Abstract
Interleukin (IL)-6 is known to indirectly enhance osteoclast formation by promoting receptor activator of nuclear factor kappa-B ligand (RANKL) production by osteoblastic/stromal cells. However, little is known about the direct effect of IL-6 on osteoclastogenesis. Here, we determined the direct effects of IL-6 and its soluble receptor (sIL-6R) on RANKL-induced osteoclast formation by osteoclast precursors in vitro. We found IL-6/sIL-6R significantly promoted and suppressed osteoclast differentiation induced by low- (10 ng/ml) and high-level (50 ng/ml) RANKL, respectively. Using a bone resorption pit formation assay, expression of osteoclastic marker genes and transcription factors confirmed differential regulation of RANKL-induced osteoclastogenesis by IL-6/sIL-6R. Intracellular signaling transduction analysis revealed IL-6/sIL-6R specifically upregulated and downregulated the phosphorylation of NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells), ERK (extracellular signal–regulated kinase) and JNK (c-Jun N-terminal kinase) induced by low- and high level RANKL, respectively. Taken together, our findings demonstrate that IL-6/sIL-6R differentially regulate RANKL-induced osteoclast differentiation and activity through modulation of NF-κB, ERK and JNK signaling pathways. Thus, IL-6 likely plays a dual role in osteoclastogenesis either as a pro-resorption factor or as a protector of bone, depending on the level of RANKL within the local microenvironment.
Highlights
Bone remodeling is achieved by coupling between osteoblasts and osteoclasts
When IL-6 and soluble IL-6 receptor (sIL-6R) were simultaneously applied to the bone marrow macrophages (BMMs) cultures, a small but significant increase in osteoclast formation was observed at concentrations of 100 ng/ml
These results suggest that the biological expression of membrane-bound IL-6R in BMMs is not sufficient for IL-6 to promote osteogenesis and exogenous sIL-6R supplementation is required to induce significant osteoclast formation by IL-6
Summary
Bone remodeling is achieved by coupling between osteoblasts and osteoclasts. Osteoblasts are bone-forming cells that support the biological function of osteoclasts, which are highly specialized multinucleated cells derived from hematopoietic precursors and are uniquely capable of lacunar bone resorption[1,2]. RANKL binds to the receptor activator of nuclear factor-κB (RANK) receptor expressed on the surface of osteoclast precursors, and subsequently activates tumor necrosis factor (TNF) receptor-associated factor-6 and downstream signaling transduction pathways, such as the mitogen-activated protein kinase (MAPK) pathway This in turn induces activation of transcription factor nuclear factor-κB (NF-κB), leading to the formation and maturation of osteoclasts[5,6]. A number of other cytokines have been shown capable of substituting RANKL to induce osteoclast formation from marrow-derived osteoclast precursors, including TNF-α, IL-1, IL-6, and IL-117–10 These non-canonical osteoclastogenesis factors are postulated to play a critical role in pathological bone resorption, their underlying mechanisms remain unclear. This study aimed to investigate the influence of IL-6 and sIL-6R on gradient concentrations of RANKL-induced osteogenesis and to identify the potential underlying mechanisms
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