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and proliferation of Cd36-nu\\ MSCs may be altered due to up-regulation of CcnA2 and Dl, coupled to PPARy-induced overexpression of Foxol. In addition, constitutively active F0X01 inhibits the differentiation of pre-adipocytes into maturę adipocytes (Nakae et al., 2003), potentially explaining the Cd36-nuli mice lipodystrophy.

It was recently proposed that Wnt signaling is partially regulated by Foxo transcription factors (Almeida et al., 2007; Iyer et al., 2013). The increased Foxol expression in Cd36 deficient MSCs hinted at potential alterations of Wnt signaling. We therefore studied the expression of major Wnt pathway molecules. No change was observed in the expression of Rspo2 and Lrp5/6 co-receptors. However, the Wnt3a and Wnt5a agonist was found to be 40% less expressed in Cd36-nuli cells. Furthermore, Wnt antagonists Sost and Dkkl expression was increased over 2-fold compared to WT cells. Thus, the deregulation of Wnt pathway members may be explained, at least in part, by Foxol increased expression in Cd36-nuli mice. Sost and Dkkl both inhibit osteoblast function and bonę formation by competing with Wnt for binding sites to LRP5 and LRP6. Transgenic mice overexpressing human SOST exhibit lower bonę mass (Loots et al., 2005), as SostKO mice demonstrate higher bonę mass with increased bonę formation (Li et al., 2008). Similarly, Dkkl haploinsufficiency promotes bonę formation through increased Wnt canonical signaling (Morvan et al., 2006), as its overexpression lead to a Iow bonę mass phenotype related to reduced bonę formation (Li et al., 2006; Yao et al., 2011).

Binding of p-catenin to FOXOs diverts TCF-mediated to FOXO-mediated transcription, decreasing osteoblastogenesis in vitro (Almeida et al., 2007) and attenuating p-catenin/TCF transcription in osteoblast progenitors in vivo (Iyer et al., 2013). Activation of the Wnt pathway leads to increased expression of Axin2, which acts as a negative regulator of canonical Wnt signaling through the promotion of (3-catenin degradation. Targeted disruption of Axin2 in mice accelerates osteoblast