SHIP-deficient mice are severely osteoporotic due to increased numbers of hyper-resorptive osteoclasts

Nat Med. 2002 Sep;8(9):943-9. doi: 10.1038/nm752. Epub 2002 Aug 5.


The hematopoietic-restricted protein Src homology 2-containing inositol-5-phosphatase (SHIP) blunts phosphatidylinositol-3-kinase-initiated signaling by dephosphorylating its major substrate, phosphatidylinositol-3,4,5-trisphosphate. As SHIP(-/-) mice contain increased numbers of osteoclast precursors, that is, macrophages, we examined bones from these animals and found that osteoclast number is increased two-fold. This increased number is due to the prolonged life span of these cells and to hypersensitivity of precursors to macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor-kappa B ligand (RANKL). Similar to pagetic osteoclasts, SHIP(-/-) osteoclasts are enlarged, containing upwards of 100 nuclei, and exhibit enhanced resorptive activity. Moreover, as in Paget disease, serum levels of interleukin-6 are markedly increased in SHIP(-/-) mice. Consistent with accelerated resorptive activity, 3D trabecular volume fraction, trabecular thickness, number and connectivity density of SHIP(-/-) long bones are reduced, resulting in a 22% loss of bone-mineral density and a 49% decrease in fracture energy. Thus, SHIP negatively regulates osteoclast formation and function and the absence of this enzyme results in severe osteoporosis.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Bone Density
  • Bone Resorption / genetics
  • Carrier Proteins / pharmacology
  • Cell Count
  • Cells, Cultured
  • Interleukin-6 / blood
  • Macrophage Colony-Stimulating Factor / pharmacology
  • Macrophages / drug effects
  • Membrane Glycoproteins / pharmacology
  • Mice
  • Mice, Mutant Strains
  • Osteoclasts / drug effects
  • Osteoclasts / metabolism
  • Osteoclasts / pathology*
  • Osteoporosis / pathology*
  • Osteoporosis / physiopathology*
  • Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases
  • Phosphoric Monoester Hydrolases / deficiency*
  • Phosphoric Monoester Hydrolases / genetics
  • RANK Ligand
  • Receptor Activator of Nuclear Factor-kappa B


  • Carrier Proteins
  • Interleukin-6
  • Membrane Glycoproteins
  • RANK Ligand
  • Receptor Activator of Nuclear Factor-kappa B
  • TNFRSF11A protein, human
  • TNFSF11 protein, human
  • Tnfrsf11a protein, mouse
  • Tnfsf11 protein, mouse
  • Macrophage Colony-Stimulating Factor
  • Phosphoric Monoester Hydrolases
  • INPPL1 protein, human
  • Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases