Ablation of the Sam68 RNA binding protein protects mice from age-related bone loss |
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Authors: | Richard Stéphane Torabi Nazi Franco Gladys Valverde Tremblay Guy A Chen Taiping Vogel Gillian Morel Mélanie Cléroux Patrick Forget-Richard Alexandre Komarova Svetlana Tremblay Michel L Li Wei Li Ailian Gao Yun Jing Henderson Janet E |
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Institution: | Stéphane Richard, Nazi Torabi, Gladys Valverde Franco, Guy A Tremblay, Taiping Chen, Gillian Vogel, Mélanie Morel, Patrick Cléroux, Alexandre Forget-Richard, Svetlana Komarova, Michel L Tremblay, Wei Li, Ailian Li, Yun Jing Gao, and Janet E Henderson |
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Abstract: | The Src substrate associated in mitosis of 68 kDa (Sam68) is a KH-type RNA binding protein that has been shown to regulate several aspects of RNA metabolism; however, its physiologic role has remained elusive. Herein we report the generation of Sam68-null mice by homologous recombination. Aged Sam68−/− mice preserved their bone mass, in sharp contrast with 12-month-old wild-type littermates in which bone mass was decreased up to approximately 75%. In fact, the bone volume of the 12-month-old Sam68−/− mice was virtually indistinguishable from that of 4-month-old wild-type or Sam68−/− mice. Sam68−/− bone marrow stromal cells had a differentiation advantage for the osteogenic pathway. Moreover, the knockdown of Sam68 using short hairpin RNA in the embryonic mesenchymal multipotential progenitor C3H10T1/2 cells resulted in more pronounced expression of the mature osteoblast marker osteocalcin when differentiation was induced with bone morphogenetic protein-2. Cultures of mouse embryo fibroblasts generated from Sam68+/+ and Sam68−/− littermates were induced to differentiate into adipocytes with culture medium containing pioglitazone and the Sam68−/− mouse embryo fibroblasts shown to have impaired adipocyte differentiation. Furthermore, in vivo it was shown that sections of bone from 12-month-old Sam68−/− mice had few marrow adipocytes compared with their age-matched wild-type littermate controls, which exhibited fatty bone marrow. Our findings identify endogenous Sam68 as a positive regulator of adipocyte differentiation and a negative regulator of osteoblast differentiation, which is consistent with Sam68 being a modulator of bone marrow mesenchymal cell differentiation, and hence bone metabolism, in aged mice. |
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