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

Abstract

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.