Roles of osteocytes in phosphate metabolism

Abstract

Osteocytes are dendritic cells in the mineralized bone matrix that descend from osteoblasts. They play critical roles in controlling bone mass through the production of sclerostin, an inhibitor of bone formation, and receptor activator of nuclear factor κ B ligand, an inducer of osteoblastic bone resorption. Osteocytes also govern phosphate homeostasis through the production of fibroblast growth factor 23 (FGF23), which lowers serum phosphate levels by increasing renal phosphate excretion and reducing the synthesis of 1,25-dihydroxyvitamin D (1,25(OH)₂D), an active metabolite of vitamin D. The production of FGF23 in osteocytes is regulated by various local and systemic factors. Phosphate-regulating gene homologous to endopeptidase on X chromosome (PHEX), dentin matrix protein 1 (DMP1), and family with sequence similarity 20, member C function as local negative regulators of FGF23 production in osteocytes, and their inactivation causes the overproduction of FGF23 and hypophosphatemia. Sclerostin has been suggested to regulate the production of FGF23, which may link the two functions of osteocytes, namely, the control of bone mass and regulation of phosphate homeostasis. Systemic regulators of FGF23 production include 1,25(OH)₂D, phosphate, parathyroid hormone, insulin, iron, and inflammation. Therefore, the regulation of FGF23 in osteocytes is complex and multifactorial. Recent mouse studies have suggested that decreases in serum phosphate levels from youth to adulthood are caused by growth-related increases in FGF23 production by osteocytes, which are associated with the down-regulation of Phex and Dmp1.

Keywords: fibroblast growth factor 23; osteoblast; osteocyte; phosphate; regulation.

Figure 1

Roles of osteocytes in the control of bone mass and the regulation of phosphate metabolism. Osteocytes regulate bone formation and resorption through the production of sclerostin and RANKL. Sclerostin suppresses bone formation by inhibiting Wnt/β-catenin signaling. FGF23 produced by osteocytes plays central roles in phosphate metabolism by increasing renal phosphate excretion and decreasing the production of 1,25(OH)₂D. The production of FGF23 in osteocytes is influenced by various positive and negative regulators.

Figure 2

Growth-related changes in osteocytes cause a decrease in serum phosphate levels from youth to adulthood. The osteocytic expression of DMP1 and PHEX declines from youth to adulthood, which leads to an increase in the production of FGF23 and decrease in serum phosphate (Pi) levels. Gene responses of osteocytes to extracellular Pi are distinct between youth and adulthood (depicted as a shaded bar), suggesting growth-related differences in the sensitivity to the altered availability of Pi.