IL-6 exhibits both cis- and trans-signaling in osteocytes and osteoblasts, but only trans-signaling promotes bone formation and osteoclastogenesis

• Published in: The Journal of biological chemistry Vol. 294; no. 19; pp. 7850 - 7863
• Main Authors: McGregor, Narelle E., Murat, Melissa, Elango, Jeevithan, Poulton, Ingrid J., Walker, Emma C., Crimeen-Irwin, Blessing, Ho, Patricia W.M., Gooi, Jonathan H., Martin, T. John, Sims, Natalie A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10.05.2019; American Society for Biochemistry and Molecular Biology
• Subjects: ADAM17 Protein - metabolism; Animals; bone; bone growth; CCAAT-Enhancer-Binding Protein-delta - metabolism; Cell Biology; cell signaling; cytokine; Cytokine Receptor gp130 - metabolism; inflammation; interleukin 6 (IL-6); Interleukin-6 - metabolism; Mice; osteoblast; osteoclast; Osteoclasts - metabolism; osteocyte; Osteocytes - metabolism; Osteogenesis; osteopenia; RANK Ligand - metabolism; Signal Transduction; STAT3; Suppressor of Cytokine Signaling 3 Protein - metabolism; cytokine; osteopenia; inflammation; interleukin 6 (IL-6); STAT3; cell signaling; bone; osteoblast; osteocyte; bone growth; osteoclast
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.RA119.008074

Interleukin 6 (IL-6) supports development of bone-resorbing osteoclasts by acting early in the osteoblast lineage via membrane-bound (cis) or soluble (trans) receptors. Here, we investigated how IL-6 signals and modifies gene expression in differentiated osteoblasts and osteocytes and determined whether these activities can promote bone formation or support osteoclastogenesis. Moreover, we used a genetically altered mouse with circulating levels of the pharmacological IL-6 trans-signaling inhibitor sgp130-Fc to determine whether IL-6 trans-signaling is required for normal bone growth and remodeling. We found that IL-6 increases suppressor of cytokine signaling 3 (Socs3) and CCAAT enhancer-binding protein δ (Cebpd) mRNA levels and promotes signal transducer and activator of transcription 3 (STAT3) phosphorylation by both cis- and trans-signaling in cultured osteocytes. In contrast, RANKL (Tnfsf11) mRNA levels were elevated only by trans-signaling. Furthermore, we observed soluble IL-6 receptor release and ADAM metallopeptidase domain 17 (ADAM17) sheddase expression by osteocytes. Despite the observation that IL-6 cis-signaling occurs, IL-6 stimulated bone formation in vivo only via trans-signaling. Although IL-6 stimulated RANKL (Tnfsf11) mRNA in osteocytes, these cells did not support osteoclast formation in response to IL-6 alone; binucleated TRAP+ cells formed, and only in response to trans-signaling. Finally, pharmacological, sgp130-Fc–mediated inhibition of IL-6 trans-signaling did not impair bone growth or remodeling unless mice had circulating sgp130-Fc levels > 10 μg/ml. At those levels, osteopenia and impaired bone growth occurred, reducing bone strength. We conclude that high sgp130-Fc levels may have detrimental off-target effects on the skeleton.