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

• Published in: The Journal of experimental medicine Vol. 201; no. 7; pp. 1169 - 1177
• Main Authors: Li, Hongmei, Cuartas, Esteban, Cui, Weiguo, Choi, Yongwon, Crawford, Todd D, Ke, Hua Zhu, Kobayashi, Koichi S, Flavell, Richard A, Vignery, Agnès
• Format: Journal Article
• Language: English
• Published: United States The Rockefeller University Press 04.04.2005
• Subjects: Animals; Blotting, Western; Body Weights and Measures; Cell Differentiation - physiology; Densitometry; Histological Techniques; Interleukin-1 Receptor-Associated Kinases; Mice; Mice, Knockout; Osteoclasts - physiology; Osteoporosis - etiology; Phosphotransferases (Alcohol Group Acceptor) - metabolism; Protein Kinases - metabolism; Protein Kinases - physiology; Signal Transduction - physiology; Tibia - diagnostic imaging; TNF Receptor-Associated Factor 6 - metabolism; Tomography, X-Ray Computed
• ISSN: 0022-1007; 1540-9538; 1892-1007
• DOI: 10.1084/jem.20041444

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-kappaB 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.