Leptin accelerates the pathogenesis of heterotopic ossification in rat tendon tissues via mTORC1 signaling
Leptin accelerates the pathogenesis of heterotopic ossification in rat tendon tissues via mTORC1 signaling
复制标题
瘦素通过 mTORC1 信号传导加速大鼠肌腱组织异位骨化的发病机制
DOI：
10.1002/jcp.25955
复制
发表时间：
2018-02-01
影响因子：
5.6
通讯作者：
Xian, Cory J.
中科院分区：
文献类型：
--
作者：
Jiang, Huaji;Chen, Yuhui;Xian, Cory J.
瘦素是一种与骨代谢相关的脂肪细胞衍生细胞因子，被认为在异位骨化（HO）的发病机制中起关键作用。本研究在体外探讨了瘦素对肌腱衍生干细胞（TDSCs）成骨分化的影响及其潜在作用机制，并在大鼠肌腱中研究了其对HO形成的影响。在体外，将分离的大鼠TDSCs在有或无mTORC1信号特异性抑制剂雷帕霉素的情况下，用不同浓度的瘦素进行处理。采用跟腱切断的大鼠模型，评估在有或无雷帕霉素治疗的情况下瘦素对HO形成的影响。对TDSCs的体外研究表明，瘦素通过激活mTORC1信号通路（如p70核糖体S6激酶1和p70核糖体S6的磷酸化所示）增加了成骨生物标志物（碱性磷酸酶、runt相关转录因子2、osterix、骨钙素）的表达，并增强了TDSCs的矿化。然而，用雷帕霉素处理阻断mTORC1信号抑制了瘦素诱导的成骨分化和矿化。体内研究表明，瘦素促进了跟腱切断术后HO的形成，而雷帕霉素治疗阻断了瘦素诱导的HO形成。总之，在体外和体内模型中，瘦素均可通过mTORC1信号促进TDSCs的成骨分化和异位骨形成，这为HO的预防提供了一个新的潜在治疗靶点。
Leptin, an adipocyte-derived cytokine associated with bone metabolism, is believed to play a critical role in the pathogenesis of heterotopic ossification (HO). The effect and underlying action mechanism of leptin were investigated on osteogenic differentiation of tendon-derived stem cells (TDSCs) in vitro and the HO formation in rat tendons. Isolated rat TDSCs were treated with various concentrations of leptin in the presence or absence of mTORC1 signaling specific inhibitor rapamycin in vitro. A rat model with Achilles tenotomy was employed to evaluate the effect of leptin on HO formation together with or without rapamycin treatment. In vitro studies with TDSCs showed that leptin increased the expression of osteogenic biomarkers (alkaline phosphatase, runt-related transcription factor 2, osterix, osteocalcin) and enhanced mineralization of TDSCs via activating the mTORC1 signal pathway (as indicated by phosphorylation of p70 ribosomal S6 kinase 1 and p70 ribosomal S6). However, mTORC1 signaling blockade with rapamycin treatment suppressed leptin-induced osteogenic differentiation and mineralization. In vivo studies showed that leptin promoted HO formation in the Achilles tendon after tenotomy, and rapamycin treatment blocked leptin-induced HO formation. In conclusion, leptin can promote TDSC osteogenic differentiation and heterotopic bone formation via mTORC1 signaling in both vitro and vivo model, which provides a new potential therapeutic target for HO prevention.