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Impaired osteoblast function in GPRC6A null mice
Min Pi1, Lishu Zhang, Shu-Feng Lei
1Department of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA. mpi@uthsc.edu
Abstract:
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.
Insights
The GPRC6A receptor plays a crucial role in bone health. Its absence in mice leads to reduced bone mineral density and impaired osteoblast function, suggesting GPRC6A is vital for bone mineralization.
Area of Science:
- Molecular Biology
- Endocrinology
- Bone Biology
Background:
- G protein-coupled receptor 6A (GPRC6A) is an orphan receptor sensing amino acids, osteocalcin, and cations.
- GPRC6A knockout mice display metabolic issues, including osteopenia.
Purpose of the Study:
- To determine if GPRC6A deficiency directly impacts osteoblast function and bone metabolism.
- To investigate the association between GPRC6A gene variations and bone mineral density in humans.
Main Methods:
- Examined primary osteoblasts and bone marrow stromal cells from GPRC6A knockout mice.
- Utilized siRNA to knock down GPRC6A in MC3T3 osteoblasts.
- Analyzed GPRC6A gene polymorphisms in relation to bone mineral density in 1000 Caucasians.
Main Results:
- GPRC6A knockout mice showed decreased bone mineral density and reduced expression of key bone markers (osteocalcin, ALP, OPG, Runx2-II).
- Osteoblasts and BMSCs from knockout mice had impaired response to calcium, reduced alkaline phosphatase, and defective mineralization.
- GPRC6A knockdown reduced calcium-stimulated ERK activity in osteoblasts.
- GPRC6A gene polymorphisms were significantly linked to human spine bone mineral density.
Conclusions:
- GPRC6A directly regulates osteoblast-mediated bone mineralization.
- GPRC6A may mediate the anabolic effects of amino acids, osteocalcin, and divalent cations in bone.
- GPRC6A is a potential therapeutic target for bone disorders.
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