Osteocyte regulation of phosphate homeostasis and bone mineralization underlies the pathophysiology of the heritable disorders of rickets and osteomalacia

Abstract

Although recent studies have established that osteocytes function as secretory cells that regulate phosphate metabolism, the biomolecular mechanism(s) underlying these effects remain incompletely defined. However, investigations focusing on the pathogenesis of X-linked hypophosphatemia (XLH), autosomal dominant hypophosphatemic rickets (ADHR), and autosomal recessive hypophosphatemic rickets (ARHR), heritable disorders characterized by abnormal renal phosphate wasting and bone mineralization, have clearly implicated FGF23 as a central factor in osteocytes underlying renal phosphate wasting, documented new molecular pathways regulating FGF23 production, and revealed complementary abnormalities in osteocytes that regulate bone mineralization. The seminal observations leading to these discoveries were the following: 1) mutations in FGF23 cause ADHR by limiting cleavage of the bioactive intact molecule, at a subtilisin-like protein convertase (SPC) site, resulting in increased circulating FGF23 levels and hypophosphatemia; 2) mutations in DMP1 cause ARHR, not only by increasing serum FGF23, albeit by enhanced production and not limited cleavage, but also by limiting production of the active DMP1 component, the C-terminal fragment, resulting in dysregulated production of DKK1 and β-catenin, which contributes to impaired bone mineralization; and 3) mutations in PHEX cause XLH both by altering FGF23 proteolysis and production and causing dysregulated production of DKK1 and β-catenin, similar to abnormalities in ADHR and ARHR, but secondary to different central pathophysiological events. These discoveries indicate that ADHR, XLH, and ARHR represent three related heritable hypophosphatemic diseases that arise from mutations in, or dysregulation of, a single common gene product, FGF23 and, in ARHR and XLH, complimentary DMP1 and PHEX directed events that contribute to abnormal bone mineralization.

Fibroblast growth factor signaling in skeletal development and disease

“…Functionally, the expression of FGF23 in osteoblasts and osteocytes is controlled by FGFR1 signaling (Martin et al 2011), which in turn controls phosphate homeostasis and bone mineralization (Quarles 2012;Feng et al 2013). Low-molecular-weight FGF2 stimulates FGF23 promoter activity through PLCγ/NFAT and MAPK signaling, whereas high-molecular-weight FGF2 promotes FGF23 promoter activity through cAMP-dependent binding of FGFR1 and CREB to a conserved cAMP response element in the FGF23 promoter (Han et al 2015).…”

Molecular and Biochemical Aspects of Hypophosphatemic Rickets; an Updated Review

“…The reason is that mutant form of FGF23 is resistant to proteolysis and it mainly remains as an intact protein, and this intact protein exerts the entire effects of FGF23 in cellular levels. 13,19 A study on large kindred affected by ADHR revealed that patients in their childhood had bone pain, short stature, lower extremity deformities, dental abscess, and rickets. The patients affected by ADHR in their adulthood had symptoms like tumor-induced osteomalacia (TIO).…”

“…For instance, the inheritance pattern of male-to-male transmission, eliminates the possibility of XLH, while the presence of affected parent obviates the possibility of ARHR. 19 6. Treatments Available for Hypophosphatemic Rickets Phenotype heterogeneity is a common feature observed among patients with similar genotype.…”

“…25,71,72 However, in other types of HR, the combination of phosphate and vitamin D supplementation is required for effective treatment. 19 The implication of anti-FGF23 antibody, namely KRN23 has a considerable outcome in PHEX mutant mouse. This IgG1 monoclonal antibody inhibits the activity of FGF23, leading to elevated levels of Pi and 1,25OH 2 D 3 .…”

Glucose metabolic abnormality is associated with defective mineral homeostasis in skeletal disorder mouse model

“…Furthermore, phosphate homeostasis, destructed in XLH patients [25], is also connected to energy metabolism [26,27]. Phosphorus contributes to bone development and maintenance [28].…”