Ablation of the Sam68 RNA binding protein protects mice from age-related bone loss

PLoS Genet. 2005 Dec;1(6):e74. doi: 10.1371/journal.pgen.0010074. Epub 2005 Dec 16.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / physiology*
  • Adipocytes / cytology
  • Animals
  • Bone Marrow Cells / cytology
  • Cell Differentiation
  • DNA-Binding Proteins / physiology*
  • Female
  • Fibroblasts / metabolism
  • Humans
  • Male
  • Mice
  • Mice, Inbred C3H
  • Mice, Transgenic
  • Osteoblasts / cytology
  • Osteocalcin / genetics
  • Osteoporosis / genetics*
  • Phosphoproteins / physiology*
  • RNA-Binding Proteins / physiology*
  • Recombination, Genetic


  • Adaptor Proteins, Signal Transducing
  • DNA-Binding Proteins
  • KHDRBS1 protein, human
  • Khdrbs1 protein, mouse
  • Phosphoproteins
  • RNA-Binding Proteins
  • Osteocalcin