Nature Medicine
8, 943 - 949 (2002)
Published online: 5 August 2002; | doi:10.1038/nm752
SHIP-deficient mice are severely osteoporotic due to increased numbers of hyper-resorptive osteoclastsSunao Takeshita1, 6, Noriyuki Namba1, 2, 6, Jenny J. Zhao3, Yebin Jiang3, Harry K. Genant3, Matthew J. Silva4, Michael D. Brodt4, Cheryl D. Helgason5, Janet Kalesnikoff5, Michael J. Rauh5, R. Keith Humphries5, Gerald Krystal5, Steven L. Teitelbaum1
& F. Patrick Ross11
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA
2
Department of Pediatrics, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan
3
Osteoporosis and Arthritis Research Group, Department of Radiology, University of California, San Francisco, USA
4
Department of Orthopedic Surgery, Washington University School of Medicine, St. Louis, Missouri, USA
5
Terry Fox Laboratory, BC Cancer Agency, Vancouver, Canada
6
S.T. and N.N. contributed equally to this study.
Correspondence should be addressed to F. Patrick Ross rossf@medicine.wustl.eduThe 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- 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.
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