Osteocytes and the pathogenesis of hypophosphatemic rickets

Abstract

Since phosphorus is a component of hydroxyapatite, its prolonged deprivation affects bone mineralization. Fibroblast growth factor 23 (FGF23) is essential for maintaining phosphate homeostasis and is mainly produced by osteocytes. FGF23 increases the excretion of inorganic phosphate (Pi) and decreases the production of 1,25-dihydroxyvitamin D in the kidneys. Osteocytes are cells of osteoblastic lineage that have undergone terminal differentiation and become embedded in mineralized bone matrix. Osteocytes express FGF23 and other multiple genes responsible for hereditary hypophosphatemic rickets, which include phosphate-regulating gene homologous to endopeptidase on X chromosome (PHEX), dentin matrix protein 1 (DMP1), and family with sequence similarity 20, member C (FAM20C). Since inactivating mutations in PHEX, DMP1, and FAM20C boost the production of FGF23, these molecules might be considered as local negative regulators of FGF23. Mouse studies have suggested that enhanced FGF receptor (FGFR) signaling is involved in the overproduction of FGF23 in PHEX-deficient X-linked hypophosphatemic rickets (XLH) and DMP1-deficient autosomal recessive hypophosphatemic rickets type 1. Since FGFR is involved in the transduction of signals evoked by extracellular Pi, Pi sensing in osteocytes may be abnormal in these diseases. Serum levels of sclerostin, an inhibitor Wnt/β-catenin signaling secreted by osteocytes, are increased in XLH patients, and mouse studies have suggested the potential of inhibiting sclerostin as a new therapeutic option for the disease. The elucidation of complex abnormalities in the osteocytes of FGF23-related hypophosphatemic diseases will provide a more detailed understanding of their pathogenesis and more effective treatments.

Keywords: fibroblast growth factor 23; mutation; osteocyte; phosphate; rickets.

Figure 1

Complex abnormalities in osteocytes of Phex-deficient Hyp mice. In Hyp osteocytes, the expression of Fgfr1 is increased and enhanced FGFR signaling may underlie the overproduction of FGF23. The overproduction of FGF23 leads to the renal wasting of inorganic phosphate (Pi) and impaired vitamin D metabolism. Hyp osteocytes produce an increased amount of sclerostin, which may stimulate the production of FGF23. The production of osteopontin is up-regulated in Hyp osteocytes, which impairs skeletal mineralization. The expression of Dmp1 and Fam20c is also increased.