The mechanically activated p38/MMP-2 signaling pathway promotes bone marrow mesenchymal stem cell migration in rats

Abstract

Objective: The aim of the present study was to investigate the effect of static strain on bone marrow mesenchymal stem cell (BMMSC) migration and whether the p38/matrix metalloproteinase-2 (MMP-2) axis plays a role in induction of BMMSC migration under mechanical strain.

Design: Both in vivo and in vitro investigations were performed. Twelve adult male Sprague-Dawley rats were randomly divided into 2 groups (n=6 per group). Rats in the experimental group underwent right mandibular distraction osteogenesis, whereas rats in the control group were subjected to osteotomy in the mandible without distraction. Immunohistochemistry and immunofluorescence were performed to evaluate phospho-p38 (p-p38) and Nestin expression. BMMSCs were isolated from rat mandibles. BMMSCs in the experimental group were subjected to static mechanical strain for 2h, whereas those in the control group underwent no strain. The biological roles of static strain and the p38/MMP-2 axis in BMMSC migration were evaluated by Transwell assays and western blotting by inhibiting p38 phosphorylation.

Results: There were significantly more Nestin⁺ cells in the bone calluses of the experimental group than in those of the control group. In addition, Nestin⁺/p-p38⁺ cell numbers were significantly higher in the experimental group than in the control group, indicating that static strain activated p38 signaling in BMMSCs in vivo. In accordance with in vivo results, static strain in vitro stimulated phosphorylation of p38 in BMMSCs. Furthermore, expression of MMP-2 was elevated in BMMSCs under static strain compared with the control, and strain-induced MMP-2 expression was abolished by inhibition of p38 phosphorylation in BMMSCs. Moreover, Transwell assay results showed that static strain promoted BMMSC migration, which was abolished by inhibition of p38 phosphorylation.

Conclusions: The present study demonstrated that static strain can promote the migration ability of BMMSCs via p38/MMP-2 signaling. To the best of our knowledge, this study is the first report demonstrating that the p38/MMP-2 axis governs BMMSC migration under static mechanical strain.

Keywords: Bone marrow mesenchymal stem cells; Bone regeneration; Distraction osteogenesis; Mandible; Mechanical strain; Signaling pathway.