Liu Shiguang, Tang Wen, Zhou Jianping, Vierthaler Luke, Quarles L Darryl
The Kidney Institute, UNIversity of Kansas Medical Center, Kansas City, Kansas, USA.
Am J Physiol Endocrinol Metab. 2007 Dec;293(6):E1636-44. doi: 10.1152/ajpendo.00396.2007. Epub 2007 Sep 11.
X-linked hypophosphatemia (XLH) is characterized by hypophosphatemia and impaired mineralization caused by mutations of the PHEX endopeptidase (phosphate-regulating gene with homologies to endopeptidases on the X chromosome), which leads to the overproduction of the phosphaturic fibroblast growth factor 23 (FGF23) in osteocytes. The mechanism whereby PHEX mutations increase FGF23 expression and impair mineralization is uncertain. Either an intrinsic osteocyte abnormality or unidentified PHEX substrates could stimulate FGF23 in XLH. Similarly, impaired mineralization in XLH could result solely from hypophosphatemia or from a concomitant PHEX-dependent intrinsic osteocyte abnormality. To distinguish between these possibilities, we assessed FGF23 expression and mineralization after reciprocal bone cross-transplantations between wild-type (WT) mice and the Hyp mouse model of XLH. We found that increased FGF23 expression in Hyp bone results from a local effect of PHEX deficiency, since FGF23 was increased in Hyp osteocytes before and after explantation into WT mice but was not increased in WT osteocytes after explantation into Hyp mice. WT bone explanted into Hyp mice developed rickets and osteomalacia, but Hyp bone explanted into WT mice displayed persistent osteomalacia and abnormalities in the primary spongiosa, indicating that both phosphate and PHEX independently regulate extracellular matrix mineralization. Unexpectedly, we observed a paradoxical suppression of FGF23 in juvenile Hyp bone explanted into adult Hyp mice, indicating the presence of an age-dependent systemic inhibitor of FGF23. Thus PHEX functions in bone to coordinate bone mineralization and systemic phosphate homeostasis by directly regulating the mineralization process and producing FGF23. In addition, systemic counterregulatory factors that attenuate the upregulation of FGF23 expression in Hyp mouse osteocytes are present in older mice.
X连锁低磷血症（XLH）的特征是低磷血症以及由PHEX内肽酶（与X染色体上的内肽酶具有同源性的磷酸盐调节基因）突变导致的矿化受损，这会导致骨细胞中排磷性成纤维细胞生长因子23（FGF23）过度产生。PHEX突变增加FGF23表达并损害矿化的机制尚不清楚。内在的骨细胞异常或未鉴定的PHEX底物可能会在XLH中刺激FGF23。同样，XLH中的矿化受损可能仅由低磷血症引起，也可能由伴随的PHEX依赖性内在骨细胞异常引起。为了区分这些可能性，我们在野生型（WT）小鼠和XLH的Hyp小鼠模型之间进行相互骨交叉移植后，评估了FGF23表达和矿化情况。我们发现，Hyp骨中FGF23表达增加是由PHEX缺乏的局部效应引起的，因为在植入WT小鼠之前和之后，Hyp骨细胞中的FGF23都增加了，但植入Hyp小鼠后的WT骨细胞中的FGF23没有增加。植入Hyp小鼠的WT骨出现佝偻病和骨软化症，但植入WT小鼠的Hyp骨显示出持续性骨软化症和初级海绵骨异常，表明磷酸盐和PHEX都独立调节细胞外基质矿化。出乎意料的是，我们观察到植入成年Hyp小鼠的幼年Hyp骨中FGF23出现矛盾性抑制，表明存在一种年龄依赖性的FGF23全身抑制剂。因此，PHEX在骨中发挥作用，通过直接调节矿化过程和产生FGF23来协调骨矿化和全身磷酸盐稳态。此外，老年小鼠中存在系统性反调节因子，可减弱Hyp小鼠骨细胞中FGF23表达的上调。
