Survey of the Enthesopathy of X-Linked Hypophosphatemia and Its Characterization in Hyp Mice
Survey of the Enthesopathy of X-Linked Hypophosphatemia and Its Characterization in Hyp Mice
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DOI：
10.1007/s00223-009-9270-6
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发表时间：
2009-09-01
影响因子：
4.2
通讯作者：
Macica, Carolyn M.
中科院分区：
文献类型：
--
作者：
Liang, Guoying;Katz, Lee D.;Macica, Carolyn M.
X连锁低磷血症（XLH）的特征是由于PHEX（与X染色体上的内肽酶同源的磷酸盐调节基因）基因的失活突变而导致的佝偻病和骨软化。PHEX编码一种内肽酶，当其失活时，会导致FGF-23（一种新型磷酸盐调节激素（一种磷酸激素））的循环水平升高，从而导致磷酸盐排泄增加和骨矿化受损。1985年首次报道了XLH患者的全身性和严重的矿化附着点病变;我们同样报告了一项调查，其中我们发现大多数患者的纤维软骨附着部位存在附着点病变以及骨赘形成的证据。然而，很少有人关注肌腱和韧带附着点异位钙化的进展和发病机制。由于缺乏矿化附着点病的模型，这类研究受到阻碍。因此，我们对Hyp小鼠中最常见的靶向纤维软骨肌腱插入部位的参与进行了表征，Hyp小鼠是一种XLH突变的小鼠模型，其在各个细节上表现出与人类综合征相似的表现，包括低磷血症和升高的FGF-23。受影响的附着点的组织学检查显示，矿化插入部位，虽然被认为涉及骨刺形成，不是由于骨形成成骨细胞，而是由于矿化纤维软骨的显着扩张。我们发现附着点纤维软骨细胞特异性表达成纤维细胞生长因子受体3（FGFR 3）/Klotho，这表明XLH和Hyp小鼠特有的FGF-23的高循环水平可能是矿化附着点纤维软骨扩张的生化环境的一部分。
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.