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

Nature Medicine volume 8, pages 943–949 (2002)Cite this article

Abstract

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.

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Figure 1: Absence of SHIP results in increased OCs.
Figure 2: Osteoclastogenesis by M-CSF and RANKL is increased in SHIP−/−mice.
Figure 3: SHIP deficiency results in decreased OC apoptosis.
Figure 4: SHIP suppresses osteoclastic bone resorption and serum IL-6 levels.
Figure 5: SHIP−/− mice are osteoporotic.
Figure 6: SHIP−/− bones have reduced areal BMD and whole-bone strength.

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Acknowledgements

This work was supported by grants from National Institutes of Health (NIH) to S.L.T. and F.P.R. and the National Cancer Institute of Canada ro K.A.H. and G.K.

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Author notes

  1. Sunao Takeshita and Noriyuki Namba: S.T. and N.N. contributed equally to this study.

Authors and Affiliations

  1. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA

    Sunao Takeshita, Noriyuki Namba, Steven L. Teitelbaum & F. Patrick Ross

  2. Department of Pediatrics, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan

    Noriyuki Namba

  3. Department of Radiology, Osteoporosis and Arthritis Research Group, University of California, San Francisco, USA

    Jenny J. Zhao, Yebin Jiang & Harry K. Genant

  4. Department of Orthopedic Surgery, Washington University School of Medicine, St. Louis, Missouri, USA

    Matthew J. Silva & Michael D. Brodt

  5. Terry Fox Laboratory, BC Cancer Agency, Vancouver, Canada

    Cheryl D. Helgason, Janet Kalesnikoff, Michael J. Rauh, R. Keith Humphries & Gerald Krystal

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Correspondence to F. Patrick Ross.

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Takeshita, S., Namba, N., Zhao, J. et al. SHIP-deficient mice are severely osteoporotic due to increased numbers of hyper-resorptive osteoclasts. Nat Med 8, 943–949 (2002). https://doi.org/10.1038/nm752

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