Impaired osteoblast function in GPRC6A null mice.
GPRC6A is a widely expressed orphan G protein-coupled receptor that senses extracellular amino acids, osteocalcin, and divalent cations in vitro. GPRC6A null (GPRC6A(-/-)) mice exhibit multiple metabolic abnormalities including osteopenia. To investigate whether the osseous abnormalities are a direct function of GPRC6A in osteoblasts, we examined the function of primary osteoblasts and bone marrow stromal cell cultures (BMSCs) in GPRC6A(-/-) mice. We confirmed that GPRC6A(-/-) mice exhibited a decrease in bone mineral density (BMD) associated with reduced expression of osteocalcin, ALP, osteoprotegerin, and Runx2-II transcripts in bone. Osteoblasts and BMSCs derived from GPRC6A(-/-) mice exhibited an attenuated response to extracellular calcium-stimulated extracellular signal-related kinase (ERK) activation, diminished alkaline phosphatase (ALP) expression, and impaired mineralization ex vivo. In addition, siRNA-mediated knockdown of GPRC6A in MC3T3 osteoblasts also resulted in a reduction in extracellular calcium-stimulated ERK activity. To explore the potential relevance of GPRC6A function in humans, we looked for an association between GPRC6A gene polymorphisms and BMD in a sample of 1000 unrelated American Caucasians. We found that GPRC6A gene polymorphisms were significantly associated with human spine BMD. These data indicate that GRPC6A directly participates in the regulation of osteoblast-mediated bone mineralization and may mediate the anabolic effects of extracellular amino acids, osteocalcin, and divalent cations in bone.
Pi
Min
M
Department of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA. mpi@uthsc.edu
Zhang
Lishu
L
Lei
Shu-Feng
SF
Huang
Min-Zhao
MZ
Zhu
Wenyu
W
Zhang
Jianghong
J
Shen
Hui
H
Deng
Hong-Wen
HW
Quarles
L Darryl
LD
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D015519:Bone Density / Q000235:genetics; D001854:Bone Marrow Cells / Q000378:metabolism; D002113:Calcification, Physiologic / Q000502:physiology; D002460:Cell Line; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D010006:Osteoblasts / Q000502:physiology*; D015675:Osteocalcin / Q000235:genetics; D053244:Osteoprotegerin / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D043562:Receptors, G-Protein-Coupled / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D017154:Stromal Cells / Q000378:metabolism
C488584:GPRC6A protein, human; C515750:GPRC6A protein, mouse; D053244:Osteoprotegerin; D043562:Receptors, G-Protein-Coupled; D015675:Osteocalcin; D000469:Alkaline Phosphatase