N-linked glycoprotein family of proteins, which interacts with certain variants of the hyaluronan receptor CD44 and with a variety of integrins by both RGD-dependent and independent mechanisms

Efficient regeneration of injured or dystrophic skeletal muscle relies upon the coordinated action of invading inflammatory cells that induce muscle fibre necrosis and phagocytosis (Lescaudron et al., 1999; Tidball and Wehling-Henricks, 2007), and an endogenous pool of quiescent myogenic stem cells known as satellite cells that form new muscle fibres (Zammit et al., 2006). The failure of efficient muscle regeneration, such as occurs in dystrophic muscle, results in fibrosis of the muscle, which reduces its functional capacity and its ability to regenerate in response to further injury (Huard et al., 2002). The factors that control and coordinate inflammation and myogenesis during muscle regeneration are both complex and poorly understood. This study aims to examine the role of the multifunctional glycoprotein osteopontin in these processes. Osteopontin, also known as early T-lymphocyte activation 1 protein (ETA1), secreted phosphoprotein 1 (SPP1) and bone sialoprotein 1 (BSP1), is a member of the small integrin-binding N-linked glycoprotein family of proteins, which interacts with certain variants of the hyaluronan receptor CD44 and with a variety of integrins by both RGD-dependent and independent mechanisms (Denhardt and Guo, 1993). Osteopontin exists both as an adhesive component of the extracellular matrix and as a soluble molecule with cytokine-like functions (O’Regan and Berman, 2000). It is expressed by a wide range of cells and promotes attachment, proliferation, migration, chemotaxis and apoptosis of macrophages, lymphocytes, osteoblasts and a range of tumour cells (Giachelli et al., 1998; O’Regan et al., 1999; Standal et al., 2004), regulating many pathological and physiological processes, including tissue repair, inflammation and fibrosis (Mori et al., 2008; O’Regan and Berman, 2000; Pardo et al., 2005). Although no developmental abnormalities have been reported in mice in which the osteopontin gene has been targeted by homologous recombination (Rittling et al., 1998), altered responses to injury such as skin incision, spinal cord injury, bone healing and ventricular and lung fibrosis have been described (Berman et al., 2004; Duvall et al., 2007; Hashimoto et al., 2007; Liaw et al., 1998; Sam et al., 2004). Osteopontin has been described as a component of the inflammatory milieu of dystrophic and injured skeletal muscles (Haslett et al., 2002; Hirata et al., 2003; Porter et al., 2002). We have recently demonstrated that osteopontin is expressed by myoblasts in areas of focal muscle necrosis in the muscles of dystrophic mdx mice (dystrophin-deficient mice used as a model for muscular dystrophy), and that recombinant mouse osteopontin is able to influence adhesion, proliferation and differentiation of skeletal muscle myoblasts (Uaesoontrachoon et al., 2008). However, the role of osteopontin in muscle injury and regeneration remains unclear. For example, Vetrone and colleagues found that osteopontin promotes fibrosis of aged dystrophic mouse skeletal diaphragm muscles (Vetrone et al., 2009), whereas Pegoraro and colleagues reported that a polymorphism (rs28357094) in the osteopontin gene promoter, which reduces osteopontin mRNA expression in transfected HeLa cells (Giacopelli et al., 2004), is correlated with decreased muscle strength and a younger age at loss of ambulation in patients with Duchenne muscular dystrophy (Pegoraro et al., 2011). These findings suggest that the role that osteopontin plays in response to injury is complex, contributing to both muscle repair