原癌基因cMaf是联结老年性肌肉减少症和骨质疏松症的分子枢纽

Osteoporosis (OP), together with sarcopenia (SP), brings serious implications for the health of the elderly. The causal connection between the two has arisen high concerns of the academic world. Many studies have indicated that the bone formation is determined by the proliferation and differentiation of osteoblasts (OB), the processes of which may be regulated by many factors such as the mechanical stress, systemic hormones, intracellular mediators and so forth.Our previous studies have showed that IGF-I can promote the differentiation of OBs through the MAPK signaling pathway by regulating the expression of OB specific transcription factor Runx2. Recent studies suggest that musculoaponeurotic- fibrosarcoma oncogene homologue c (cMaf), as a co-regulator of Runx2, plays an essential role in the down-regulation of aging-related OB differentiation and bone formation.In this study, we put forward the hypothesis that cMaf is the key molecular link for senile SP in causing OP. Taking the aged and limb-pressurized rats as the animal models, we observed the direct influence of cMaf gene in decreasing OB differentiation caused by the decline of mechanical stress in sarcopenia. We also cultured the C3H10T1/2 cells in vitro, and aimed to explore the underlying mechanisms of signal transduction, for example MAPK signal or phosphorylation, through microgravity technique and mechanical pressure method. cMaf gene is the vital molecular link between senile sarcopenia and osteoporosis. The theoretical system of cMaf may provide new therapeutic targets for future prevention and treatment for senile OP, especially the OP accompanied by SP，such as disuse-induced or agravity-induced OP.

老年人骨质疏松症(OP)和肌肉减少症（SP）如影随形，二者的因果联系受到高度关注。成骨细胞（OB）的增殖和分化决定了骨转换中骨形成的多寡，其过程受机械应力等多因素调控。我们前期发现IFG-I等生长因子通过MAPK途径调节OB特异转录因子Runx2的表达而调节OB分化，新近发现原癌基因cMaf，作为Runx2的共调节子，在调节衰老相关的OB分化减退、骨形成下降中起关键作用。本课题提出"cMaf是老年性SP引发OP的关键分子枢纽"假说，以增龄及肢体加压大鼠为模型，验证cMaf基因在SP致机械应力下降致OB分化减少过程中具有直接作用；体外培养C3H10T1/2细胞，结合模拟微重力、机械加压等方法，探讨其可能信号传导机制，如MAPK途径、磷酸化作用等。cMaf基因是老年性SP和OP的重要分子枢纽，此理论的研究将为未来开发防治老年性OP，特别是合并SP(如废用性或失重相关性)的OP提供新的治疗靶点。

老年人骨质疏松症(OP)和肌肉减少症（SP）如影随形，二者既伴发又互为因果。本课题围绕“cMaf是老年性SP引发OP的关键分子枢纽”假说，成功建立老年组及老年机械应力刺激组大鼠模型，观察到增龄后SP伴发OP的同时，骨髓基质干细胞（MSC）向成骨细胞（OB）分化减弱。OP可通过跑台运动增加机械应力刺激而得到改善。但增龄后骨骼cMaf基因表达极低，未能进一步验证出cMaf基因在SP致机械应力下降导致的OB分化减少过程中的开关作用。进一步的体外试验通过培养C3H10T1/2细胞系，BMP刺激其向OB分化，应用回旋加速器模拟SP致骨骼细胞受到机械应力减少的状态，机械应力减少后，C3H10T1/2细胞OB分化减弱，且OB特异转录因子Runx2受到MAPK信号通路调控。因cMaf基因表达过低，未验证出机械应力减少与cMaf基因下调具有相关性。但过表达cMaf后，Runx2基因表达增加，可对抗微重力的影响，且其作用可被PD98059所阻断。提示cMaf可能部分通过MAPK途径调节Runx2的表达，cMaf基因可能是老年性SP和OP的重要分子枢纽。深入阐明“SP致使机械应力刺激减少是老年性OP发生的触发器”的机制，将会对未来老年性OP的诊疗产生深远的影响。基于上述认识，一方面在老年性OP的诊断时，除行骨密度测定外，尚需高度重视肌肉力量和容量的测定；另一方面在针对老年性OP的防治中，除合理应用骨吸收抑制剂及骨形成促进剂外，尚需强调包括增加体力活动，雄激素、生长激素等药物，以及中医中药、康复医学等促进肌肉功能重建的有效措施。更为重要的是：研究和证实老年性SP和OP的重要分子枢纽, 这一理论体系和分子纽带的提出，可能成为未来开发防治老年性OP，特别是合并肌肉减少症（如废用性、失重相关性）的骨质疏松症的新的治疗靶点。