Cargando…

Ablation of the Sam68 RNA Binding Protein Protects Mice from Age-Related Bone Loss

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2005
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1315279/
https://www.ncbi.nlm.nih.gov/pubmed/16362077
http://dx.doi.org/10.1371/journal.pgen.0010074
_version_ 1782126374114295808
author 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
author_facet 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
author_sort Richard, Stéphane
collection PubMed
description 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.
format Text
id pubmed-1315279
institution National Center for Biotechnology Information
language English
publishDate 2005
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-13152792005-12-16 Ablation of the Sam68 RNA Binding Protein Protects Mice from Age-Related Bone Loss 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 PLoS Genet Research Article 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. Public Library of Science 2005-12 2005-12-16 /pmc/articles/PMC1315279/ /pubmed/16362077 http://dx.doi.org/10.1371/journal.pgen.0010074 Text en Copyright: © 2005 Richard et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
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
Ablation of the Sam68 RNA Binding Protein Protects Mice from Age-Related Bone Loss
title Ablation of the Sam68 RNA Binding Protein Protects Mice from Age-Related Bone Loss
title_full Ablation of the Sam68 RNA Binding Protein Protects Mice from Age-Related Bone Loss
title_fullStr Ablation of the Sam68 RNA Binding Protein Protects Mice from Age-Related Bone Loss
title_full_unstemmed Ablation of the Sam68 RNA Binding Protein Protects Mice from Age-Related Bone Loss
title_short Ablation of the Sam68 RNA Binding Protein Protects Mice from Age-Related Bone Loss
title_sort ablation of the sam68 rna binding protein protects mice from age-related bone loss
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1315279/
https://www.ncbi.nlm.nih.gov/pubmed/16362077
http://dx.doi.org/10.1371/journal.pgen.0010074
work_keys_str_mv AT richardstephane ablationofthesam68rnabindingproteinprotectsmicefromagerelatedboneloss
AT torabinazi ablationofthesam68rnabindingproteinprotectsmicefromagerelatedboneloss
AT francogladysvalverde ablationofthesam68rnabindingproteinprotectsmicefromagerelatedboneloss
AT tremblayguya ablationofthesam68rnabindingproteinprotectsmicefromagerelatedboneloss
AT chentaiping ablationofthesam68rnabindingproteinprotectsmicefromagerelatedboneloss
AT vogelgillian ablationofthesam68rnabindingproteinprotectsmicefromagerelatedboneloss
AT morelmelanie ablationofthesam68rnabindingproteinprotectsmicefromagerelatedboneloss
AT clerouxpatrick ablationofthesam68rnabindingproteinprotectsmicefromagerelatedboneloss
AT forgetrichardalexandre ablationofthesam68rnabindingproteinprotectsmicefromagerelatedboneloss
AT komarovasvetlana ablationofthesam68rnabindingproteinprotectsmicefromagerelatedboneloss
AT tremblaymichell ablationofthesam68rnabindingproteinprotectsmicefromagerelatedboneloss
AT liwei ablationofthesam68rnabindingproteinprotectsmicefromagerelatedboneloss
AT liailian ablationofthesam68rnabindingproteinprotectsmicefromagerelatedboneloss
AT gaoyunjing ablationofthesam68rnabindingproteinprotectsmicefromagerelatedboneloss
AT hendersonjanete ablationofthesam68rnabindingproteinprotectsmicefromagerelatedboneloss