SHIP-deficient mice are severely osteoporotic due to increased numbers of hyper-resorptive osteoclasts.
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.
Takeshita
Sunao
S
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.
Namba
Noriyuki
N
Zhao
Jenny J
JJ
Jiang
Yebin
Y
Genant
Harry K
HK
Silva
Matthew J
MJ
Brodt
Michael D
MD
Helgason
Cheryl D
CD
Kalesnikoff
Janet
J
Rauh
Michael J
MJ
Humphries
R Keith
RK
Krystal
Gerald
G
Teitelbaum
Steven L
SL
Ross
F Patrick
FP
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D015519:Bone Density; D001862:Bone Resorption / Q000235:genetics; D002352:Carrier Proteins / Q000494:pharmacology; D002452:Cell Count; D002478:Cells, Cultured; D015850:Interleukin-6 / Q000097:blood; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects; D008562:Membrane Glycoproteins / Q000494:pharmacology; D051379:Mice; D008817:Mice, Mutant Strains; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D010024:Osteoporosis / Q000473:pathology* / Q000503:physiopathology*; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000172:deficiency* / Q000235:genetics; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B
D002352:Carrier Proteins; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C505686:TNFRSF11A protein, human; C505688:TNFSF11 protein, human; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse; D016173:Macrophage Colony-Stimulating Factor; D010744:Phosphoric Monoester Hydrolases; C098706:INPPL1 protein, human; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases