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Survey of the Enthesopathy of X-Linked Hypophosphatemia and Its Characterization in Hyp Mice

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Abstract

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.

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Acknowledgement

We thank Nancy Troiano for technical assistance. We also thank the subjects participating in our clinical research protocols for their generous donation of time and effort, allowing the clinical characterization of features of the disease described here. Funding was provided by the NIH/NIAMSD (P50-AR054086-02) and the NIH/NIDDK (R01DK62515-26).

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Authors and Affiliations

  1. Department of Internal Medicine/Endocrinology, Yale University, P.O. Box 208020, New Haven, CT, 06520-8020, USA

    Guoying Liang, Karl L. Insogna & Carolyn M. Macica

  2. Department of Diagnostic Radiology, Yale University, New Haven, CT, USA

    Lee D. Katz

  3. Department of Pediatrics, Yale University, New Haven, CT, USA

    Thomas O. Carpenter

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  1. Guoying Liang
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  2. Lee D. Katz
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Correspondence to Carolyn M. Macica.

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Liang, G., Katz, L.D., Insogna, K.L. et al. Survey of the Enthesopathy of X-Linked Hypophosphatemia and Its Characterization in Hyp Mice. Calcif Tissue Int 85, 235–246 (2009). https://doi.org/10.1007/s00223-009-9270-6

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