Previous studies by the investigative group have provided evidence for a cation-sensing mechanism in osteoblasts that regulates osteoblast-mediated bone formation. Initial in vivo investigations of aluminum-induced neo- osteogenesis led to the discovery that cations stimulate de novo bone formation through activation of osteoblastic precursors residing in the bone marrow. More recently, in vitro investigations in the prototypic MC3T3-E1 osteoblast model indicate that aluminum and other polyvalent cations directly stimulate pre-osteoblast proliferation through G-protein coupled receptor activation and protein kinase C (PKC)-dependent signaling pathways. The cation specificity and relative affinities for osteoblast stimulation resembles that of the recently cloned parathyroid calcium receptor (PCaR1). However, definite knowledge of a similar cation sensing receptor in osteoblasts is lacking. The investigators indicate that they have successfully employed a PCaR1 homology-based polymerase chain reaction screening strategy to isolate and clone, from osteoblasts, a novel and putative G-protein coupled receptor, ObCaRs (for Osteoblast Cation-sensing Receptor-related Sequence), that is highly expressed in MC3T3-E1 osteoblasts. ObCaRs is highly homologous to PCaR1, but is a separate, closely-related gene located on a different chromosome. In the proposed investigations, plans are advanced to continue studies of the mechanisms by which aluminum and other cations stimulate osteoblast function. Efforts will be directed towards advancing the hypothesis that a cation-sensing PCaR1-like receptor plays an important regulatory role in osteoblast-mediated bone formation. Specifically, the investigators will complete their functional characterization of the PCaR1-like cation-sensing mechanism in osteoblasts by evaluating the ability of cations and calcimimetics to stimulate the endogenous receptor in vitro, by examining cation ligand- receptor interactions in osteoblast membranes and by defining the cation receptor coupling to its intracellular effectors. In addition, they will screen osteoblast cDNA libraries to isolate the full length ObCaRs cDNA. Further studies will examine the tissue distribution and intraosseous expression of the ObCaRs using Northern and in situ hybridization approaches. To evaluate the cation-sensing properties of ObCaRs, the investigators will functionally express in host cells this putative cation-sensing receptor and use antisense cDNA to disrupt the expression of the endogenous ObCaRs receptor in MC3T3-E1 osteoblasts. It is suggested that information derived from these studies will provide vital data regarding the cation-sensing mechanism in osteoblasts. It is hoped that such kn owledge will permit a better understanding of physiologic and pharmacologic control of de novo bone formation by cations that may lead to new therapies for osteopenic disorders.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
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Special Emphasis Panel (ZRG4-ORTH (02))
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Duke University
Internal Medicine/Medicine
Schools of Medicine
United States
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Xiao, Zhousheng; Baudry, Jerome; Cao, Li et al. (2018) Polycystin-1 interacts with TAZ to stimulate osteoblastogenesis and inhibit adipogenesis. J Clin Invest 128:157-174
Pi, Min; Kapoor, Karan; Ye, Ruisong et al. (2018) GPCR6A Is a Molecular Target for the Natural Products Gallate and EGCG in Green Tea. Mol Nutr Food Res 62:e1700770
Ye, Ruisong; Pi, Min; Cox, John V et al. (2017) CRISPR/Cas9 targeting of GPRC6A suppresses prostate cancer tumorigenesis in a human xenograft model. J Exp Clin Cancer Res 36:90
Pi, Min; Kapoor, Karan; Ye, Ruisong et al. (2016) Evidence for Osteocalcin Binding and Activation of GPRC6A in ?-Cells. Endocrinology 157:1866-80
Pi, Min; Kapoor, Karan; Wu, Yunpeng et al. (2015) Structural and Functional Evidence for Testosterone Activation of GPRC6A in Peripheral Tissues. Mol Endocrinol 29:1759-73
Pi, Min; Quarles, L Darryl (2012) GPRC6A regulates prostate cancer progression. Prostate 72:399-409
Pi, Min; Quarles, L Darryl (2012) Multiligand specificity and wide tissue expression of GPRC6A reveals new endocrine networks. Endocrinology 153:2062-9
Dreaden, Erik C; Gryder, Berkley E; Austin, Lauren A et al. (2012) Antiandrogen gold nanoparticles dual-target and overcome treatment resistance in hormone-insensitive prostate cancer cells. Bioconjug Chem 23:1507-12
Pi, Min; Wu, Yunpeng; Lenchik, Nataliya I et al. (2012) GPRC6A mediates the effects of L-arginine on insulin secretion in mouse pancreatic islets. Endocrinology 153:4608-15
Pi, Min; Wu, Yunpeng; Quarles, L Darryl (2011) GPRC6A mediates responses to osteocalcin in ?-cells in vitro and pancreas in vivo. J Bone Miner Res 26:1680-3

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