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¹ Department of Orthopaedics and Rehabilitation, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510
² Section of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510
³ Department of Pathology and Laboratory of Medicine, University of Pennsylvania, Philadelphia, PA 19104
⁴ Department of Cardiovascular and Metabolic Diseases, Pfizer Global Research and Development, Groton, CT 06340

CORRESPONDENCE Agnès Vignery: agnes.vignery{at}yale.edu

Osteoporosis is a serious problem worldwide; it is characterized by bone fractures in response to relatively mild trauma. Osteoclasts originate from the fusion of macrophages and they play a central role in bone development and remodeling via the resorption of bone. Therefore, osteoclasts are important mediators of bone loss that leads, for example, to osteoporosis. Interleukin (IL)-1 receptor (IL-1R)–associated kinase M (IRAK-M) is only expressed in cells of the myeloid lineage and it inhibits signaling downstream of IL-1R and Toll-like receptors (TLRs). However, it lacks a functional catalytic site and, thus, cannot function as a kinase. IRAK-M associates with, and prevents the dissociation of, IRAK–IRAK-4–TNF receptor–associated factor 6 from the TLR signaling complex, with resultant disruption of downstream signaling. Thus, IRAK-M acts as a dominant negative IRAK. We show here that mice that lack IRAK-M develop severe osteoporosis, which is associated with the accelerated differentiation of osteoclasts, an increase in the half-life of osteoclasts, and their activation. Ligation of IL-1R or TLRs results in hyperactivation of NF-B and mitogen-activated protein kinase signaling pathways, which are essential for osteoclast differentiation. Thus, IRAK-M is a key regulator of the bone loss that is due to osteoclastic resorption of bone.

Abbreviations used: ERK, extracellular signal-regulated kinase; IRAK, IL-1R–associated kinase; JNK, c-Jun NH₂-terminal kinase; MAPK, mitogen-activated protein kinase; M-CSF, macrophage colony–stimulating factor; RANK, receptor activator of NF-B; RANKL, RANK ligand; TLR, Toll-like receptor; TRAF, TNF receptor–associated factor.

H. Li and E. Cuartas contributed equally to this work.

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