X-linked hypophosphatemia (XLH) is characterized by rickets and osteomalacia as a result of an inactivating mutation of the PHEX (phosphate-regulating gene with homology to endopeptidases on the X chromosome) gene. PHEX encodes an endopeptidase that, when inactivated, results in elevated circulating levels of FGF-23, a novel phosphate-regulating hormone (a phosphatonin), thereby resulting in increased phosphate excretion and impaired bone mineralization. A generalized and severe mineralizing enthesopathy in patients with XLH was first reported in 1985; we likewise report a survey in which we found evidence of enthesopathy in fibrocartilaginous insertion sites, as well as osteophyte formation, in the majority of patients. Nonetheless, there has been very little focus on the progression and pathogenesis underlying the paradoxical heterotopic calcification of tendon and ligament insertion sites. Such studies have been hampered by lack of a model of mineralizing enthesopathy. We therefore characterized the involvement of the most frequently targeted fibrocartilaginous tendon insertion sites in Hyp mice, a murine model of the XLH mutation that phenocopies the human syndrome in every detail including hypophosphatemia and elevated FGF-23. Histological examination of the affected entheses revealed that mineralizing insertion sites, while thought to involve bone spur formation, were not due to bone-forming osteoblasts but instead to a significant expansion of mineralizing fibrocartilage. Our finding that enthesis fibrocartilage cells specifically express fibroblast growth factor receptor 3 (FGFR3)/Klotho suggests that the high circulating levels of FGF-23, characteristic of XLH and Hyp mice, may be part of the biochemical milieu that underlies the expansion of mineralizing enthesis fibrocartilage.
KeywordsRickets; Osteomalacia; Ectopic calcification; Ligaments; Tendons Correspondence to: Carolyn M. Macica, carolyn.macica@yale.edu.
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NIH-PA Author ManuscriptThe characteristic hypophosphatemia of X-linked hypophosphatemia (XLH) arises as a consequence of a defective PHEX (phosphate-regulating gene with homology to endopeptidases on the X chromosome) gene product, which ultimately results in impaired proximal tubule phosphate reabsorption. In addition, despite severe hypophosphatemia, 1,25-dihydroxyvitamin D 3 (1,25[OH] 2 D 3 ) production is not appropriately enhanced, due to FGF-23-mediated suppression of 1α-hydroxylase activity. A number of phosphate-wasting disorders phenotypically similar to XLH have been attributed to high circulating levels of FGF-23, including tumor-induced osteomalacia (TIO), autosomal dominant hypophosphatemic rickets (ADHR), and autosomal recessive hypophosphatemic rickets (ARHR) [1][2][3][4][5].Despite the characteristic osteomalacia of XLH, there is a paradoxical heterotopic calcification of tendon and ligament insertion sites, a manifestation of the disease described over 20 years ago [6,7]. These manifestations are of c...