IL-1 plays an important role in the bone metabolism under physiological conditions

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.