肿瘤性骨软化症的致病机制及治疗方法

Pathogenic mechanism and treatments of tumor-induced osteomalacia

肿瘤性骨软化症(tumor-induced osteomalacia,TIO)是一种由于肿瘤分泌过量成纤维细胞生长因子23(fibroblast growth factor 23,FGF23)引起肾脏排磷增多的罕见代谢性骨病,以进行性发展的骨痛、肌肉无力、骨折等为临床表现。TIO肿瘤多来源于软组织及骨组织,大多数肿瘤病理类型为磷酸盐尿性间叶组织肿瘤混合结缔组织亚型(phosphaturic mesenchymal tumors mixed connective tissue variants,PMTMCT)。目前PMTMCT的发生及其过量分泌FGF23的机制尚未明确。研究报道将近一半的PMTMCT中发现融合基因FN1-FGFR1或FN1-FGF1阳性,推测其为促进肿瘤发生及FGF23分泌的重要机制;Klotho的过表达则可能促进融合基因阴性的PMTMCT的发生及FGF23分泌;缺氧诱导因子-1α(hypoxia-inducible factor-1α,HIF-1α)的过度激活促进肿瘤FGF23转录及血管形成。肿瘤切除是目前治疗TIO的最有效手段。新兴的治疗方式包括FGF23单抗和FGFR抑制剂,有望成为不可切除、复发及恶性TIO的有效治疗方法。

Tumor-induced osteomalacia(TIO)is a rare metabolic bone disease caused by renal phosphate wasting due to overexpression of fibroblast growth factor 23(FGF23)by tumors.Clinical manifestations include progressive bone pain,muscle weakness,fracture,and so on.Tumors mainly stem from osseous tissue or soft tissue,being considered pathologically as phosphaturic mesenchymal tumors mixed connective tissue variants(PMTMCT).The mechanism of genesis of PMTMCT and excessive production of FGF23 has not been clear yet.It was reported that FN1-FGFR1 or FN1-FGF1 fusion gene was positive in nearly half of PMTMCT,indicating an important mechanism to promote tumor development and FGF23 secretion.Overexpression of klotho may promote the tumor development and FGF23 secretion in PMTMCT without fusion gene.Stimulation of hypoxia-inducible factor-1α(HIF-1α)leads to increased transcription of FGF23 and angiogenesis in PMTMCT.Complete tumor resection is the definitive therapy of TIO.Novel treatments including monoclonal antibody against FGF23 and inhibitors of FGFR are expected to become effective treatment for unresectable,recurrent and malignant tumors.