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Monocytes beget macrophages, and fused macrophages beget bone-resorbing osteoclasts. Factors such as monocyte-colony stimulating factor (from stromal cells) and interleukin-1 (IL-1; from macrophages) keep this process ticking along, but now Li and colleagues report (page 1169) that osteoclasts make a protein that forms part of a critical feedback loop. Without the IRAK-M (IL-1 receptor associated kinase M) protein, which was previously thought to be expressed only in macrophages, osteoclasts are hyperactivated and mice get severe osteoporosis.

The absence of IRAK-M (bottom) causes severe osteoporosis in mice.

Bone maintenance depends on the coordination of bone formation by osteoblasts and bone resorption by osteoclasts. Li et al., prompted by the description of IRAK-M as a macrophage-specific inhibitor of signals from the IL-1 and Toll-like receptors, examined the function of this protein in osteoclasts. They found that mice lacking IRAK-M had increased numbers of osteoclasts, which lived longer and were more responsive to growth factor-derived activating signals. IRAK-M–deficient mice developed severe osteoporosis.

The osteoclast growth factor RANKL (receptor activator of the NF-B ligand) turns on IRAK-M expression; IRAK-M then may inhibit osteoclast differentiation and activation by inhibiting IL-1–dependent signals. IRAK-M also inhibits the fusion process that produces osteoclasts. Genetic mutations that cause aberrant activation of the RANKL signaling pathway have been identified in some cases of severe, inherited osteoporosis—the authors think IRAK-M mutations might be to blame for other unexplained cases.

hvanepps{at}rockefeller.edu

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IL-1 receptor–associated kinase M is a central regulator of osteoclast differentiation and activation

Hongmei Li, Esteban Cuartas, Weiguo Cui, Yongwon Choi, Todd D. Crawford, Hua Zhu Ke, Koichi S. Kobayashi, Richard A. Flavell, and Agnès Vignery
J. Exp. Med. 2005 201: 1169-1177. [Abstract] [Full Text] [PDF]

This Article Full Text (PDF, 647K) PPT slides of all figures Alert me when this article is cited Services Email this article Similar articles in this journal Alert me to new content in the JEM Download to citation manager Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Van Epps, H. L. Search for Related Content PubMed Articles by Van Epps, H. L. Related Collections Related Article Social Bookmarking                            What's this?