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

Sunao Takeshita, Noriyuki Namba, Jenny J. Zhao, Yebin Jiang, Harry K. Genant, Matthew J. Silva, Michael D. Brodt, Cheryl D. Helgason, Janet Kalesnikoff, Michael J. Rauh, R. Keith Humphries, Gerald Krystal, Steven L. Teitelbaum, F. Patrick Ross

Research output: Contribution to journalArticlepeer-review

223 Scopus citations


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-κB 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.

Original languageEnglish
Pages (from-to)943-949
Number of pages7
JournalNature medicine
Issue number9
StatePublished - Sep 2002


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