Abstract：
Renal cell carcinoma (RCC) bone metastatis progression is driven by crosstalk between tumor cells and the bone microenvironment, which includes osteoblasts, osteoclasts, and osteocytes. RCC bone metastases (RCCBM) are predominantly osteolytic and resistant to antiresorptive therapy. The molecular mechanisms underlying pathologic osteolysis and disruption of bone homeostasis remain incompletely understood. We previously reported that BIGH3/TGFBI (transforming growth factor-beta-induced protein ig-h3, shortened to BIGH3 henceforth) secreted by colonizing RCC cells drives osteolysis by inhibiting osteoblast differentiation, impairing healing of osteolytic lesions, which is reversible with osteoanabolic agents. Here, we report that BIGH3 induces osteocyte apoptosis in both human RCCBM tissue specimens and in a preclinical mouse model. We also demonstrate that BIGH3 reduces Cx43 expression, blocking gap junction (GJ) function and osteocyte network communication. BIGH3-mediated GJ inhibition is blocked by the lysosomal inhibitor hydroxychloroquine (HCQ), but not osteoanabolic agents. Our results broaden the understanding of pathologic osteolysis in RCCBM and indicate that targeting the BIGH3 mechanism could be a combinational strategy for the treatment of RCCBM-induced bone disease that overcomes the limited efficacy of antiresorptives that target osteoclasts.
摘要：
肾细胞癌（RCC）骨转移的进展是由肿瘤细胞和骨微环境之间的串扰驱动的，其中包括成骨细胞，破骨细胞,和骨细胞。RCC骨转移（RCCBM）主要是溶骨性的，并且对抗再吸收疗法具有抗性。病理性骨溶解和骨稳态破坏的分子机制仍未完全了解。我们先前报道了通过定殖RCC细胞分泌的BIGH3/TGFBI（转化生长因子-β诱导的蛋白ig-h3，以下简称BIGH3）通过抑制成骨细胞分化来驱动骨溶解，损害溶骨性病变的愈合，这与骨合成代谢剂是可逆的。这里,我们报道BIGH3在人RCCBM组织标本和临床前小鼠模型中诱导骨细胞凋亡。我们还证明BIGH3减少Cx43表达，阻断间隙连接（GJ）功能和骨细胞网络通信。BIGH3介导的GJ抑制被溶酶体抑制剂羟氯喹（HCQ）阻断，但不是骨合成代谢剂。我们的结果拓宽了对RCCBM病理性骨溶解的理解，并表明靶向BIGH3机制可能是治疗RCCBM诱导的骨疾病的组合策略，该策略克服了靶向破骨细胞的抗再吸收药物的有限功效。
