The P2Y13 receptor regulates phosphate metabolism and FGF-23 secretion with effects on skeletal development.
Purinergic signaling mediates many cellular processes, including embryonic development and regulation of endocrine signaling. The ADP P2Y13 receptor is known to regulate bone and stem cells activities, although relatively little is known about its role in bone development. In this study we demonstrate, using contemporary techniques, that deletion of the P2Y13 receptor results in an age-dependent skeletal phenotype that is governed by changes in phosphate metabolism and hormone levels. Neonatal and postnatal (2 wk) P2Y13 receptor-knockout (KO) mice were indistinguishable from their wild-type (WT) littermate controls. A clear bone phenotype was observed in young (4-wk-old) KO mice compared WT controls, with 14% more trabecular bone, 35% more osteoblasts, 73% fewer osteoclasts, and a 17% thicker growth plate. Mature (>10 wk of age) KO mice showed the opposite bone phenotype, with 14% less trabecular bone, 22% fewer osteoblasts, and 10% thinner growth plate. This age-dependent phenotype correlated with serum fibroblast growth factor-23 (FGF-23) and phosphorus levels that were 65 and 16% higher, respectively, in young KO mice but remained unchanged in mature mice. These findings provide novel insights for the role of the P2Y13 receptor in skeletal development via coordination with hormonal regulators of phosphate homeostasis.
1The Mellanby Centre for Bone Research, Department of Human Metabolism, The University of Sheffield, Beech Hill Rd., Sheffield, S10 2RX, UK. a.gartland@sheffield.ac.uk.
Ning
N
Wang
Bernard
B
Robaye
Fatima
F
Gossiel
Jean-Marie
JM
Boeynaems
Alison
A
Gartland
D000818:Animals; D000831:Animals, Newborn; D015519:Bone Density; D001846:Bone Development; D001862:Bone Resorption; D001842:Bone and Bones / Q000378:metabolism*; D002454:Cell Differentiation; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010006:Osteoblasts / Q000166:cytology; D010010:Osteoclasts / Q000166:cytology; D010641:Phenotype; D010710:Phosphates / Q000378:metabolism*; D018048:Receptors, Purinergic P2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013977:Tibia / Q000473:pathology; D013997:Time Factors; D055114:X-Ray Microtomography
C000717427:FGF23 protein, human; C000717428:Fgf23 protein, mouse; C486689:P2ry13 protein, mouse; D010710:Phosphates; D018048:Receptors, Purinergic P2; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23
ADP; bone phenotype; knockout; purinergic