Interleukin-6 directly inhibits osteoclast differentiation by suppressing receptor activator of NF-kappaB signaling pathways
- PMID: 18296709
- DOI: 10.1074/jbc.M607999200
Interleukin-6 directly inhibits osteoclast differentiation by suppressing receptor activator of NF-kappaB signaling pathways
Abstract
Interleukin-6 (IL-6) is a multifunctional cytokine produced by various cells to regulate hematopoiesis, inflammation, immune responses, and bone homeostasis. IL-6 is also known to modulate the differentiation of osteoblasts and osteoclasts. IL-6 is believed to play a positive regulatory role in osteoclast differentiation by inducing the expression of receptor activator of NF-kappaB ligand (RANKL) on the surface of osteoblasts: RANKL then interacts with RANK expressed on osteoclast progenitors, inducing osteoclast differentiation via the RANK signaling pathway, which involves NF-kappaB, JNK, and p38. In this report, we demonstrate that IL-6 can also directly act on osteoclast progenitors to suppress their differentiation via an inhibition of RANK signaling pathways. IL-6 specifically suppressed RANK-mediated IkappaB degradation and JNK activation. Microarray analysis revealed that costimulation with IL-6 and RANKL up-regulates the transcription of MKP1 and MKP7, which encode enzymes that dephosphorylate JNK, and down-regulates the transcription of Senp2 and Cul4A, which are related to the ubiquitin pathway. Thus, IL-6 directly acts on osteoclast progenitors and suppresses their differentiation by regulating the transcription of specific genes related to MAPK phosphatases and the ubiquitin pathway.
Similar articles
-
RANKL-stimulated osteoclast-like cell formation in vitro is partially dependent on endogenous interleukin-1 production.Bone. 2006 May;38(5):678-85. doi: 10.1016/j.bone.2005.10.011. Epub 2005 Nov 23. Bone. 2006. PMID: 16309985
-
NF-kappaB p50 and p52 expression is not required for RANK-expressing osteoclast progenitor formation but is essential for RANK- and cytokine-mediated osteoclastogenesis.J Bone Miner Res. 2002 Jul;17(7):1200-10. doi: 10.1359/jbmr.2002.17.7.1200. J Bone Miner Res. 2002. PMID: 12096833
-
Maslinic acid suppresses osteoclastogenesis and prevents ovariectomy-induced bone loss by regulating RANKL-mediated NF-κB and MAPK signaling pathways.J Bone Miner Res. 2011 Mar;26(3):644-56. doi: 10.1002/jbmr.242. J Bone Miner Res. 2011. PMID: 20814972
-
Caffeic acid 3,4-dihydroxy-phenethyl ester suppresses receptor activator of NF-κB ligand–induced osteoclastogenesis and prevents ovariectomy-induced bone loss through inhibition of mitogen-activated protein kinase/activator protein 1 and Ca2+–nuclear factor of activated T-cells cytoplasmic 1 signaling pathways.J Bone Miner Res. 2012 Jun;27(6):1298-1308. doi: 10.1002/jbmr.1576. J Bone Miner Res. 2012. PMID: 22337253
-
IL-3 acts directly on osteoclast precursors and irreversibly inhibits receptor activator of NF-kappa B ligand-induced osteoclast differentiation by diverting the cells to macrophage lineage.J Immunol. 2003 Jul 1;171(1):142-51. doi: 10.4049/jimmunol.171.1.142. J Immunol. 2003. PMID: 12816992
Cited by
-
Circulating monocytes: an appropriate model for bone-related study.Osteoporos Int. 2015 Nov;26(11):2561-72. doi: 10.1007/s00198-015-3250-7. Epub 2015 Jul 21. Osteoporos Int. 2015. PMID: 26194495 Review.
-
Hairy and Enhancer of Split-related with YRPW motif (HEY)2 regulates bone remodeling in mice.J Biol Chem. 2013 Jul 26;288(30):21547-57. doi: 10.1074/jbc.M113.489435. Epub 2013 Jun 19. J Biol Chem. 2013. PMID: 23782701 Free PMC article.
-
IL-6 and the dysregulation of immune, bone, muscle, and metabolic homeostasis during spaceflight.NPJ Microgravity. 2018 Dec 4;4:24. doi: 10.1038/s41526-018-0057-9. eCollection 2018. NPJ Microgravity. 2018. PMID: 30534586 Free PMC article. Review.
-
Massively HIV-1-infected macrophages exhibit a severely hampered ability to differentiate into osteoclasts.Front Immunol. 2023 Jun 19;14:1206099. doi: 10.3389/fimmu.2023.1206099. eCollection 2023. Front Immunol. 2023. PMID: 37404829 Free PMC article.
-
Impact of Mechanical Strain and Nicotinamide on RUNX2-Deficient Osteoblast Mimicking Cleidocranial Dysplasia.Int J Mol Sci. 2023 Nov 21;24(23):16581. doi: 10.3390/ijms242316581. Int J Mol Sci. 2023. PMID: 38068903 Free PMC article.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Research Materials
Miscellaneous
