title: Interleukin 27 (IL-27) Alleviates Bone Loss in Estrogen-deficient Conditions by Induction of Early Growth Response-2 Gene.
abstract: 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.
authors.affiliation: From the Division of Endocrinology and Centre for Research in Anabolic Skeletal Targets in Health and Illness (ASTHI), Council of Scientific and Industrial Research-Central Drug Research Institute, B.S. 10/1, Sector-10, Jankipuram Extension, Lucknow CDRI-226031 and.
authors.forename: Priyanka
authors.initials: P
authors.lastname: Shukla
authors.affiliation: From the Division of Endocrinology and Centre for Research in Anabolic Skeletal Targets in Health and Illness (ASTHI), Council of Scientific and Industrial Research-Central Drug Research Institute, B.S. 10/1, Sector-10, Jankipuram Extension, Lucknow CDRI-226031 and.
authors.forename: Mohd Nizam
authors.initials: MN
authors.lastname: Mansoori
authors.affiliation: the Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow PGI-226014, India.
authors.forename: Manisha
authors.initials: M
authors.lastname: Kakaji
authors.affiliation: the Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow PGI-226014, India.
authors.forename: Manoj
authors.initials: M
authors.lastname: Shukla
authors.affiliation: the Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow PGI-226014, India.
authors.forename: Sushil Kumar
authors.initials: SK
authors.lastname: Gupta
authors.affiliation: From the Division of Endocrinology and Centre for Research in Anabolic Skeletal Targets in Health and Illness (ASTHI), Council of Scientific and Industrial Research-Central Drug Research Institute, B.S. 10/1, Sector-10, Jankipuram Extension, Lucknow CDRI-226031 and divya_singh@cdri.res.in.
authors.forename: Divya
authors.initials: D
authors.lastname: Singh
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000276:immunology / Q000378:metabolism / Q000627:therapeutic use*; D001842:Bone and Bones / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D051767:Early Growth Response Protein 2 / Q000235:genetics* / Q000276:immunology; D004967:Estrogens / Q000235:genetics; D005260:Female; D017353:Gene Deletion; D006801:Humans; D016753:Interleukin-10 / Q000276:immunology; D064094:Interleukin-27 / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D010006:Osteoblasts / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D010010:Osteoclasts / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D015663:Osteoporosis, Postmenopausal / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D058504:Th17 Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D000893:Anti-Inflammatory Agents; D051767:Early Growth Response Protein 2; C497327:Egr2 protein, mouse; D004967:Estrogens; D064094:Interleukin-27; D012333:RNA, Messenger; D016753:Interleukin-10
keywords: bone; immunology; immunosuppression; osteoblast; osteoclast; osteoporosis