Hu Hui-Min, Yang Liu, Wang Zhe, Liu Yan-Wu, Fan Jin-Zhu, Fan Jing, Liu Jian, Luo Zhuo-Jing
Department of Orthopaedics, Xi-jing Hospital, Fourth Military Medical University, No. 15, Changle West Road, Xi'an, Shaanxi Province, 710032, P. R. China.
Int J Clin Exp Pathol. 2013 Apr 15;6(5):841-52. Print 2013.
Osteoporosis is a major health problem affecting the aging population, especially in patients 65 years of age and older. The imbalance between bone formation and bone resorption is generally accepted as the essential mechanism leading to osteoporosis. In addition to the abnormal activation of osteoclast-mediated bone resorption, the dysfunction of bone marrow stromal cells (BMSCs) in mediating bone formation has been accepted as a major contributor to the progression of senile osteoporosis.
In our study, senile osteoporotic hBMSCs displayed a decreasing capacity for proliferation and osteoblast differentiation, which was associated with the downregulation of integrin α2. Forced ectopic integrin α2 expression using a lentivirus vector reversed the dysfunction of senile osteoporotic hBMSCs. Additionally, the overexpression of integrin α2 upregulated the levels of Runx2 and Osterix. Mechanically, Western blot analyses revealed that integrin α2 phosphorylated ERK1/2 and the inactivation of ERK by PD98059 suppressed the osteoblastic differentiation of hBMSCs, suggesting that integrin α2 promotes osteoblast proliferation through the activation of ERK1/2 MAPK.
Taken together, our results show that hBMSCs obtained from senile osteoporotic patients gradually lose their capability to differentiate along the osteogenic lineage and proliferate, which might be associated with the abnormal regulation of the integrin α2/ERK/Runx2 signaling pathway undergoing senile osteoporosis.
骨质疏松症是一个影响老年人群的主要健康问题，尤其是65岁及以上的患者。骨形成与骨吸收之间的失衡通常被认为是导致骨质疏松症的基本机制。除了破骨细胞介导的骨吸收异常激活外，骨髓间充质干细胞（BMSC）在介导骨形成方面的功能障碍已被认为是老年性骨质疏松症进展的主要因素。
在我们的研究中，老年骨质疏松症患者的hBMSC增殖和成骨细胞分化能力下降，这与整合素α2的下调有关。使用慢病毒载体强制异位表达整合素α2可逆转老年骨质疏松症患者hBMSC的功能障碍。此外，整合素α2的过表达上调了Runx2和Osterix的水平。从机制上讲，蛋白质印迹分析显示整合素α2使ERK1/2磷酸化，而PD98059使ERK失活抑制了hBMSC的成骨细胞分化，这表明整合素α2通过激活ERK1/2 MAPK促进成骨细胞增殖。
综上所述，我们的结果表明从老年骨质疏松症患者获得的hBMSC逐渐丧失沿成骨谱系分化和增殖的能力，这可能与老年性骨质疏松症中整合素α2/ERK/Runx2信号通路的异常调节有关。
