RRC ID 18153
Author Takahata Y, Takarada T, Hinoi E, Nakamura Y, Fujita H, Yoneda Y.
Title Osteoblastic γ-aminobutyric acid, type B receptors negatively regulate osteoblastogenesis toward disturbance of osteoclastogenesis mediated by receptor activator of nuclear factor κB ligand in mouse bone.
Journal J. Biol. Chem.
Abstract The prevailing view is that signaling machineries for the neurotransmitter GABA are also expressed by cells outside the CNS. In cultured murine calvarial osteoblasts, mRNA was constitutively expressed for both subunits 1 and 2 of metabotropic GABA(B) receptor (GABA(B)R), along with inhibition by the GABA(B)R agonist baclofen of cAMP formation, alkaline phosphatase (ALP) activity, and Ca(2+) accumulation. Moreover, baclofen significantly inhibited the transactivation of receptor activator of nuclear factor-κB ligand (RANKL) gene in a manner sensitive to a GABA(B)R antagonist, in addition to decreasing mRNA expression of bone morphogenetic protein-2 (BMP2), osteocalcin, and osterix. In osteoblastic MC3T3-E1 cells stably transfected with GABA(B)R1 subunit, significant reductions were seen in ALP activity and Ca(2+) accumulation, as well as mRNA expression of osteocalcin, osteopontin, and osterix. In cultured calvarial osteoblasts from GABA(B)R1-null mice exhibiting low bone mineral density in tibia and femur, by contrast, both ALP activity and Ca(2+) accumulation were significantly increased together with promoted expression of both mRNA and proteins for BMP2 and osterix. No significant change was seen in the number of multinucleated cells stained for tartrate-resistant acid phosphatase during the culture of osteoclasts prepared from GABA(B)R1-null mice, whereas a significant increase was seen in the number of tartrate-resistant acid phosphatase-positive multinucleated cells in co-culture of osteoclasts with osteoblasts isolated from GABA(B)R1-null mice. These results suggest that GABA(B)R is predominantly expressed by osteoblasts to negatively regulate osteoblastogenesis through down-regulation of BMP2 expression toward disturbance of osteoclastogenesis after down-regulation of RANKL expression in mouse bone.
Volume 286(38)
Pages 32906-17
Published 2011-9-23
DOI 10.1074/jbc.M111.253526
PII M111.253526
PMID 21828041
PMC PMC3190880
MeSH Animals Baclofen / pharmacology Biomarkers / metabolism Bone and Bones / cytology Bone and Bones / drug effects Bone and Bones / metabolism* Cell Differentiation / drug effects Genes, Reporter / genetics Luciferases / metabolism Mice Models, Biological Osteoblasts / cytology Osteoblasts / drug effects Osteoblasts / metabolism* Osteoclasts / cytology Osteoclasts / drug effects Osteoclasts / metabolism* Osteogenesis* / drug effects Osteogenesis* / genetics Phenotype RANK Ligand / metabolism* Receptors, GABA-B / deficiency Receptors, GABA-B / metabolism* Signal Transduction / drug effects Transcriptional Activation / drug effects Transcriptional Activation / genetics Transfection
IF 4.106
Times Cited 10
Human and Animal Cells MC3T3-E1 (RCB1126)