Suvannasankha Attaya, Tompkins Douglas R, Edwards Daniel F, Petyaykina Katarina V, Crean Colin D, Fournier Pierrick G, Parker Jamie M, Sandusky George E, Ichikawa Shoji, Imel Erik A, Chirgwin John M
Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
Richard L. Roudebush VA Medical Center, Indianapolis, IN, USA.
Oncotarget. 2015 Aug 14;6(23):19647-60. doi: 10.18632/oncotarget.3794.
Multiply myeloma (MM) grows in and destroys bone, where osteocytes secrete FGF23, a hormone which affects phosphate homeostasis and aging. We report that multiple myeloma (MM) cells express receptors for and respond to FGF23. FGF23 increased mRNA for EGR1 and its target heparanase, a pro-osteolytic factor in MM. FGF23 signals through a complex of klotho and a classical FGF receptor (FGFR); both were expressed by MM cell lines and patient samples. Bone marrow plasma cells from 42 MM patients stained positively for klotho, while plasma cells from 8 patients with monoclonal gammopathy of undetermined significance (MGUS) and 6 controls were negative. Intact, active FGF23 was increased 2.9X in sera of MM patients compared to controls. FGF23 was not expressed by human MM cells, but co-culture with mouse bone increased its mRNA. The FGFR inhibitor NVP-BGJ398 blocked the heparanase response to FGF23. NVP-BGJ398 did not inhibit 8226 growth in vitro but significantly suppressed growth in bone and induction of the osteoclast regulator RANK ligand, while decreasing heparanase mRNA. The bone microenvironment provides resistance to some anti-tumor drugs but increased the activity of NVP-BGJ398 against 8226 cells. The FGF23/klotho/heparanase signaling axis may offer targets for treatment of MM in bone.
多发性骨髓瘤（MM）在骨骼中生长并破坏骨骼，骨细胞在骨骼中分泌成纤维细胞生长因子23（FGF23），这是一种影响磷酸盐稳态和衰老的激素。我们报告多发性骨髓瘤（MM）细胞表达FGF23的受体并对其作出反应。FGF23增加了早期生长反应因子1（EGR1）及其靶标乙酰肝素酶（MM中的一种促骨溶解因子）的信使核糖核酸（mRNA）。FGF23通过一种α-klotho蛋白和一种经典成纤维细胞生长因子受体（FGFR）的复合物进行信号传导；二者均在MM细胞系和患者样本中表达。42例MM患者的骨髓浆细胞α-klotho蛋白染色呈阳性，而8例意义未明的单克隆丙种球蛋白病（MGUS）患者和6例对照的浆细胞呈阴性。与对照组相比，MM患者血清中完整的活性FGF23增加了2.9倍。人MM细胞不表达FGF23，但与小鼠骨骼共培养可增加其mRNA。FGFR抑制剂NVP-BGJ398阻断了乙酰肝素酶对FGF23的反应。NVP-BGJ398在体外不抑制8226细胞生长，但显著抑制其在骨骼中的生长及破骨细胞调节因子核因子κB受体活化因子配体（RANKL）的诱导，同时降低乙酰肝素酶mRNA水平。骨微环境对某些抗肿瘤药物具有抗性，但增加了NVP-BGJ398对8226细胞的活性。FGF23/α-klotho蛋白/乙酰肝素酶信号轴可能为MM骨病的治疗提供靶点。
