteocalcin / metabolism
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Osteoclasts / cytology
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Osteoclasts / metabolism
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Osteogenesis / physiology*
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Osteoporosis / physiopathology
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Protein Isoforms / genetics
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Protein Isoforms / metabolism*
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Receptors, G-Protein-Coupled / genetics
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Receptors, G-Protein-Coupled / metabolism*
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Sialoglycoproteins / metabolism
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Signal Transduction / physiology
Substances
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Atf4 protein, mouse
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Creb1 protein, mouse
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Cyclic AMP Response Element-Binding Protein
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Ibsp protein, mouse
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Integrin-Binding Sialoprotein
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LGR4 protein, mouse
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Protein Isoforms
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Receptors, G-Protein-Coupled
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Sialoglycoproteins
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Osteocalcin
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Activating Transcription Factor 4
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Collagen
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Cyclic AMP
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Cyclic AMP-Dependent Protein Kinases