Abstract
The exact role of IL-6 in inflammatory osteoclast formation is still under debate. Our previous study demonstrated that IL-6 in the combination of sIL-6R significantly promoted low level of RANKL-induced osteoclast differentiation which was not affected by IL-6 alone. However, the precise molecular mechanisms underlying the regulation of sIL-6R-induced trans-signaling on osteoclast differentiation remains to be elucidated. Mouse bone marrow‑derived monocytes (BMMs) were isolated and cultured with RANKL and IL-6/sIL-6R in the presence or absence of sgp130. TRAP staining and pit formation assay were used to visualize multinucleated giant osteoclasts and evaluate their bone resorption ability. Western blot and real time-PCR were applied to determine the activations of IL-6 signaling pathway and osteoclastogenesis- associated signaling pathways. The results showed that sIL-6R activation of IL-6 trans-signaling enhanced IL-6 signaling cascades and promoted low concentration of RANKL-induced osteoclasts formation and bone resorption by mouse BMMs. Furthermore, blocking IL-6 trans-signaling with sgp130 abrogated this promotive effect by suppressing NF-κB and JNK signaling pathways. In conclusion, sIL-6R-mediated trans-signaling pathway plays a decisive role in promotion of low level of RANKL-induced osteoclastic differentiation by IL-6/sIL-6R and targeting the IL-6 trans-signaling pathway may represent a potential strategy for inflammatory diseases with pathological bone resorption.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Ang E et al (2011) Mangiferin attenuates osteoclastogenesis, bone resorption, and RANKL-induced activation of NF-kappaB and ERK. J Cell Biochem 112:89–97. doi:https://doi.org/10.1002/jcb.22800
Audet J, Miller CL, Rose-John S, Piret JM, Eaves CJ (2001) Distinct role of gp130 activation in promoting self-renewal divisions by mitogenically stimulated murine hematopoietic stem cells. Proc Natl Acad Sci USA 98:1757–1762. doi:https://doi.org/10.1073/pnas.98.4.1757
Axmann R, Bohm C, Kronke G, Zwerina J, Smolen J, Schett G (2009) Inhibition of interleukin-6 receptor directly blocks osteoclast formation in vitro and in vivo. Arthritis Rheum 60:2747–2756. doi:https://doi.org/10.1002/art.24781
Chomarat P, Banchereau J, Davoust J, Palucka AK (2000) IL-6 switches the differentiation of monocytes from dendritic cells to macrophages. Nat Immunol 1:510–514. doi:https://doi.org/10.1038/82763
Dixit A et al (2018) Frontline Science: Proliferation of Ly6C(+) monocytes during urinary tract infections is regulated by IL-6 trans-signaling. J Leukoc Biol 103:13–22. doi:https://doi.org/10.1189/jlb.3HI0517-198R
Duplomb L, Baud’huin M, Charrier C, Berreur M, Trichet V, Blanchard F, Heymann D (2008) Interleukin-6 inhibits receptor activator of nuclear factor kappaB ligand-induced osteoclastogenesis by diverting cells into the macrophage lineage: key role of Serine727 phosphorylation of signal transducer and activator of transcription 3. Endocrinology 149:3688–3697. doi:https://doi.org/10.1210/en.2007-1719
Feng W et al (2017) Combination of IL-6 and sIL-6R differentially regulate varying levels of RANKL-induced osteoclastogenesis through NF-kappaB, ERK and JNK signaling pathways. Sci Rep 7:41411. doi:https://doi.org/10.1038/srep41411
Garbers C et al (2011) Inhibition of classic signaling is a novel function of soluble glycoprotein 130 (sgp130), which is controlled by the ratio of interleukin 6 and soluble interleukin 6 receptor. J Biol Chem 286:42959–42970. doi:https://doi.org/10.1074/jbc.M111.295758
