The molecular mechanisms underlying telomere shortening and telomerase deficiency contributing to defective age-related bone formation are poorly studied. We have previously demonstrated the role of telomerase re-activation in enhancing osteoblast differentiation of BMSCs in vitro and in vivo. Here, we investigated further the signaling pathways underlying the regulatory function of telomerase in osteogenesis. Comparative microarray analysis of telomerase-over expressing hMSC (hMSC-TERT) vs primary hBMSC revealed significant up-regulation of IGF signaling in response to telomerase expression at baseline (−log P value; 5, obtained by right-tailed Fishers exact test). Western blot analysis of IGF/PI3K/AKT signaling showed a significant increase in IGF-induced AKT phosphorylation in hMSC-TERT vs primary hMSCs. To further investigate the loss function of telomerase on IGF-induced osteogenesis in vivo, we employed the telomerase deficient mice (Terc−/−). As compared to WT controls, the bone loss phenotype of Terc−/− mice was shown to be associated with significant reduction in serum levels of Igf1 and Igfbp3 and reduced mRNA expression of Igf1, Igf2, Igf2r, Igfbp5 and Igfbp6. Accordingly, IGF1-induced osteogenesis was inhibited in Terc−/− MSCs as compared to WT controls due to the impairment of IGF-induced AKT activation. In conclusion, our data demonstrated that the anabolic effect of telomerase on bone formation is mediated at least in part by modulating IGF/IGFBPs signaling.
17 May 2014 - 20 May 2014