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

• Published in: The Journal of biological chemistry Vol. 292; no. 11; pp. 4686 - 4699
• Main Authors: Shukla, Priyanka, Mansoori, Mohd Nizam, Kakaji, Manisha, Shukla, Manoj, Gupta, Sushil Kumar, Singh, Divya
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 17.03.2017; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Anti-Inflammatory Agents - immunology; Anti-Inflammatory Agents - metabolism; Anti-Inflammatory Agents - therapeutic use; bone; Bone and Bones - drug effects; Bone and Bones - immunology; Bone and Bones - metabolism; Bone and Bones - pathology; Cells, Cultured; Early Growth Response Protein 2 - genetics; Early Growth Response Protein 2 - immunology; Estrogens - genetics; Female; Gene Deletion; Humans; immunology; immunosuppression; Interleukin-10 - immunology; Interleukin-27 - genetics; Interleukin-27 - immunology; Interleukin-27 - therapeutic use; Mice; Mice, Inbred BALB C; Molecular Bases of Disease; osteoblast; Osteoblasts - drug effects; Osteoblasts - immunology; Osteoblasts - pathology; osteoclast; Osteoclasts - drug effects; Osteoclasts - immunology; Osteoclasts - pathology; osteoporosis; Osteoporosis, Postmenopausal - drug therapy; Osteoporosis, Postmenopausal - genetics; Osteoporosis, Postmenopausal - immunology; Osteoporosis, Postmenopausal - pathology; RNA, Messenger - genetics; Th17 Cells - drug effects; Th17 Cells - immunology; Th17 Cells - pathology; Up-Regulation - drug effects; immunosuppression; bone; osteoblast; osteoclast; osteoporosis; immunology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M116.764779

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 osteoporosis remains 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 RORγt. 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 cortical bone parameters. IL-27 also inhibited osteoblast apoptosis through increased Egr-2 expression, which induces anti-apoptotic factors like MCL-1. IL-27 suppressed osteoclastogenesis in an Egr-2-dependent manner that up-regulates Id2, the repressor of the receptor activator of nuclear factor-κB 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.