Mineralizing enthesopathy is a common feature of renal phosphate-wasting disorders attributed to FGF23 and is exacerbated by standard therapy in Hyp mice

Abstract

Enthesopathy is a common feature of X-linked hypophosphatemia (XLH). We have previously shown that the enthesopathy is recapitulated in Hyp mice, a murine model of XLH, and is characterized by significant hyperplasia of mineralizing fibrochondrocytes that coexpress FGFR3/klotho. It is unclear, however, whether it occurs in other forms of renal phosphate-wasting disorders attributable to high FGF23 levels and what is the underlying pathophysiology. Here, we describe two brothers of Lebanese origin with autosomal-recessive hypophosphatemic rickets (ARHR) due to the Met1Val (M1V) mutation in dentin matrix acidic phosphoprotein 1 (DMP1). In addition to the biochemical and skeletal features of long-standing rickets with elevated FGF23 levels, these individuals exhibited severe, debilitating, generalized enthesopathy. These data suggest that mineralizing enthesopathy is a feature common to phosphate-wasting disorders mediated by FGF23. To address this possibility, we examined a murine model of FGF23 overexpression using a transgene encoding the secreted form of human FGF23 (R176Q) cDNA (FGF23-TG mice). Mice have a biochemical profile and phenotypic traits akin to phosphate-wasting disorders attributed to FGF23. We report that FGF23-TG mice display a similar mineralizing enthesopathy of the Achilles and plantar facial insertions evident by 12 weeks, the period of developmental maturity. The enthesopathy (expressed as a percentage of total enthesis area) is characterized by an expansion of alkaline phosphatase-positive fibrochondrocytes embedded in a mineralized matrix (wild-type mice, 0.75 ± 0.5%; FGF23-TG mice, 15.1 ± 3.4%, p < 0.01; Hyp mice, 21.1 ± 2.1%, p < 0.01). The standard therapy for phosphate-wasting disorders is oral phosphate and calcitriol. However, the impact of treatment on enthesophyte progression is unknown. We thus treated Hyp mice with phosphate (1.93 g phosphate/L water) and 1,25(OH)2D3 (0.175 μg/kg/day) from weeks 3 to 12. We found that the mineralizing enthesopathy persisted despite the improving bone mass. In addition, treatment had the untoward effect of further exacerbating the mineralization of fibrochondrocytes that define the bone spur of the Achilles insertion. These studies support the need for newer interventions targeted at limiting the actions of FGF23 while minimizing both the toxicities and potential morbidities associated with standard therapy.