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* Department of Pathology, Washington University School of Medicine, St. Louis, MO 63110;
Department of Pediatrics, Osaka University, Osaka, Japan;
Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, Canada; and
Department of Bone and Joint Disease, National Institute for Longevity Sciences, National Center for Geriatrics and Gerontology, Aichi, Japan
Osteoclasts arise from macrophage progenitors in bone marrow (BMMs) as a consequence of signaling events elicited by M-CSF and receptor activator of NF-
B ligand, acting on their unique receptors, via c-Fms and receptor activator of NF-B. 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-B 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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grants from National Institutes of Health: AR032788, AR048853, and AR046523 (to S.L.T.); AR048812 and AR046852 (to F.P.R.); 5T32AR0703331 (to P.Z.); and the Paget Foundation (to S.L.T.).
2 Address correspondence and reprint requests to Dr. Sunao Takeshita, Section of Joint Disease, Department of Bone and Joint Disease, National Institute for Longevity Sciences, National Center for Geriatrics and Gerontology, 36-3, Gengo, Morioka, Obu, Aichi, 474-8522 Japan. E-mail address: sunao{at}nils.go.jp
3 Abbreviations used in this paper: BMM, bone marrow macrophage; CDK, cyclin-dependent kinase; HA, hemagglutinin; RANKL, receptor activator of NF-B ligand; Rb, retinoblastoma; TRAP, tartrate-resistant acid phosphatase; WT, wild type.
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