Garbers C, Aparicio-Siegmund S, Rose-John S (2015) The IL-6/gp130/STAT3 signaling axis: recent advances towards specific inhibition. Curr Opin Immunol 34:75–82. doi:https://doi.org/10.1016/j.coi.2015.02.008
Gohda J, Akiyama T, Koga T, Takayanagi H, Tanaka S, Inoue J (2005) RANK-mediated amplification of TRAF6 signaling leads to NFATc1 induction during osteoclastogenesis. EMBO J 24:790–799. doi:https://doi.org/10.1038/sj.emboj.7600564
Heinrich PC, Behrmann I, Muller-Newen G, Schaper F, Graeve L (1998) Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. Biochem J 334(Pt 2):297–314
Ikeda F, Matsubara T, Tsurukai T, Hata K, Nishimura R, Yoneda T (2008) JNK/c-Jun signaling mediates an anti-apoptotic effect of RANKL in osteoclasts. J bone mineral research: official J Am Soc Bone Mineral Res 23:907–914. doi:https://doi.org/10.1359/jbmr.080211
Jones SA (2005) Directing transition from innate to acquired immunity: defining a role for IL-6. J Immunol 175:3463–3468. doi:https://doi.org/10.4049/jimmunol.175.6.3463
Jones SA, Richards PJ, Scheller J, Rose-John S (2005) IL-6 transsignaling: the in vivo consequences. J Interferon Cytokine Res 25:241–253. doi:https://doi.org/10.1089/jir.2005.25.241
Jostock T et al (2001) Soluble gp130 is the natural inhibitor of soluble interleukin-6 receptor transsignaling responses. Eur J Biochem 268:160–167. doi:https://doi.org/10.1046/j.1432-1327.2001.01867.x
Kim GW et al (2015) IL-6 inhibitors for treatment of rheumatoid arthritis: past, present, and future. Arch Pharm Res 38:575–584. doi:https://doi.org/10.1007/s12272-015-0569-8
Kudo O, Sabokbar A, Pocock A, Itonaga I, Fujikawa Y, Athanasou NA (2003) Interleukin-6 and interleukin-11 support human osteoclast formation by a RANKL-independent mechanism. Bone 32:1–7
Lindberg MK et al (2001) Estrogen receptor alpha, but not estrogen receptor beta, is involved in the regulation of the OPG/RANKL (osteoprotegerin/receptor activator of NF-kappa B ligand) ratio and serum interleukin-6 in male mice. J Endocrinol 171:425–433. doi:https://doi.org/10.1677/joe.0.1710425
Liu XH, Kirschenbaum A, Yao S, Levine AC (2005) Cross-talk between the interleukin-6 and prostaglandin E(2) signaling systems results in enhancement of osteoclastogenesis through effects on the osteoprotegerin/receptor activator of nuclear factor-{kappa}B (RANK) ligand/RANK system. Endocrinology 146:1991–1998. doi:https://doi.org/10.1210/en.2004-1167
McInnes IB, Buckley CD, Isaacs JD (2016) Cytokines in rheumatoid arthritis - shaping the immunological landscape. Nat Rev Rheumatol 12:63–68. doi:https://doi.org/10.1038/nrrheum.2015.171
Nishimoto N, Kishimoto T (2006) Interleukin 6: from bench to bedside. Nat Clin Pract Rheumatol 2:619–626. doi:https://doi.org/10.1038/ncprheum0338
Ohsaki Y, Takahashi S, Scarcez T, Demulder A, Nishihara T, Williams R, Roodman GD (1992) Evidence for an autocrine/paracrine role for interleukin-6 in bone resorption by giant cells from giant cell tumors of bone. Endocrinology 131:2229–2234. doi:https://doi.org/10.1210/endo.131.5.1425421
Palmqvist P, Persson E, Conaway HH, Lerner UH (2002) IL-6, leukemia inhibitory factor, and oncostatin M stimulate bone resorption and regulate the expression of receptor activator of NF-kappa B ligand, osteoprotegerin, and receptor activator of NF-kappa B in mouse calvariae. J Immunol 169:3353–3362
Peters M et al (1997) Extramedullary expansion of hematopoietic progenitor cells in interleukin (IL)-6-sIL-6R double transgenic mice. J Exp Med 185:755–766. doi:https://doi.org/10.1084/jem.185.4.755
