Deficiency of the G-protein alpha-subunit G(s)alpha in osteoblasts leads to differential effects on trabecular and cortical bone.
The G-protein alpha-subunit G(s)alpha is required for the intracellular cAMP responses to hormones and other agonists. G(s)alpha is known to mediate the cAMP response to parathyroid hormone and other hormones and cytokines in bone and cartilage. To analyze the in vivo role of G(s)alpha signaling in osteoblasts, we developed mice with osteoblast/osteocyte-specific G(s)alpha deficiency (BGsKO) by mating G(s)alpha-floxed mice with collagen Ialpha1 promoter-Cre recombinase transgenic mice. Early skeletal development was normal in BGsKO mice, because formation of the initial cartilage template and bone collar was unaffected. The chondrocytic zones of the growth plates also appeared normal in BGsKO mice. BGsKO mice had a defect in the formation of the primary spongiosa with reduced immature osteoid (new bone formation) and overall length, which led to reduced trabecular bone volume. In contrast, cortical bone was thickened with narrowing of the bone marrow cavity. This was probably due to decreased cortical bone resorption, because osteoclasts were markedly reduced on the endosteal surface of cortical bone. In addition, the expression of alkaline phosphatase, an early osteoblastic differentiation marker, was normal, whereas the expression of the late osteoblast differentiation markers osteopontin and osteocalcin was reduced, suggesting that the number of mature osteoblasts in bone is reduced. Expression of the osteoclast-stimulating factor receptor activator of NF-kappaB ligand was also reduced. Overall, our findings have similarities to parathyroid hormone null mice and confirm that the differential effects of parathyroid hormone on trabecular and cortical bone are primarily mediated via G(s)alpha in osteoblasts. Osteoblast-specific G(s)alpha deficiency leads to reduced bone turnover.
Sakamoto
Akio
A
Metabolic Diseases Branch, NIDDK, National Institutes of Health, Bethesda, Maryland 20892, USA.
Chen
Min
M
Nakamura
Takashi
T
Xie
Tao
T
Karsenty
Gerard
G
Weinstein
Lee S
LS
D000135:Acid Phosphatase / Q000494:pharmacology; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D001842:Bone and Bones / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D002356:Cartilage / Q000378:metabolism; D002454:Cell Differentiation; D019902:Chondrocytes / Q000378:metabolism; D024042:Collagen Type I / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D000242:Cyclic AMP / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D017931:DNA Primers / Q000737:chemistry; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000737:chemistry* / Q000378:metabolism; D005786:Gene Expression Regulation; D007527:Isoenzymes / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008954:Models, Biological; D008957:Models, Genetic; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D015675:Osteocalcin / Q000378:metabolism; D053495:Osteopontin; D010641:Phenotype; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012795:Sialoglycoproteins / Q000378:metabolism; D015398:Signal Transduction; D012886:Skull / Q000378:metabolism; D000071681:Tartrate-Resistant Acid Phosphatase; D013997:Time Factors
D002352:Carrier Proteins; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D016207:Cytokines; D017931:DNA Primers; D007527:Isoenzymes; D008562:Membrane Glycoproteins; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D012795:Sialoglycoproteins; C506896:Spp1 protein, mouse; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse; D015675:Osteocalcin; D053495:Osteopontin; D000242:Cyclic AMP; D000469:Alkaline Phosphatase; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase; D019205:GTP-Binding Protein alpha Subunits, Gs