The G-Protein-Coupled Receptor GPR103 Regulates Bone Formation

Abstract

GPR103 is a G-protein-coupled receptor with reported expression in brain, heart, kidney, adrenal gland, retina, and testis. It encodes a 455-amino-acid protein homologous to neuropeptide FF2, neuropeptide Y2, and galanin GalR1 receptors. Its natural ligand was recently identified as 26RFa, a novel human RF-amide-related peptide with orexigenic activity. To identify the function of GPR103, we generated GPR103-deficient mice. Homozygous mutant mice were viable and fertile. Their body weight was undistinguishable from that of their wild-type littermates. Histological analysis revealed that GPR103 ؊/؊ mice exhibited a thinned osteochondral growth plate, a thickening of trabecular branches, and a reduction in osteoclast number, suggestive of an early arrest of osteochondral bone formation. Microcomputed tomography confirmed the reduction in trabecular bone and connective tissue densities in GPR103 knockout animals. Whole-body radiography followed by morphometric analysis revealed a kyphosis in mutant animals. Reverse transcription-PCR analysis showed that GPR103 was expressed in human skull, mouse spine, and several osteoblast cell lines. Dexamethasone, a known inhibitor of osteoblast growth and inducer of osteoblast differentiation, inhibited GPR103 expression in human osteoblast primary cultures. Altogether, these results suggest that osteopenia in GPR103 ؊/؊ mice may be mediated directly by the loss of GPR103 expression in bone.

Nuclear Factor I X Deficiency Causes Brain Malformation and Severe Skeletal Defects

“…It is assumed that the loss of tetranectin leads to the softening of the extracellular bone matrix and the intervertebral disk, which then results in spinal deformation. In accordance with that assumption, reduced tetranectin expression was also reported in mice deficient for the G-proteincoupled receptor GPR103, and these mice also developed kyphosis and reduction of trabecular bone (3). Taken together, the observed kyphotic phenotype in NFIX-deficient mice is consistent with reduced expression of tetranectin and suggests that tetranectin is a new downstream target of NFIX.…”

MOLECULAR EVOLUTION OF GPCRS: 26Rfa/GPR103

“…Mice deficient in the receptor for 26RFa/QRFP (Qrfpr) suffer from osteopenia (Baribault et al 2006). This observation indicates that 26RFa/QRFP plays a major role in bone formation, via QRFPR that is expressed in bone (Baribault et al 2006).…”

The role of RFamide peptides in feeding

“…26RFa QRFP and GPR103 are expressed in the VMN and the lateral hypothalamus, areas of the brain critically associated with the control of food intake (Chartrel et al 2003, Fukusumi et al 2003, Baribault et al 2006. In fact, in mice, the expression of the peptides is limited almost exclusively to neurons in these two hypothalamic nuclei (Chartrel et al 2003).…”

“…In addition to pharmacological evidence showing a role for QRFP and 26RFa in food intake, the expression of mRNA for the QRFP/26RFa precursor, measured using real-time reverse transcription (RT)-PCR of dissected tissues, is elevated in the 'hypothalamic' region of fasted mice, as well as in obese ob/ob and db/db mice (Takayasu et al 2006). Importantly, a study looking at bone formation in GPR103-knockout mice reported that body weights are similar between wild-type and knockout littermates, although no data were shown and it was not made clear how the animals were housed or fed (Baribault et al 2006). QRFP has also been reported to have direct effects on aldosterone secretion from rat adrenal gland (Fukusumi et al 2003).…”