3513659552

98

explained, at least in part, by diminution of blood leptin level and alterations of Wnt signaling pathway in MSCs.

3.4 Introduction

Bonę tissue development and maintenance require balance between bonę celi proliferation, survival, and differentiation, which are modulated by a network of signaling pathways and transcription factors. The osteoblasts are specialized mononuclear cells responsible for the deposition and mineralisation of bonę matrix. These bone-forming cells derive from the bonę marrow mesenchymal stem cells (MSCs) (Fakhry et al., 2013) which are also precursors for chondrocytes and adipocytes. The commitment and differentiation of MSC towards specialized cells depend on a variety of signaling pathways and transcription factors.

Several major signaling pathways, such a Wnt, BMP, FGF and hedgehog (HH), play an important role in regulating osteogenic differentiation from MSCs (Gordon et Nusse 2006; Luu et al., 2007; James et al., 2010). Wnt signaling represses MSCs commitment to the chondrogenic and adipogenic lineages and enhances commitment to, and differentiation along, the osteoblastic lineage (Hill et al2005; Kennell et MacDougald, 2005; Miclea et al., 2009). The Wnt family is represented by 20 secreted glycoproteins with post-translational lipid modifications (palmitoylation), involved in signaling cascades (classified as canonical and non-canonical) essential for embryonic development and tissue regeneration (Logan et Nusse, 2004). Wnt proteins function through a complex of FZD and LRP5/6, which activate two signaling pathways: the p-catenin-dependent canonical or P-catenin-independent non-canonical pathway (Gordon et Nusse, 2006). Following Wnt binding, the intracellular taił of LRP5/6 binds Axinl or Axin2 and causes dissociation of P-catenin from its protein complex and activation of P-catenin signaling (Mao et al., 2001). p-catenin