SHIP1 negatively regulates proliferation of osteoclast precursors via Akt-dependent alterations in D-type cyclins and p27.
Osteoclasts arise from macrophage progenitors in bone marrow (BMMs) as a consequence of signaling events elicited by M-CSF and receptor activator of NF-kappaB ligand, acting on their unique receptors, via c-Fms and receptor activator of NF-kappaB. Both receptors activate the PI3K and MAPK pathways, which promote cell proliferation and survival. SHIP1 is essential for normal bone homeostasis, as mice lacking the protein exhibit osteoporosis resulting from increased numbers of hyper-resorptive osteoclasts. In this study, we show that BMMs from SHIP1 null mice respond to M-CSF, but not receptor activator of NF-kappaB ligand, by increasing Akt activation. In consequence, there are up-regulation of D-type cyclins, down-regulation of the cyclin-dependent kinase inhibitor p27, and, therefore, increased phosphorylation of the retinoblastoma protein and cell proliferation. Surprisingly, cell survival of wild-type and knockout BMMs is unaltered. Finally, osteoclastogenesis and periarticular bone erosions are markedly increased in SHIP1(-/-) mice with inflammatory arthritis, a condition characterized by increased M-CSF expression. The SHIP1/Akt pathway therefore suppresses bone loss in pathological states associated with an excess of the cytokine.
Zhou
Ping
P
Department of Pathology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Kitaura
Hideki
H
Teitelbaum
Steven L
SL
Krystal
Gerald
G
Ross
F Patrick
FP
Takeshita
Sunao
S
D000818:Animals; D001168:Arthritis / Q000473:pathology; D001854:Bone Marrow Cells; D001862:Bone Resorption / Q000517:prevention & control; D049109:Cell Proliferation; D056741:Cyclin D; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism*; D016213:Cyclins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D000072181:Inositol Polyphosphate 5-Phosphatases; D016173:Macrophage Colony-Stimulating Factor / Q000502:physiology; D008264:Macrophages / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D010010:Osteoclasts / Q000473:pathology*; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000172:deficiency / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*
D056741:Cyclin D; D016213:Cyclins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016173:Macrophage Colony-Stimulating Factor; D051057:Proto-Oncogene Proteins c-akt; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases; C000606433:Inpp5d protein, mouse; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases