title: Combination of IL-6 and sIL-6R differentially regulate varying levels of RANKL-induced osteoclastogenesis through NF-κB, ERK and JNK signaling pathways.
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.
authors.affiliation: Department of Bone Metabolism, School of Stomatology Shandong University, Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Jinan, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Feng
authors.affiliation: Department of Bone Metabolism, School of Stomatology Shandong University, Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Jinan, China.
authors.forename: Hongrui
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Bone Metabolism, School of Stomatology Shandong University, Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Jinan, China.|Shanxi Medical University, Taiyuan, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Luo
authors.affiliation: Department of Bone Metabolism, School of Stomatology Shandong University, Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Jinan, China.
authors.forename: Di
authors.initials: D
authors.lastname: Liu
authors.affiliation: Department of Bone Metabolism, School of Stomatology Shandong University, Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Jinan, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Du
authors.affiliation: Department of Bone Metabolism, School of Stomatology Shandong University, Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Jinan, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of Bone Metabolism, School of Stomatology Shandong University, Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Jinan, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Bone Metabolism, School of Stomatology Shandong University, Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Jinan, China.
authors.forename: Xiuchun
authors.initials: X
authors.lastname: Han
authors.affiliation: Department of Stomatology, Qilu Hospital of Shandong University, Jinan, China.
authors.forename: Kaiyun
authors.initials: K
authors.lastname: Yang
authors.affiliation: Department of Bone Metabolism, School of Stomatology Shandong University, Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Jinan, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Guo
authors.affiliation: Department of Developmental Biology of Hard Tissue, Graduate School of Dental Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Amizuka
authors.affiliation: Department of Bone Metabolism, School of Stomatology Shandong University, Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Jinan, China.
authors.forename: Minqi
authors.initials: M
authors.lastname: Li
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D001862:Bone Resorption / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D015850:Interleukin-6 / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism*; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010012:Osteogenesis / Q000187:drug effects*; D053245:RANK Ligand / Q000494:pharmacology*; D000067996:RAW 264.7 Cells; D019947:Receptors, Interleukin-6 / Q000378:metabolism*; D012995:Solubility; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D015850:Interleukin-6; D016328:NF-kappa B; D053245:RANK Ligand; D019947:Receptors, Interleukin-6; D048029:TNF Receptor-Associated Factor 6; D014157:Transcription Factors; D048049:Extracellular Signal-Regulated MAP Kinases