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    • The following are the supplementary data

    2018-11-06

    The following are the supplementary data related to this article.
    Acknowledgments
    Introduction Inflammation, trauma and tumors may all lead to articular cartilage defects. However, the treatment of these defects remains a clinical challenge. Currently, clinical treatments for articular cartilage defects primarily include autologous cartilage repair (Steadman et al., 2003) and autologous periosteum, cartilage or chondrocyte transplantation (Hangody and Fules, 2003; Outerbridge et al., 1995). The therapeutic efficacies of these approaches are far from ideal. The application of tissue engineering for the repair of articular cartilage defects has become a clinical focus (Johnstone et al., 2013; Wei et al., 2005). Currently, bone marrow mesenchymal stem purchase Atractyloside Dipotassium Salt (BMSCs) have become one of the most important seed cell options in cartilage tissue engineering (Dezawa et al., 2004; Luk et al., 2005) due to readily available sources, strong in vitro proliferative abilities, weak immune rejection responses, and strong chondrogenic differentiation potentials (Alford and Cole, 2005; Hangody and Fules, 2003; Hunziker, 2001; Panseri et al., 2012; Shapiro et al., 1993; Smith et al., 2003). Articular cartilage plays an important role in mechanical load support and load transfer in a joint. Mechanical loading stimulates cartilage matrix synthesis and enhances the biomechanical properties of the cartilage (De Croos et al., 2006; Hunter et al., 2002). Therefore, numerous studies have focused on the effects of the mechanoenvironment on seed cells in tissue-engineered cartilage (Carter et al., 1998; Carter and Wong, 1988; Henderson and Carter, 2002; Loboa et al., 2001; Thompson et al., 2012). Hydrostatic pressure applications are methods of applying mechanical loading that mimics the compressive forces borne by cartilage in a joint cavity (Gray et al., 1988). Studies have shown that mechanical stimulation by hydrostatic pressure promotes the expression of the chondrogenic marker genes of BMSCs (Angele et al., 2003; Miyanishi et al., 2006a, 2006b; Wagner et al., 2008; Zeiter et al., 2009). Our preliminary studies have also demonstrated that hydrostatic pressure promotes BMSC proliferation and cytoskeletal assembly (Zhang et al., 2012). However, the mechanisms through which the mechanical signals are transmitted to BMSCs and induce the above-mentioned responses remain unclear. The perception and transduction of the stimulus by cells are closely related to the cytoskeleton, which plays a number of key roles in cellular mechanotransduction (Ingber, 2002; Wang et al., 2002). A wide variety of cellular activities involving actin dynamics are regulated by the Ras homolog gene family (Rho) subfamily of small guanosine triphosphatases (GTPases) (Etienne-Manneville and Hall, 2002). Rho GTPases not only function as key regulators of stress fiber assembly and focal adhesion formation (Darling and Guilak, 2008) but also play a central role in the regulation of the actin cytoskeleton (Shifrin et al., 2009). Studies have shown that compared with undifferentiated cells, stem cells are softer and more sensitive to local stress stimulation, and the extraordinary sensitivity of embryonic stem cells to stress is closely regulated by the Rho family of GTPases (Chowdhury et al., 2010). Rho GTPases are involved in integrin-mediated mechanotransduction (Burridge and Wennerberg, 2004; Matthews et al., 2006) and regulate stress fiber formation in adult stem cells under mechanical stimulation (Discher et al., 2009). Rac1 plays an important regulatory role in cytoskeletal assembly during lamellipodia formation in cells under mechanical stimulation (Hu et al., 2002; Masuda and Fujiwara, 1993a, 1993b). However, the exact roles of RhoA and Rac1 in the regulation of hydrostatic pressure-induced BMSC cytoskeleton assembly and its down-stream molecular mechanisms are unclear. In addition, studies have found that the inhibition of the RhoA-Rho-associated protein kinase (ROCK) signaling pathway results in an enhanced expression of chondrogenic genes (Woods et al., 2005). The activation of Rac1 results in the increased expression of cadherin protein and chondrogenic genes in BMSCs (Woods et al., 2007). These results indicate that the activities of Rho GTPase signaling molecules are closely related to the differentiation and the fate of BMSCs. Nevertheless, the roles of Rho GTPases in BMSC differentiation induced by the hydrostatic microenvironment have yet to be elucidated.