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-/- 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.
Richard
Stéphane
S
Terry Fox Molecular Oncology Group and the Bloomfield Center for Research on Aging, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, Montréal, Québec, Canada. stephane.richard@mcgill.ca
Torabi
Nazi
N
Franco
Gladys Valverde
GV
Tremblay
Guy A
GA
Chen
Taiping
T
Vogel
Gillian
G
Morel
Mélanie
M
Cléroux
Patrick
P
Forget-Richard
Alexandre
A
Komarova
Svetlana
S
Tremblay
Michel L
ML
Li
Wei
W
Li
Ailian
A
Gao
Yun Jing
YJ
Henderson
Janet E
JE
D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D017667:Adipocytes / Q000166:cytology; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000502:physiology*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000166:cytology; D015675:Osteocalcin / Q000235:genetics; D010024:Osteoporosis / Q000235:genetics*; D010750:Phosphoproteins / Q000502:physiology*; D016601:RNA-Binding Proteins / Q000502:physiology*; D011995:Recombination, Genetic
D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C489559:KHDRBS1 protein, human; C513253:Khdrbs1 protein, mouse; D010750:Phosphoproteins; D016601:RNA-Binding Proteins; D015675:Osteocalcin