Peters M, Muller AM, Rose-John S (1998) Interleukin-6 and soluble interleukin-6 receptor: direct stimulation of gp130 and hematopoiesis. Blood 92:3495–3504
Rose-John S, Neurath MF (2004) IL-6 trans-signaling: the heat is on. Immunity 20:2–4
Rose-John S (2006) Designer cytokines for human haematopoietic progenitor cell expansion: impact for tissue regeneration.Handb Exp Pharmacol:229–247
Rose-John S, Scheller J, Elson G, Jones SA (2006) Interleukin-6 biology is coordinated by membrane-bound and soluble receptors: role in inflammation and cancer. J Leukoc Biol 80:227–236. doi:https://doi.org/10.1189/jlb.1105674
Rose-John S (2017) The Soluble Interleukin 6 Receptor: Advanced Therapeutic Options in Inflammation. Clin Pharmacol Ther 102:591–598. doi:https://doi.org/10.1002/cpt.782
Tao H, Okamoto M, Nishikawa M, Yoshikawa H, Myoui A (2011) P38 mitogen-activated protein kinase inhibitor, FR167653, inhibits parathyroid hormone related protein-induced osteoclastogenesis and bone resorption. PLoS ONE 6:e23199. doi:https://doi.org/10.1371/journal.pone.0023199
Wong PK, Quinn JM, Sims NA, van Nieuwenhuijze A, Campbell IK, Wicks IP (2006) Interleukin-6 modulates production of T lymphocyte-derived cytokines in antigen-induced arthritis and drives inflammation-induced osteoclastogenesis. Arthritis Rheum 54:158–168. doi:https://doi.org/10.1002/art.21537
Yoshitake F, Itoh S, Narita H, Ishihara K, Ebisu S (2008) Interleukin-6 directly inhibits osteoclast differentiation by suppressing receptor activator of NF-kappaB signaling pathways. J Biol Chem 283:11535–11540. doi:https://doi.org/10.1074/jbc.M607999200
Acknowledgements
This work was partially supported by the National Natural Science Foundation of China (No. 81972072) to M Li, the National Natural Science Foundation of China (No. 81800982) to HR Liu, the Construction Engineering Special Fund of “Taishan Scholars” of Shandong Province (No. tsqn202103177) to HR Liu, the Open Foundation of Shandong Province Key Laboratory of Oral Tissue Regeneration (No. SDKQ201703) to W Feng and the Key Research and Development Program of Shandong Province (No. 2019GSF107016) to F Zhang.
Author information
Authors and Affiliations
Contributions
All authors have made substantial contributions to conceptualization and design of the study. Wei Feng and Panpan Yang have been involved in data collection and formal analysis. Hongrui Liu have been involved in investigation and methodology. Wei Feng and Fan zhang have been involved in resources, software, validation and visualization. Minqi Li, Hongrui Liu and Fan Zhang have been involved in funding acquisition, project administration and supervision. Wei Feng, Panpan Yang, Hongrui Liu, Fanzhang and Minqi Li have been involved in roles/writing - original draft and writing - review & editing.
Corresponding author
Ethics declarations
Conflict of interest
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Ethical approval:
All experimental procedures complied with the ARRIVE guidelines and were conducted in accordance with the guidelines for the Care and Use of Laboratory Animals of the National Institutes of Health. And all animal experiments and the use of the cell line were approved by the ethics committee of School and Hospital of Stomatology, Shandong University (No. 20210118).
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Feng, W., Yang, P., Liu, H. et al. IL-6 promotes low concentration of RANKL-induced osteoclastic differentiation by mouse BMMs through trans-signaling pathway. J Mol Histol 53, 599–610 (2022). https://doi.org/10.1007/s10735-022-10077-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10735-022-10077-7