Interleukin 27 (IL-27) Alleviates Bone Loss in Estrogen-deficient Conditions by Induction of Early Growth Response-2 Gene

A growing understanding of the bone remodeling process suggests that inflammation significantly contributes to the pathogenesis of osteoporosis. T cells and various cytokines contribute majorly to the estrogen deficiency-induced bone loss. Recent studies have identified the IL-12 cytokine family as consisting of pro-inflammatory IL-12 and IL-23 and the anti-inflammatory IL-27 and IL-35 cytokines. IL-27 exerts protective effects in autoimmune diseases like experimental autoimmune encephalomyelitis; however, its role in the pathogenesis of osteoporosisremains to be determined. In this report, we study the effect of IL-27 supplementation on ovariectomized estrogen-deficient mice on various immune and skeletal parameters. IL-27 treatment in ovariectomized mice suppressed Th17 cell differentiation by inhibiting transcription factor ROR gamma t. Supplementation of IL-27 activates Egr-2 to induce IL-10 producing Tr1 cells. IL-27 treatment prevented the loss of trabecular micro-architecture and preserved corticalboneparameters. IL-27 also in hibite do steoblastapoptosis through increased Egr-2 expression, which induces antiapoptotic factors like MCL-1. IL-27 suppressed osteoclastogenesis in an Egr-2-dependentmannerthat up-regulates Id2, the repressor of the receptor activator of nuclear factor-kappa B ligand-mediated osteoclastogenesis. Additionally, these results were corroborated in female osteoporotic subjects where we found decreased serum IL-27 levels along with reduced Egr-2 expression. Our study forms a strong basis for using humanized IL-27 toward the treatment of post-menopausal osteoporosis.