Gsα Controls Cortical Bone Quality by Regulating Osteoclast Differentiation via cAMP/PKA and β-Catenin Pathways.
Skeletal bone formation and maintenance requires coordinate functions of several cell types, including bone forming osteoblasts and bone resorbing osteoclasts. Gsα, the stimulatory subunit of heterotrimeric G proteins, activates downstream signaling through cAMP and plays important roles in skeletal development by regulating osteoblast differentiation. Here, we demonstrate that Gsα signaling also regulates osteoclast differentiation during bone modeling and remodeling. Gnas, the gene encoding Gsα, is imprinted. Mice with paternal allele deletion of Gnas (Gnas+/p-) have defects in cortical bone quality and strength during early development (bone modeling) that persist during adult bone remodeling. Reduced bone quality in Gnas+/p-mice was associated with increased endosteal osteoclast numbers, with no significant effects on osteoblast number and function. Osteoclast differentiation and resorption activity was enhanced in Gnas+/p-cells. During differentiation, Gnas+/p-cells showed diminished pCREB, β-catenin and cyclin D1, and enhanced Nfatc1 levels, conditions favoring osteoclastogenesis. Forskolin treatment increased pCREB and rescued osteoclast differentiation in Gnas+/p-by reducing Nfatc1 levels. Cortical bone of Gnas+/p-mice showed elevated expression of Wnt inhibitors sclerostin and Sfrp4 consistent with reduced Wnt/β-catenin signaling. Our data identify a new role for Gsα signaling in maintaining bone quality by regulating osteoclast differentiation and function through cAMP/PKA and Wnt/β-catenin pathways.
Department of Orthopaedic Surgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.|Center for Research in FOP and Related Disorders, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
Girish
G
Ramaswamy
Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
Hyunsoo
H
Kim
Department of Orthopaedic Surgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.|Center for Research in FOP and Related Disorders, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
Deyu
D
Zhang
Department of Orthopaedic Surgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.|Center for Research in FOP and Related Disorders, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
Vitali
V
Lounev
Division of Endocrinology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Joy Y
JY
Wu
Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
Yongwon
Y
Choi
Department of Orthopaedic Surgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.|Center for Research in FOP and Related Disorders, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.|Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
Frederick S
FS
Kaplan
Division of Geriatric Medicine and Gerontology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Robert J
RJ
Pignolo
Department of Orthopaedic Surgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.|Center for Research in FOP and Related Disorders, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.|Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
Eileen M
EM
Shore
D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D002864:Chromogranins / Q000235:genetics / Q000378:metabolism*; D000071538:Cortical Bone / Q000166:cytology* / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D019938:Cyclin D1 / Q000378:metabolism; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D050778:NFATC Transcription Factors / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism*; D015398:Signal Transduction; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
D002864:Chromogranins; D017362:Cyclic AMP Response Element-Binding Protein; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D051153:Wnt Proteins; D051176:beta Catenin; D019938:Cyclin D1; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; C498642:Gnas protein, mouse; D019205:GTP-Binding Protein alpha Subunits, Gs