No evidence for a bone phenotype in GPRC6A knockout mice under normal physiological conditions

Wellendorph, Petrine; Johansen, Lars Dan; Jensen, Anders A.; Casanova, Emilio; Gassmann, Martin; Deprez, Pierre; Clément-Lacroix, Philippe; Bettler, Bernhard; Bräuner‐Osborne, Hans

doi:10.1677/jme-08-0149

Cited by 64 publications

(63 citation statements)

References 58 publications

(66 reference statements)

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“…(30) Other studies have suggested the presence of an alternate calcium receptor in bone, GPRC6A, that might be involved in skeletal mineralization, (31,32) although conflicting reports on the skeletal phenotype of GPRC6A null mice have been published recently. (32,33) Our results cannot exclude the possibility that other receptor mechanisms or nonreceptor mechanisms are involved in mineralization of bone via increased [Ca 2þ ] e .…”

Section: Discussionmentioning

confidence: 74%

The calcium-sensing receptor and 25-hydroxyvitamin D–1α-hydroxylase interact to modulate skeletal growth and bone turnover

Richard

Huo

Samadfam

et al. 2010

Journal of Bone and Mineral Research

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We examined parathyroid and skeletal function in 3-month-old mice expressing the null mutation for 25-hydroxyvitamin D-1a-hydroxylase [1a(OH)ase À/À ] and in mice expressing the null mutation for both the 1a(OH)ase and the calcium-sensing receptor [Casr À/À 1a(OH)ase À/À ] genes. On a normal diet, all mice were hypocalcemic, with markedly increased parathyroid hormone (PTH), increased trabecular bone volume, increased osteoblast activity, poorly mineralized bone, enlarged and distorted cartilaginous growth plates, and marked growth retardation, especially in the compound mutants. Osteoclast numbers were reduced in the Casr À/À 1a(OH)ase À/À mice. On a high-lactose, high-calcium, high-phosphorus ''rescue'' diet, serum calcium and PTH were normal in the 1a(OH)ase À/À mice but increased in the Casr À/À 1a(OH)ase À/À mice with reduced serum phosphorus. Growth plate architecture and mineralization were improved in both mutants, but linear growth of the double mutants remained abnormal. Mineralization of bone improved in all mice, but osteoblast activity and trabecular bone volume remained elevated in the Casr À/À 1a(OH)ase À/À mice. These studies support a role for calcium-stimulated maturation of the cartilaginous growth plate and mineralization of the growth plate and bone and calcium-stimulated CaSR-mediated effects on bone resorption. PTH-mediated bone resorption may require calcium-stimulated CaSR-mediated enhancement of osteoclastic activity. ß

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Section: Discussionmentioning

confidence: 74%

The calcium-sensing receptor and 25-hydroxyvitamin D–1α-hydroxylase interact to modulate skeletal growth and bone turnover

Richard

Huo

Samadfam

et al. 2010

Journal of Bone and Mineral Research

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“…This restricted pattern of expression in gonads may explain why osteocalcin can increase testosterone production from testis, but not from ovaries. The investigation of the role of Gprc6a in regulation of bone mass accrual has generated contradicting findings (Pi et al 2008, Wellendorph et al 2009, and thus this aspect of Gprc6a function will not be developed further in this review.…”

Section: Osteocalcin Acts On Leydig Cells Through Its Receptor Gprc6amentioning

confidence: 99%

The mutual dependence between bone and gonads

Karsenty¹

2012

Journal of Endocrinology

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It has long been known that sex steroid hormones regulate bone mass accrual. This observation raises the testable hypothesis that bone may in turn regulate the synthesis and secretion of sex steroid hormones in one or both genders. This hypothesis is comprised within a more general hypothesis that bone mass, energy metabolism, and reproduction are regulated coordinately. The identification of osteocalcin as an osteoblast-specific secreted molecule allows us to address this question in molecular terms. This review details how the regulation of male fertility by osteocalcin was unraveled, and how osteocalcin signaling in Leydig cells of the testis occurs. It also discusses the implication of this novel mode of regulation of testosterone synthesis observed in males but not in females.

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“…A promiscuous range of nonselective ligands and a broad but low-level expression profile have complicated elucidation of the physiologic function of this receptor. Based on studies in GPRC6A knockout mice, the receptor is now suggested to be involved in inflammatory, metabolic, and endocrine regulation; however, the specific role of GPRC6A is still unknown (Pi et al, 2008(Pi et al, , 2011Wellendorph et al, 2009;Rossol et al, 2012;Smajilovic et al, 2013;Clemmensen et al, 2013a,b).…”

Section: Introductionmentioning

confidence: 99%

Delineation of the GPRC6A Receptor Signaling Pathways Using a Mammalian Cell Line Stably Expressing the Receptor

Jacobsen

Nørskov-Lauritsen

Thomsen

et al. 2013

J Pharmacol Exp Ther

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The GPRC6A receptor is a recently "deorphanized" class C G protein-coupled receptor. We and others have shown that this receptor is coactivated by basic L-a-amino acids and divalent cations, whereas other groups have also suggested osteocalcin and testosterone to be agonists. Likewise, the GPRC6A receptor has been suggested to couple to multiple G protein classes albeit via indirect methods. Thus, the exact ligand preferences and signaling pathways are yet to be elucidated. In the present study, we generated a Chinese hamster ovary (CHO) cell line that stably expresses mouse GPRC6A. In an effort to establish fully the signaling properties of the receptor, we tested representatives of four previously reported GPRC6A agonist classes for activity in the G q , G s , G i , and extracellular-signal regulated kinase signaling pathways. Our results confirm that GPRC6A is activated by basic L-a-amino acids and divalent cations, and for the first time, we conclusively show that these responses are mediated through the G q pathway. We were not able to confirm previously published data demonstrating G i -and G s -mediated signaling; neither could we detect agonistic activity of testosterone and osteocalcin. Generation of the stable CHO cell line with robust receptor responsiveness and optimization of the highly sensitive homogeneous time resolved fluorescence technology allow fast assessment of G q activation without previous manipulations like cotransfection of mutated G proteins. This cell-based assay system for GPRC6A is thus useful in highthroughput screening for novel pharmacological tool compounds, which are necessary to unravel the physiologic function of the receptor.

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No evidence for a bone phenotype in GPRC6A knockout mice under normal physiological conditions

Cited by 64 publications

References 58 publications

The calcium-sensing receptor and 25-hydroxyvitamin D–1α-hydroxylase interact to modulate skeletal growth and bone turnover

The calcium-sensing receptor and 25-hydroxyvitamin D–1α-hydroxylase interact to modulate skeletal growth and bone turnover

The mutual dependence between bone and gonads

Delineation of the GPRC6A Receptor Signaling Pathways Using a Mammalian Cell Line Stably Expressing the Receptor

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