IL-1 receptor-associated kinase M is a central regulator of osteoclast differentiation and activation.
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.
Li
Hongmei
H
Department of Orthopaedics and Rehabilitation, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510, USA.
Cuartas
Esteban
E
Cui
Weiguo
W
Choi
Yongwon
Y
Crawford
Todd D
TD
Ke
Hua Zhu
HZ
Kobayashi
Koichi S
KS
Flavell
Richard A
RA
Vignery
Agnès
A
D000818:Animals; D015153:Blotting, Western; D001837:Body Weights and Measures; D002454:Cell Differentiation / Q000502:physiology*; D003720:Densitometry; D006652:Histological Techniques; D053592:Interleukin-1 Receptor-Associated Kinases; D051379:Mice; D018345:Mice, Knockout; D010010:Osteoclasts / Q000502:physiology*; D010024:Osteoporosis / Q000209:etiology*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism; D013977:Tibia / Q000000981:diagnostic imaging; D014057:Tomography, X-Ray Computed
D048029:TNF Receptor-Associated Factor 6; D011494:Protein Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D053592:Interleukin-1 Receptor-Associated Kinases; C507772:Irak3 protein, mouse; C507774:Irak4 protein, mouse