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-1 alpha-deficient (KO), IL-1 beta KO and IL-1 alpha/beta 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-1 alpha/beta KO mice, IL-1 alpha/beta KO BM cell co-cultures failed to undergo efficient osteoclast-like multinucleated cell (OCL) differentiation, although high levels of receptor activator of nuclear factor-kappa B (NF-kappa B) ligand (RANKL) was induced. In contrast, efficient OCL differentiation was observed in IL-1 alpha/beta KO osteoblast/WT BM cell co-cultures, in which high levels of IL-1 alpha/beta and low levels of RANKL were produced. Addition of IL-1 alpha to IL-1 alpha/beta KO BM-derived macrophage cultures markedly enhanced OCL differentiation induced by soluble RANKL, and the downstream molecules of receptor activator of NF-kappa B (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.