title: Prominent bone loss mediated by RANKL and IL-17 produced by CD4+ T cells in TallyHo/JngJ mice.
abstract: Increasing evidence that decreased bone density and increased rates of bone fracture are associated with abnormal metabolic states such as hyperglycemia and insulin resistance indicates that diabetes is a risk factor for osteoporosis. In this study, we observed that TallyHo/JngJ (TH) mice, a polygenic model of type II diabetes, spontaneously developed bone deformities with osteoporotic features. Female and male TH mice significantly gained more body weight than control C57BL/6 mice upon aging. Interestingly, bone density was considerably decreased in male TH mice, which displayed hyperglycemia. The osteoblast-specific bone forming markers osteocalcin and osteoprotegerin were decreased in TH mice, whereas osteoclast-driven bone resorption markers such as IL-6 and RANKL were significantly elevated in the bone marrow and blood of TH mice. In addition, RANKL expression was prominently increased in CD4+ T cells of TH mice upon T cell receptor stimulation, which was in accordance with enhanced IL-17 production. IL-17 production in CD4+ T cells was directly promoted by treatment with leptin while IFN-γ production was not. Moreover, blockade of IFN-γ further increased RANKL expression and IL-17 production in TH-CD4+ T cells. In addition, the osteoporotic phenotype of TH mice was improved by treatment with alendronate. These results strongly indicate that increased leptin in TH mice may act in conjunction with IL-6 to preferentially stimulate IL-17 production in CD4+ T cells and induce RANKL-mediated osteoclastogenesis. Accordingly, we propose that TH mice could constitute a beneficial model for osteoporosis.
authors.affiliation: Division of Life and Pharmaceutical Sciences, College of Pharmacy, Center for Cell Signaling & Drug Discovery Research, Ewha Womans University, Seoul, Korea.
authors.forename: Hee Yeon
authors.initials: HY
authors.lastname: Won
authors.forename: Jin-Ah
authors.initials: JA
authors.lastname: Lee
authors.forename: Zong Sik
authors.initials: ZS
authors.lastname: Park
authors.forename: Jin Sook
authors.initials: JS
authors.lastname: Song
authors.forename: Hee Yun
authors.initials: HY
authors.lastname: Kim
authors.forename: Su-Min
authors.initials: SM
authors.lastname: Jang
authors.forename: Sung-Eun
authors.initials: SE
authors.lastname: Yoo
authors.forename: Youmi
authors.initials: Y
authors.lastname: Rhee
authors.forename: Eun Sook
authors.initials: ES
authors.lastname: Hwang
authors.forename: Myung Ae
authors.initials: MA
authors.lastname: Bae
mesh_terms: D019386:Alendronate / Q000494:pharmacology; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D015519:Bone Density / Q000187:drug effects; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism; D001862:Bone Resorption / Q000097:blood / Q000378:metabolism* / Q000503:physiopathology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D007371:Interferon-gamma / Q000097:blood; D020381:Interleukin-17 / Q000096:biosynthesis*; D015850:Interleukin-6 / Q000097:blood; D020738:Leptin / Q000097:blood / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015675:Osteocalcin / Q000097:blood; D010012:Osteogenesis / Q000187:drug effects; D053245:RANK Ligand / Q000378:metabolism*; D013739:Testosterone / Q000494:pharmacology
chemical_list: D015415:Biomarkers; C098680:Il17a protein, mouse; D020381:Interleukin-17; D015850:Interleukin-6; D020738:Leptin; D053245:RANK Ligand; C505689:Tnfsf11 protein, mouse; D015675:Osteocalcin; D013739:Testosterone; D007371:Interferon-gamma; D019386:Alendronate