近期，国际学术期刊Journal of Cellular Physiology在线发表了中科院上海生命科学研究院/上海交大医学院健康所、中科院干细胞生物学重点实验室戴尅戎院士研究组的研究成果Continuous Cyclic Mechanical Tension Inhibited Runx2 Expression in Mesenchymal Stem Cells through RhoA-ERK1/2 Pathway。本项研究发现，连续施加周期性拉应力对于间充质干细胞成骨分化有明显的抑制作用，同时首次揭示这一抑制过程则是通过RhoA-ERK1/2-Runx2通路介导。
间充质干细胞（Mesenchymal Stem Cells，MSCs）具有多向分化的潜能，即在特定的诱导条件下可分化为骨、软骨、脂肪、肌腱、肌肉以及骨髓基质等多种组织细胞，在临床治疗以及组织工程中具有广阔的应用前景。因此，探究MSCs分化的调控机制成为该领域研究的焦点。力学刺激作为一种物理性的刺激形式，是细胞微环境中细胞命运调控的重要因素，也成为研究MSCs分化调控机制的重要手段，而关注力学刺激如何调控MSCs向骨方向分化方面的研究，对进一步揭示细胞微环境对MSCs命运调控机制的研究将提供有价值的理论依据，也为MSCs的临床治疗与组织工程奠定基础。
戴尅戎院士课题组的石玉博士研究生等科研人员应用国际上先进的细胞力学刺激仪器（Flexcell 4000+系统），对MSCs进行连续周期性拉应力刺激（Continuous Cyclic Mechanical Tension，CCMT），结果发现：MSCs向成骨分化的主要标记包括核心结合因子（Runt-related 2，Runx2）、骨桥蛋白（osteopontin，OPN）、碱性磷酸酶（Alkaline phosphatase，ALP）、1型胶原(Collagen Type 1，COL-1)等表达明显降低，且这种连续周期性拉应力可抑制一类重要的小GTP结合蛋白——RhoA的活化，外源性地激活RhoA可以解除力学刺激对成骨分化的抑制作用。进一步的研究发现，RhoA活化可影响下游重要的MAPK-ERK1/2的磷酸化水平，进而调节Runx2的表达水平，最终抑制了间充质干细胞向成骨分化。
该项研究为应用力学刺激进行骨再生、骨塑性的临床治疗提供了重要的理论依据。
该项工作得到了国家科技部、国家基金委、中国科学院以及上海市科委经费的支持。（生物谷Bioon.com）
生物谷推荐原文出处：
Journal of Cellular Physiology DOI: 10.1002/jcp.22551
Continuous cyclic mechanical tension inhibited Runx2 expression in mesenchymal stem cells through RhoA-ERK1/2 pathway
Yu Shi1, Huiwu Li2, Xiaoling Zhang1, Yujie Fu1, Yan Huang1, Pauline Po Yee Lui3,4,5, Tingting Tang2, Kerong Dai1,2,*
Keywords:continuous cyclic mechanical tension (CCMT);mesenchymal stem cell;osteogenesis;RhoA;ERK1/2-Runx2
Abstract
Tensile load is known to regulate the osteogenesis of mesenchymal stem cells (MSCs) and osteogenic progenitors; therefore it is widely used in clinical treatment and tissue engineering. Meanwhile, in vitro, both published studies and our lab data demonstrate that the application of intermittent tensile loading which stimulates cells several minutes or hours each day for several days has promoted the osteogenic differentiation of MSCs. Whereas, for clinic trails, it is important to know accurately how and how long mechanical tension should be applied. Hence, it is necessary to investigate different kinds of mechanical tension on osteogenesis of MSCs. Until now, during the osteogenesis, there has been no research on the effect of continuous cyclic mechanical tension (CCMT) which provides continuous stimulation throughout the study period. We firstly figure out CCMT inhibiting the expression of osteogenic genes such as key transcription factor Runx2. It is known that RhoA regulates cell differentiation in response to mechanical stimuli. MAPK signaling acts as a downstream effector of RhoA. So, we ask in MSCs, if CCMT regulates the osteogenic master gene Runx2 through RhoA-ERK1/2 pathway. And then, we find out there is a decrease in RhoA activity after CCMT stimulation. Pre-treatment of CCMT-loaded MSCs with LPA, a RhoA activator, restores ALP activity and significantly rescues Runx2 expression, while pre-treatment with C3 toxin, a RhoA inhibitor, further decreases the activity of ALP and down-regulates the expression of Runx2. Following results indicate that the inhibition of Runx2 expression after CCMT stimulation is mediated by RhoA-ERK1/2 pathway. J. Cell. Physiol. ? 2010 Wiley-Liss, Inc.
