Osteocytes and the pathogenesis of hypophosphatemic rickets

Front Endocrinol (Lausanne). 2022 Sep 29:13:1005189. doi: 10.3389/fendo.2022.1005189. eCollection 2022.


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.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium-Binding Proteins / metabolism
  • Endopeptidases / metabolism
  • Extracellular Matrix Proteins / genetics
  • Familial Hypophosphatemic Rickets* / genetics
  • Fibroblast Growth Factors / metabolism
  • Hydroxyapatites / metabolism
  • Mice
  • Osteocytes / metabolism
  • Phosphates
  • Phosphorus / metabolism
  • Receptors, Fibroblast Growth Factor / metabolism
  • Rickets, Hypophosphatemic* / metabolism
  • beta Catenin / metabolism


  • Calcium-Binding Proteins
  • Extracellular Matrix Proteins
  • FAM20C protein, mouse
  • Hydroxyapatites
  • Phosphates
  • Receptors, Fibroblast Growth Factor
  • beta Catenin
  • Phosphorus
  • Fibroblast Growth Factors
  • Endopeptidases