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

J Exp Med. 2005 Apr 4;201(7):1169-77. doi: 10.1084/jem.20041444.

Abstract

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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 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*
  • TNF Receptor-Associated Factor 6 / metabolism
  • Tibia / diagnostic imaging
  • Tomography, X-Ray Computed

Substances

  • TNF Receptor-Associated Factor 6
  • Protein Kinases
  • Phosphotransferases (Alcohol Group Acceptor)
  • Interleukin-1 Receptor-Associated Kinases
  • Irak3 protein, mouse
  • Irak4 protein, mouse