Osteoporosis Research Today is a free monthly online journal that collates and summarizes the latest research about Osteoporosis, including details on symptoms, treatment, prevention, causes. | ||||||||
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IL-1 receptor-associated kinase M is a central regulator of osteoclast differentiation and activation.Li H, Cuartas E, Cui W, Choi Y, Crawford TD, Ke HZ, Kobayashi KS, Flavell RA, Vignery A Department of Orthopaedics and Rehabilitation, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510, USA. 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. Published 5 April 2005 in J Exp Med, 201(7): 1169-77.
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