Liu Changlu, Jiang Dianming
Department of Orthopaedics, The First Affiliated Hospital of Chongqing Medical University, 400016 Chongqing, China.
Department of Orthopaedics, The First Affiliated Hospital of Chongqing Medical University, 400016 Chongqing, China.
Cytokine. 2017 Mar;91:132-139. doi: 10.1016/j.cyto.2016.12.016. Epub 2017 Jan 5.
High glucose (HG) is conceived to regulate bone metabolism in patients with diabetic mellitus (DM). In the present study, we examined the level of leukemia inhibitory factor (LIF), a pleiotropic cytokine in interleukin (IL)-6 family, in T2DM patients and investigated the regulation by HG on the induction of LIF/signal transducer and activator of transcription 3 (STAT3) signaling. Then we determined the regulation of HG and LIF on the osteoblast differentiation via measuring the ALP activity, matrix mineralization, and the expression of alkaline phosphatase (ALP), Runt-related transcription factor 2 (RUNX2), Osteocalcin (OCN) and osteopontin (OPN) in human osteoblast MG-63 cells. In addition, we evaluated the dependence of suppressor of cytokine signaling 3 (SOCS3)/STAT3 signaling in the progress. Results indicated significantly higher serum levels of high-sensitivity C-reactive protein (hsCRP), IL-1β, IL-6 and LIF in T2DM patients. HG induced markedly higher levels of these cytokines in vitro. Furthermore, either HG or LIF reduced the expression of ALP, OCN and RUNX2 in both mRNA and protein levels. In addition, LIF markedly promoted the expression of SOCS3, significantly upregulated the phosphorylation of STAT3 in MG-63 cells; and the downregulation of the four osteogenic differentiation-associated markers were restored by 50 or 100nM STAT3 inhibitor, JSI-124. In summary, this study has shown that LIF is implicated in the HG-mediated inhibition of osteoblast differentiation, via promoting STAT3/SOCS3 signaling. This study may provide insights into the signal pathway of HG-induced bone loss or delayed injured joint healing.
高血糖（HG）被认为可调节糖尿病（DM）患者的骨代谢。在本研究中，我们检测了2型糖尿病（T2DM）患者体内白细胞介素（IL）-6家族中的多效性细胞因子白血病抑制因子（LIF）水平，并研究了HG对LIF/信号转导和转录激活因子3（STAT3）信号诱导的调节作用。然后，我们通过测量人成骨细胞MG-63细胞中的碱性磷酸酶（ALP）活性、基质矿化以及碱性磷酸酶（ALP）、 runt相关转录因子2（RUNX2）、骨钙素（OCN）和骨桥蛋白（OPN）的表达，确定了HG和LIF对成骨细胞分化的调节作用。此外，我们评估了细胞因子信号转导抑制因子3（SOCS3）/STAT3信号在这一过程中的依赖性。结果表明，T2DM患者血清中的高敏C反应蛋白（hsCRP）、IL-1β、IL-6和LIF水平显著升高。HG在体外显著诱导了这些细胞因子水平的升高。此外，HG或LIF均降低了ALP、OCN和RUNX2在mRNA和蛋白质水平上的表达。此外，LIF显著促进了SOCS3的表达，显著上调了MG-63细胞中STAT3的磷酸化；50或100nM的STAT3抑制剂JSI-124恢复了四种成骨分化相关标志物的下调。总之，本研究表明，LIF通过促进STAT3/SOCS3信号传导参与了HG介导的成骨细胞分化抑制。本研究可能为HG诱导的骨质流失或延迟的关节损伤愈合的信号通路提供见解。
