Fibroblast growth factor 7: An inhibitor of phosphate transport derived from oncogenic osteomalacia-causing tumors
Fibroblast growth factor 7: An inhibitor of phosphate transport derived from oncogenic osteomalacia-causing tumors
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DOI：
10.1210/jc.2004-0357
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发表时间：
2005-02-01
影响因子：
5.8
通讯作者：
Shimkets, R
中科院分区：
文献类型：
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作者：
Carpenter, TO;Ellis, BK;Shimkets, R
致癌性骨软化症 (00) 是一种与肿瘤相关的磷酸盐消耗综合征，为识别肾磷酸盐稳态调节因子提供了机会。我们建立了 OO 相关肿瘤的培养物。来自这些培养物的条件培养基抑制肾小管上皮细胞对磷酸盐的吸收。然后，我们将表达抑制活性的肿瘤来源培养物中的 RNA 与抑制活性不明显的肿瘤来源培养物中的 RNA 进行比较，并鉴定了抑制肾磷酸盐转运的培养物特异性表达的候选 mRNA。对已确定候选物的测试表明，一种蛋白质，即成纤维细胞生长因子 7 (FGF7)，是体外磷酸盐吸收的有效且直接的抑制剂。 FGF7 的中和单克隆抗体可逆转 FGF7 依赖性磷酸盐转运抑制和肿瘤细胞培养条件培养基中的抑制活性。免疫测定显示抑制性条件培养基中存在丰富的FGF7，而非条件培养基或没有磷酸盐转运抑制活性的条件培养基中存在极少量的FGF7。此外，抑制性条件培养基中仅存在少量 FGF23，与无磷酸盐转运抑制活性的条件培养基中发现的浓度相当。因此，在选择肿瘤来源的培养物的体外磷酸盐转运抑制活性时，FGF7被特别鉴定，并被证实是磷酸盐转运的有效抑制剂。最后，从每个肿瘤片段提取的 mRNA 的 PCR 产物中证实了 FGF7 信息。 FGF 家族成员（FGF23 除外）由 OO 相关肿瘤表达，可能在介导该综合征中发挥作用。
Oncogenic osteomalacia (00), a tumor-associated phosphate-wasting syndrome, provides an opportunity to identify regulators of renal phosphate homeostasis. We established cultures from OO-associated tumors. Conditioned medium from these cultures inhibited phosphate uptake in renal tubular epithelial cells. We then compared RNA from tumor-derived cultures expressing inhibitory activity with RNA from tumor-derived cultures in which inhibitory activity was not evident and identified candidate mRNAs specifically expressed by cultures inhibiting renal phosphate transport. Testing of identified candidates revealed that one protein, fibroblast growth factor 7 (FGF7), was a potent and direct inhibitor of phosphate uptake in vitro. A neutralizing monoclonal antibody to FGF7 reversed FGF7-dependent phosphate transport inhibition and inhibitory activity in conditioned medium from tumor cell cultures. Immunoassay revealed abundant FGF7 in inhibitory conditioned medium and minimal amounts in nonconditioned medium or conditioned medium with no phosphate transport inhibitory activity. Furthermore, only small amounts of FGF23 were present in inhibitory conditioned medium, comparable to concentrations found in conditioned medium with no phosphate transport inhibitory activity. Thus, FGF7 was specifically identified when selecting for in vitro phosphate transport inhibitory activity of tumor-derived cultures and was confirmed as a potent inhibitor of phosphate transport. Finally, FGF7 message was confirmed in PCR products of mRNA extracted from fragments of each tumor. Members of the FGF family (other than FGF23) are expressed by OO-associated tumors and may play a role in mediating this syndrome.