Ni Li-Hua, Tang Ri-Ning, Yuan Cheng, Song Kai-Yun, Wang Li-Ting, Zhang Xiao-Liang, Lv Lin-Li, Wang Bin, Wu Min, Tang Tao-Tao, Li Zuo-Lin, Yin Di, Cao Jing-Yuan, Wang Xiao-Chen, Liu Hong, Chen Qiang, Liu Bi-Cheng
Institute of Nephrology, Zhongda Hospital, Southeast University School of Medicine, Nanjing 210009, China.
NanJing Lishui People's Hospital, Zhongda Hospital Lishui Branch, Nanjing 210009, China.
Ann Transl Med. 2019 Jul;7(14):312. doi: 10.21037/atm.2019.06.44.
Recently, cinacalcet (CINA) has been shown to be effective for attenuating bone loss in the treatment of secondary hyperparathyroidism (SHPT) in patients with chronic kidney disease (CKD), which might be associated with the reduction in serum parathyroid hormone (PTH) levels. However, the exact mechanism is largely unclear. Emerging studies have revealed that an increased number of bone marrow adipocytes (BMAs) are involved in bone loss and the endothelial-to-adipocyte transition via the endothelial-to-mesenchymal transition (EndMT) might play a key role in this pathological process. Here, we assessed whether CINA could attenuate bone loss via inhibiting endothelial-to-adipocyte transition in CKD rats.
A rat model of CKD was induced by adenine and a high phosphorus diet. CINA was orally administrated to CKD animals (10 mg/kg once a day). Dual energy X-ray absorptiometry, micro-computed tomography, bone histomorphometry, and bone mechanical tests were used to determine the skeletal changes. The bone marrow expression of EndMT markers was also examined. The effect of elevated PTH levels on the endothelial-to-adipocyte transition was studied in endothelial cells (ECs).
Elevation of serum PTH levels, remarkable bone loss and increased numbers of BMAs were observed in rats with CKD compared with the controls, and these changes were attenuated after treatment with CINA. Furthermore, the CINA treatment abolished the upregulation of mesenchymal markers (FSP1 and α-SMA) and the downregulation of an endothelial marker (CD31) in bone tissues from rats with CKD. The serum PTH concentrations were correlated with the bone marrow protein levels of these EndMT-related proteins. An treatment in ECs demonstrated that PTH induced the EndMT in a concentration- and time-dependent manner. Accordingly, ECs treated with PTH exhibited adipogenic potential following growth in adipogenic culture medium.
Our study indicated CINA treatment attenuated bone loss in CKD rats, which might be associated with inhibiting PTH-induced endothelial-to-adipocyte transition in CKD rats.
最近，西那卡塞（CINA）已被证明在治疗慢性肾脏病（CKD）患者的继发性甲状旁腺功能亢进（SHPT）中对减轻骨质流失有效，这可能与血清甲状旁腺激素（PTH）水平降低有关。然而，确切机制尚不清楚。新兴研究表明，骨髓脂肪细胞（BMA）数量增加参与骨质流失，并且通过内皮-间充质转化（EndMT）的内皮-脂肪细胞转化可能在这一病理过程中起关键作用。在此，我们评估了CINA是否能通过抑制CKD大鼠的内皮-脂肪细胞转化来减轻骨质流失。
通过腺嘌呤和高磷饮食诱导建立CKD大鼠模型。对CKD动物口服给予CINA（10mg/kg，每日一次）。采用双能X线吸收法、显微计算机断层扫描、骨组织形态计量学和骨力学测试来确定骨骼变化。还检测了EndMT标志物在骨髓中的表达。在内皮细胞（ECs）中研究了升高的PTH水平对内皮-脂肪细胞转化的影响。
与对照组相比，CKD大鼠血清PTH水平升高、骨质明显流失且BMA数量增加，而CINA治疗后这些变化有所减轻。此外，CINA治疗消除了CKD大鼠骨组织中间充质标志物（FSP1和α-SMA）的上调以及内皮标志物（CD31）的下调。血清PTH浓度与这些EndMT相关蛋白的骨髓蛋白水平相关。ECs中的研究表明，PTH以浓度和时间依赖性方式诱导EndMT。因此，用PTH处理的ECs在脂肪生成培养基中生长后表现出脂肪生成潜能。
我们的研究表明，CINA治疗减轻了CKD大鼠的骨质流失，这可能与抑制CKD大鼠中PTH诱导的内皮-脂肪细胞转化有关。
