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: Wei Feng, Hongrui Liu, Tingting Luo, Di Liu, Juan Du, Jing Sun, Wei Wang, Xiuchun Han, Kaiyun Yang, Jie Guo, Norio Amizuka, Minqi Li
• Journal: Scientific reports (Sci Rep) Vol. 7 Pg. 41411 (01 27 2017) ISSN: 2045-2322 [Electronic] England
• PMID: 28128332 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Interleukin-6
• NF-kappa B
• RANK Ligand
• Receptors, Interleukin-6
• TNF Receptor-Associated Factor 6
• Transcription Factors
• Extracellular Signal-Regulated MAP Kinases

Topics

• Animals
• Bone Marrow Cells (metabolism)
• Bone Resorption (pathology)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Gene Expression Regulation (drug effects)
• Interleukin-6 (metabolism)
• MAP Kinase Signaling System (drug effects)
• Macrophages (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Models, Biological
• NF-kappa B (metabolism)
• Osteoclasts (drug effects, metabolism, pathology)
• Osteogenesis (drug effects)
• RANK Ligand (pharmacology)
• RAW 264.7 Cells
• Receptors, Interleukin-6 (metabolism)
• Solubility
• TNF Receptor-Associated Factor 6 (metabolism)
• Transcription Factors (metabolism)