Faculty Collaboration Database

IL-1 receptor-associated kinase M is a central regulator of osteoclast differentiation and activation. J Exp Med 2005 Apr 04;201(7):1169-77

Date

04/06/2005

Pubmed ID

15809356

Pubmed Central ID

PMC2213136

DOI

10.1084/jem.20041444

Scopus ID

2-s2.0-17144367325 (requires institutional sign-in at Scopus site)   54 Citations

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.

Author List

Li H, Cuartas E, Cui W, Choi Y, Crawford TD, Ke HZ, Kobayashi KS, Flavell RA, Vignery A

MESH terms used to index this publication - Major topics in bold

Animals
Blotting, Western
Body Weights and Measures
Cell Differentiation
Densitometry
Histological Techniques
Interleukin-1 Receptor-Associated Kinases
Mice
Mice, Knockout
Osteoclasts
Osteoporosis
Phosphotransferases (Alcohol Group Acceptor)
Protein Kinases
Signal Transduction
TNF Receptor-Associated Factor 6
Tibia
Tomography, X-Ray Computed