The P2Y ₁₃ receptor regulates phosphate metabolism and FGF‐23 secretion with effects on skeletal development

Abstract

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.

Osteoclast differentiation from human blood precursors on biomimetic calcium-phosphate substrates

“…An in vivo study on phosphate metabolism in ADP P2Y13 receptor-knockout mice demonstrated that young mice with 16 % higher serum phosphorous level compared to mature mice had 73 % fewer osteoclasts [52].…”

Biphasic Effects of Vitamin D and FGF23 on Human Osteoclast Biology

“…The authors discussed the need for further studies to investigate the role of increased FGF23 levels on bone homeostasis [27]. Second, the P2Y 13 receptor has been shown to regulate phosphate metabolism and FGF23 secretion, with significant effects on skeletal development; in this comparison between WT and P2Y 13 KO mice, the KO mice displayed significantly more osteoblasts and less osteoclasts than WT, while their FGF23 level was 65 % higher [28]. However, in these P2Y 13 KO mice, phosphate levels increased and alkaline phosphatase decreased, thus requiring to be cautious on a potential direct link between FGF23 and osteoclasts in this model.…”

The role of purinergic signalling in the musculoskeletal system

“…A follow up study by the same group demonstrated that P2Y13 knockout mice display enhanced osteogenic responses to mechanical loading which the authors attribute to reduced levels of extracellular ATP metabolism . The P2Y13 receptor has also been shown to play an important role in phosphate metabolism (Wang et al, 2014) and the terminal differentiation of osteoprogenitor cells into osteoblasts or adipocytes (Biver et al, 2013).…”