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Papers In Press, published online ahead of print February 6, 2006
Pathology, University of Rochester, Rochester, NY 14642
Corresponding Author: lianping_xing{at}urmc.rochester.edu
Osteoclasts are essential cells for bone erosion in inflammatory arthritis and are derived from cells in the myeloid lineage. Recently, we reported that TNF increases the blood osteoclast precursor (OCP) numbers in arthritic patients and animals, which are reduced by anti-TNF therapy, implying that circulating OCPs may have an important role in the pathogenesis of erosive arthritis. The aim of this study is to investigate the mechanism by which TNF induces this increase in OCP frequency. We found that TNF stimulated cell division and conversion of CD11b+/Gr-1-/lo/c-Fms- to CD11b+/Gr-1-/lo/c-Fms+ cells, which was not blocked by neutralizing M-CSF antibody. Ex vivo analysis of monocytes demonstrated that: i) blood and bone marrow CD11b+/Gr-1-/lo, but not CD11b-/Gr-1- cells, give rise to osteoclasts when they were cultured with RANKL and M-CSF; and ii) TNF-Tg mice have a significant increase in blood CD11b+/Gr-1-/lo cells and bone marrow proliferating CD11b+/Gr-1-/lo cells. Administration of TNF to wt mice induced bone marrow CD11b+/Gr-1-/lo cell proliferation, which was associated with a increase in CD11b+/Gr-1-/lo OCPs in the circulation. Thus, TNF directly stimulates bone marrow OCP genesis by enhancing c-Fms expression. This results in progenitor cell proliferation and differentiation in response to M-CSF, leading to an enlargement of the marrow OCP pool. Increased marrow OCPs subsequently egress to the circulation, forming a basis for elevated OCP frequency. Therefore, the first step of TNF-induced osteoclastogenesis is at the level of OCP genesis in the bone marrow, which represents another layer of regulation to control erosive disease.
J. Biol. Chem, 10.1074/jbc.M512624200
Submitted on November 28, 2005
Accepted on February 6, 2006
Tnf increases circulating osteoclast precursor numbers by promoting their proliferation and differentiation in the bone marrow through up-regulation of c-fms expression
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