The mechanically activated p38/MMP-2 signaling pathway promotes bone marrow mesenchymal stem cell migration in rats
Introduction
Biomechanical stimuli are critical factors in development and maintenance of the skeleton as well as the cell phenotype and function (Goodman and Aspenberg, 1993, Luu et al., 2009). Accumulated evidence suggest that the stem cell niche in bone marrow provides a significant pool of mesenchymal stem cells (MSCs) (Kfoury and Scadden, 2015, Mendez-Ferrer et al., 2010). The biology of bone marrow mesenchymal stem cells (BMMSCs) is inevitably affected by mechanical strain loaded on the bone, particularly in the treatment of distraction osteogenesis (DO) and orthodontics, which make use of static strain for bone regeneration. It has been documented that static strain exerts significant regulatory control over the fate of BMMSCs. (Engler, Sen, Sweeney, & Discher, 2006). In addition, static strain had been demonstrated to promote BMMSC proliferation in vitro (Kim, Song, & Hwang, 2010).
The migration of BMMSCs is one of the most critical processes during BMMSC responses to mechanical strain. As pericytes of a perivascular niche, BMMSCs must escape the stem cell niche and migrate to the bone forming areas for bone regeneration and repair (Du et al., 2014). This process involves secretion of matrix metalloproteinases (MMPs) by BMMSCs to degrade the surrounding extracellular matrix (ECM) (Kasper et al., 2007, Mott and Werb, 2004). Matrix metalloproteinase-2 (MMP-2) is one of the critical MMPs mediating BMMSC migration (Karadag & Fisher, 2006). However, to date, little is known about the mechanotransduction governing BMMSC migration under static mechanical strain.
p38 is a member of the mitogen-activated protein kinase superfamily, which is composed of 3 main members providing regulatory control of diverse cellular activities such as cell differentiation and apoptosis (Chang and Karin, 2001, Sui et al., 2014). It has been well documented that p38 is capable of regulating cellular responses to mechanical signals (Rosenzweig, Quinn, & Haglund, 2014; Wu et al., 2014). Recent studies demonstrated that p38 is also involved in regulation of migration ability in various cells including cancer cells and smooth muscle cells (Liu et al., 2015, Rousseau et al., 2006). It has been reported that activated p38 induces MMP-2 and MMP-9 expression to degrade the ECM and facilitate cell motility (Huang et al., 2014).
This study aimed to explore whether p38-mediated increases in level of MMP-2 regulated the migration ability of BMMSCs under static strain. To test our hypothesis, a rat mandibular DO model was established according to our previous studies, and static strain was applied for both in vivo and in vitro assays. We found that the p38/MMP-2 axis may play a significant role in regulation of BMMSC migration ability.
Section snippets
Animals and surgical procedure
The animal experimental protocol was approved by the Committee on Use of Live Animals for Teaching and Research of the Fourth Military Medical University. Twelve adult male Sprague-Dawley rats (280–300 g) were randomly divided into 2 groups. Rats in the experimental group (n = 6) underwent right mandibular DO as described in our previous studies (Wang et al., 2012). Briefly, rats were anaesthetized with 1% pentobarbital sodium (30 mg/kg) injected intraperitoneally. A vertical osteotomy was created
In vivo mechanical strain activated p38 in BMMSCs
In the present study, we used a rat mandibular DO model to investigate the effect of mechanical strain on BMMSCs in vivo (Fig. 1). Steady distraction at the broken ends of the bone provides a nearly static mechanical strain on BMMSCs. Two rats in the experimental group and one in the control group died during surgery and were excluded from the study. Nestin was used as a BMMSC marker protein in this study. As shown in Fig. 2, Nestin+ cells were more abundant in bone calluses of the experimental
Discussion
The ability to accommodate and react to the microenvironment is critical for homeostasis of bone. The process of mechanotransduction involves perception of the physical cues and conversion into intracellular molecular signals, which induce cell responses and eventually bone reactions (Papachristou, Papachroni, Basdra, & Papavassiliou, 2009). It has been suggested that osteocytes govern mechanical adaptation by sensing the mechanical cues and translating them into molecular signals that induce
Conflict of interest
The authors declare there is no conflict of interest.
Acknowledgements
This work was supported by Shanghai Summit & Plateau Disciplines and the National Natural Science Foundation of China (No. 81270015 to LW), and an independent grant from State Key Laboratory of Military Stomatology, School of Stomatology, the Fourth Military Medical University (No. 2014ZA05 to DL).
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Zihui Yang and Baolei Wu are joint first authors on this work.