title: Telomerase activity promotes osteoblast differentiation by modulating IGF-signaling pathway.
abstract: The contribution of deficient telomerase activity to age-related decline in osteoblast functions and bone formation is poorly studied. We have previously demonstrated that telomerase over-expression led to enhanced osteoblast differentiation of human bone marrow skeletal (stromal) stem cells (hMSC) in vitro and in vivo. Here, we investigated the signaling pathways underlying the regulatory functions of telomerase in osteoblastic cells. Comparative microarray analysis and Western blot analysis of telomerase-over expressing hMSC (hMSC-TERT) versus primary hMSC revealed significant up-regulation of several components of insulin-like growth factor (IGF) signaling. Specifically, a significant increase in IGF-induced AKT phosphorylation and alkaline phosphatase (ALP) activity were observed in hMSC-TERT. Enhanced ALP activity was reduced in presence of IGF1 receptor inhibitor: picropodophyllin. In addition, telomerase deficiency caused significant reduction in IGF signaling proteins in osteoblastic cells cultured from telomerase deficient mice (Terc(-/-)). The low bone mass exhibited by Terc(-/-) mice was associated with significant reduction in serum levels of IGF1 and IGFBP3 as well as reduced skeletal mRNA expression of Igf1, Igf2, Igf2r, Igfbp5 and Igfbp6. IGF1-induced osteoblast differentiation was also impaired in Terc(-/-) MSC. In conclusion, our data demonstrate that impaired IGF/AKT signaling contributes to the observed decreased bone mass and bone formation exhibited by telomerase deficient osteoblastic cells.
authors.affiliation: Molecular Endocrinology Laboratory (KMEB), Department of Endocrinology and Metabolism, Medical Biotechnology Center, Odense University Hospital & University of Southern Denmark, SDU, 5000, Odense C, Denmark. hamid.pharmacy@pu.edu.pk.|University College of Pharmacy, Punjab University, Allama Iqbal Campus, Lahore, 54000, Pakistan. hamid.pharmacy@pu.edu.pk.
authors.forename: Hamid
authors.initials: H
authors.lastname: Saeed
authors.affiliation: Molecular Endocrinology Laboratory (KMEB), Department of Endocrinology and Metabolism, Medical Biotechnology Center, Odense University Hospital & University of Southern Denmark, SDU, 5000, Odense C, Denmark. wqiu@health.sdu.dk.
authors.forename: Weimin
authors.initials: W
authors.lastname: Qiu
authors.affiliation: Molecular Endocrinology Laboratory (KMEB), Department of Endocrinology and Metabolism, Medical Biotechnology Center, Odense University Hospital & University of Southern Denmark, SDU, 5000, Odense C, Denmark. lchen@health.sdu.dk.
authors.forename: Chen
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Endcrinology, University Hosptial of Aarhus, 8000, Aarhus C, Denmark. dean.health@au.dk.
authors.forename: Allan
authors.initials: A
authors.lastname: Flyvbjerg
authors.affiliation: Molecular Endocrinology Laboratory (KMEB), Department of Endocrinology and Metabolism, Medical Biotechnology Center, Odense University Hospital & University of Southern Denmark, SDU, 5000, Odense C, Denmark. babdallah@health.sdu.dk.|Faculty of Scince, Helwan University, Cairo, Egypt. babdallah@health.sdu.dk.
authors.forename: Basem M
authors.initials: BM
authors.lastname: Abdallah
authors.affiliation: Molecular Endocrinology Laboratory (KMEB), Department of Endocrinology and Metabolism, Medical Biotechnology Center, Odense University Hospital & University of Southern Denmark, SDU, 5000, Odense C, Denmark. mkassem@health.sdu.dk.|Stem Cell Unit, King Saud University, Riyadh, Saudi Arabia. mkassem@health.sdu.dk.
authors.forename: Moustapha
authors.initials: M
authors.lastname: Kassem
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology; D004789:Enzyme Activation; D006801:Humans; D018969:Insulin-Like Growth Factor Binding Proteins / Q000097:blood / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010006:Osteoblasts / Q000166:cytology* / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012313:RNA / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013002:Somatomedins / Q000378:metabolism*; D019098:Telomerase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D018969:Insulin-Like Growth Factor Binding Proteins; D013002:Somatomedins; C422952:telomerase RNA; D012313:RNA; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D019098:Telomerase
keywords: Aging; Bone; Bone marrow stromal stem cells; IGF; Osteoblasts; Telomerase