Second Dental Center, Shanghai 9th People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Key Laboratory of Stomatology, Shanghai 200011, P.R. China.
Center of Craniofacial Orthodontics, Department of Oral and Cranio‑Maxillofacial Science, Shanghai 9th People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Key Laboratory of Stomatology, Shanghai 200011, P.R. China.
Mol Med Rep. 2017 Oct;16(4):5515-5522. doi: 10.3892/mmr.2017.7276. Epub 2017 Aug 17.
There is a growing body of evidence indicating an association between osteoporosis and vascular diseases, which are associated with reduced blood supply. Decreased vascular flow results in a hypoxic gradient in the local microenvironment, affecting local bone remodeling. Bone mesenchymal stem cells (BMSCs) have been demonstrated to be the key to bone remodeling. To elucidate the molecular mechanisms involved in vascular supply and osteoporosis, the present study investigated the effect of hypoxia on BMSCs in vitro during osteogenesis. The BMSC osteogenesis process was evaluated by alkaline phosphatase (ALP) activity assay and the mRNA expression of the osteogenic markers runt‑related transcription factor 2 (Runx2), ALP and osteocalcin. The function of extracellular signal‑regulated kinase (ERK)1/2 and p38 kinase were studied under hypoxia using specific inhibitors. The results demonstrated that hypoxia reduces the osteogenic differentiation of BMSCs by inactivating Runx2, followed by decreased ALP activity and mRNA expression levels of ALP, collagen type I and osteocalcin. Furthermore, these data suggested that the ERK1/2 and p38‑mitogen activated protein kinase signaling pathways might participate in hypoxia‑induced differentiation of BMSCs toward the osteogenic phenotype. Compared with ERK1/2, the p38‑Runx2 signaling pathway might exert a relatively more prominent effect in the above process. These findings may help to elucidate the pathophysiology of osteoporosis caused by decreased vascular supply.
越来越多的证据表明骨质疏松症与血管疾病之间存在关联，而血管疾病与血液供应减少有关。血管流量减少导致局部微环境中的缺氧梯度，影响局部骨重塑。骨间充质干细胞（BMSCs）已被证明是骨重塑的关键。为了阐明血管供应和骨质疏松症相关的分子机制，本研究在体外研究了缺氧对成骨过程中 BMSCs 的影响。通过碱性磷酸酶（ALP）活性测定和成骨标志物 runt 相关转录因子 2（Runx2）、ALP 和骨钙素的 mRNA 表达来评估 BMSC 成骨过程。使用特定抑制剂研究了细胞外信号调节激酶（ERK）1/2 和 p38 激酶在缺氧下的功能。结果表明，缺氧通过使 Runx2 失活来减少 BMSCs 的成骨分化，随后降低 ALP 活性以及 ALP、I 型胶原和骨钙素的 mRNA 表达水平。此外，这些数据表明 ERK1/2 和 p38 丝裂原活化蛋白激酶信号通路可能参与了 BMSCs 向成骨表型的缺氧诱导分化。与 ERK1/2 相比，p38-Runx2 信号通路在上述过程中可能发挥更突出的作用。这些发现可能有助于阐明由血管供应减少引起的骨质疏松症的病理生理学。
