Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia
Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia
复制标题
DOI：
10.1073/pnas.101545198
复制
发表时间：
2001-05-22
影响因子：
11.1
通讯作者：
Yamashita, T
中科院分区：
文献类型：
--
作者：
Shimada, T;Mizutani, S;Yamashita, T
肿瘤性骨软化症（TIO）是一种以肾性磷消耗引起的低磷血症为特征的副肿瘤性疾病。由于切除肿瘤可使磷酸盐代谢正常化，因此一种未知的体液磷酸尿因子被认为是引起该综合征的原因。为了鉴定TIG的致病因素，我们获得了仅在引起TIO的肿瘤中大量表达的cDNA克隆，并构建了肿瘤特异性cDNA重叠群。基于一个主要重叠群的序列，我们克隆了2，270-bp的cDNA，其编码成纤维细胞生长因子23（FGF 23）。重组FGF 23在12 h内可降低小鼠血清磷水平。当稳定表达FGF 23的中国仓鼠卵巢细胞s.c.植入裸鼠后，观察到低磷酸盐血症伴肾磷酸盐清除增加。此外，高水平的血清碱性磷酸酶，低1，25-二羟维生素D，骨畸形，体重增加的障碍变得明显。组织学检查显示类骨质明显增多，生长板增宽。因此，连续产生的FGF 23重现了体内TIO的临床、生化和组织学特征。对中国仓鼠卵巢细胞产生的重组FGF 23产物的分析表明，FGF 23在RXXR基序处发生蛋白水解裂解。最近的遗传学研究表明，FGF 23的RXXR基序中的错义突变是常染色体显性低磷血症性佝偻病的原因，这是另一种与TIO具有相似特征的低磷血症性疾病。我们得出结论，过度生产的FGF 23的原因TIO，而在FGF 23基因突变导致常染色体显性低磷血症性佝偻病可能通过阻止蛋白水解裂解和增强FGF 23的生物活性。
Tumor-induced osteomalacia (TIO) is one of the paraneoplastic diseases characterized by hypophosphatemia caused by renal phosphate wasting. Because removal of responsible tumors normalizes phosphate metabolism, an unidentified humoral phosphaturic factor is believed to be responsible for this syndrome. To identify the causative factor of TIG, we obtained cDNA clones that were abundantly expressed only in a tumor causing TIO and constructed tumor-specific cDNA contigs. Based on the sequence of one major contig, we cloned 2,270-bp cDNA, which turned out to encode fibroblast growth factor 23 (FGF23). Administration of recombinant FGF23 decreased serum phosphate in mice within 12 h. When Chinese hamster ovary cells stably expressing FGF23 were s.c. implanted into nude mice, hypophosphatemia with increased renal phosphate clearance was observed. In addition, a high level of serum alkaline phosphatase, low 1,25-dihydroxyvitamin D, deformity of bone, and impairment of body weight gain became evident. Histological examination showed marked increase of osteoid and widening of growth plate. Thus, continuous production of FGF23 reproduced clinical, biochemical, and histological features of TIO in vivo. Analyses for recombinant FGF23 products produced by Chinese hamster ovary cells indicated proteolytic cleavage of FGF23 at the RXXR motif. Recent genetic study indicates that missense mutations in this RXXR motif of FGF23 are responsible for autosomal dominant hypophosphatemic rickets, another hypophosphatemic disease with similar features to TIO. We conclude that overproduction of FGF23 causes TIO, whereas mutations in the FGF23 gene result in autosomal dominant hypophosphatemic rickets possibly by preventing proteolytic cleavage and enhancing biological activity of FGF23.