title: IL-1 plays an important role in the bone metabolism under physiological conditions.
abstract: It is well known that IL-1 is involved in bone resorption under pathological conditions. The role of this cytokine in bone remodeling under physiological conditions, however, remains obscure. In this study, we addressed the role of IL-1 in physiological bone metabolism through analyses of IL-1α-deficient (KO), IL-1β KO and IL-1α/β double KO mice that were housed under specific pathogen free conditions. The femur mineral density, trabecular bone mass and cortical thickness significantly increased in all KO mice compared with wild-type (WT) mice. The number of osteoclasts in trabecular bones decreased, suggesting that IL-1 regulates bone metabolism through regulation of osteoclast formation. When differentiation of bone marrow (BM) cells into osteoclasts was induced by parathyroid hormone in co-cultures of osteoblasts and BM cells from WT and IL-1α/β KO mice, IL-1α/β KO BM cell co-cultures failed to undergo efficient osteoclast-like multinucleated cell (OCL) differentiation, although high levels of receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL) was induced. In contrast, efficient OCL differentiation was observed in IL-1α/β KO osteoblast/WT BM cell co-cultures, in which high levels of IL-1α/β and low levels of RANKL were produced. Addition of IL-1α to IL-1α/β KO BM-derived macrophage cultures markedly enhanced OCL differentiation induced by soluble RANKL, and the downstream molecules of receptor activator of NF-κB (RANK) including c-Jun N-terminal factor, extracellular signal-regulated kinase and c-Fos were less activated in the absence of IL-1 upon treatment with RANKL. Taken together, these results indicate that IL-1 directly activates RANK signaling other than inducing RANKL to promote osteoclastogenesis and plays an important role in physiological bone metabolism.
authors.affiliation: Center for Experimental Medicine and Systems Biology, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Young-Mi
authors.initials: YM
authors.lastname: Lee
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Fujikado
authors.forename: Hiroko
authors.initials: H
authors.lastname: Manaka
authors.forename: Hisataka
authors.initials: H
authors.lastname: Yasuda
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Iwakura
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D001842:Bone and Bones / Q000378:metabolism*; D002454:Cell Differentiation; D002478:Cells, Cultured; D018920:Coculture Techniques; D005269:Femur / Q000166:cytology / Q000378:metabolism; D005786:Gene Expression Regulation; D007375:Interleukin-1 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D053582:Interleukin-1alpha / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D010006:Osteoblasts / Q000166:cytology*; D010010:Osteoclasts / Q000166:cytology*; D010012:Osteogenesis / Q000187:drug effects*; D053245:RANK Ligand / Q000378:metabolism; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000378:metabolism*
chemical_list: D007375:Interleukin-1; D053582:Interleukin-1alpha; D053583:Interleukin-1beta; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C505687:Tnfrsf11a protein, mouse