Rowe Peter S N
Department of Periodontics, The University of Texas Health Science Center at San Antonio, Mail Code 7894, 7703 Floyd Curl Drive, Room 3.579U, San Antonio, TX 78229-3900, USA.
Crit Rev Oral Biol Med. 2004 Sep 1;15(5):264-81. doi: 10.1177/154411130401500503.
The last 350 years since the publication of the first medical monograph on rickets (old English term wrickken) (Glisson et al., 1651) have seen spectacular advances in our understanding of mineral-homeostasis. Seminal and exciting discoveries have revealed the roles of PTH, vitamin D, and calcitonin in regulating calcium and phosphate, and maintaining healthy teeth and skeleton. However, it is clear that the PTH/Vitamin D axis does not account for the entire picture, and a new bone-renal metabolic milieu has emerged, implicating a novel set of matrix proteins, hormones, and Zn-metallopeptidases. The primary defects in X-linked hypophosphatemic rickets (HYP) and autosomal-dominant hypophosphatemic rickets (ADHR) are now identified as inactivating mutations in a Zn-metalloendopeptidase (PHEX) and activating mutations in fibroblast-growth-factor-23 (FGF23), respectively. In oncogenic hypophosphatemic osteomalacia (OHO), several tumor-expressed proteins (MEPE, FGF23, and FRP-4) have emerged as candidate mediators of the bone-renal pathophysiology. This has stimulated the proposal of a global model that takes into account the remarkable similarities between the inherited diseases (HYP and ADHR) and the tumor-acquired disease OHO. In HYP, loss of PHEX function is proposed to result in an increase in uncleaved full-length FGF23 and/or inappropriate processing of MEPE. In ADHR, a mutation in FGF23 results in resistance to proteolysis by PHEX or other proteases and an increase in half-life of full-length phosphaturic FGF23. In OHO, over-expression of FGF23 and/or MEPE is proposed to result in abnormal renal-phosphate handling and mineralization. Although this model is attractive, many questions remain unanswered, suggesting a more complex picture. The following review will present a global hypothesis that attempts to explain the experimental and clinical observations in HYP, ADHR, and OHO, plus diverse mouse models that include the MEPE null mutant, HYP-PHEX transgenic mouse, and MEPE-PHEX double-null-mutant.
自第一本关于佝偻病（古英语术语为wrickken）的医学专著出版（Glisson等人，1651年）以来的过去350年里，我们对矿物质稳态的理解取得了惊人的进展。具有开创性和令人兴奋的发现揭示了甲状旁腺激素（PTH）、维生素D和降钙素在调节钙和磷以及维持健康牙齿和骨骼方面的作用。然而，很明显PTH/维生素D轴并不能解释全部情况，一种新的骨-肾代谢环境已经出现，涉及一组新的基质蛋白、激素和锌金属肽酶。X连锁低磷性佝偻病（HYP）和常染色体显性低磷性佝偻病（ADHR）的主要缺陷现在分别被确定为锌金属内肽酶（PHEX）的失活突变和成纤维细胞生长因子23（FGF23）的激活突变。在肿瘤性低磷性骨软化症（OHO）中，几种肿瘤表达蛋白（MEPE、FGF23和FRP-4）已成为骨-肾病理生理学的候选介质。这激发了一个综合模型的提出，该模型考虑了遗传性疾病（HYP和ADHR）与肿瘤获得性疾病OHO之间的显著相似性。在HYP中，PHEX功能丧失被认为会导致未切割的全长FGF23增加和/或MEPE加工不当。在ADHR中，FGF23的突变导致其对PHEX或其他蛋白酶的蛋白水解产生抗性，全长磷尿性FGF23的半衰期增加。在OHO中，FGF23和/或MEPE的过度表达被认为会导致肾脏对磷的处理和矿化异常。尽管这个模型很有吸引力，但许多问题仍未得到解答，这表明情况更为复杂。以下综述将提出一个综合假说，试图解释HYP、ADHR和OHO中的实验和临床观察结果以及各种小鼠模型，包括MEPE基因敲除突变体、HYP-PHEX转基因小鼠和MEPE-PHEX双基因敲除突变体。
