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Prominent bone loss mediated by RANKL and IL-17 produced by CD4+ T cells in TallyHo/JngJ mice

 Hee Yeon Won  ;  Jin-Ah Lee  ;  Zong Sik Park  ;  Jin Sook Song  ;  Hee Yun Kim  ;  Su-Min Jang  ;  Sung-Eun Yoo  ;  Youmi Rhee  ;  Eun Sook Hwang  ;  Myung Ae Bae 
 PLOS ONE, Vol.6(3) : e18168, 2011 
Journal Title
Issue Date
Alendronate/pharmacology ; Animals ; Biomarkers/metabolism ; BoneDensity/drug effects ; BoneMarrow/drug effects ; BoneMarrow/metabolism ; BoneResorption/blood ; BoneResorption/metabolism* ; BoneResorption/physiopathology ; CD4-PositiveT-Lymphocytes/drug effects ; CD4-PositiveT-Lymphocytes/metabolism* ; Female ; Interferon-gamma/blood ; Interleukin-17/biosynthesis* ; Interleukin-6/blood ; Leptin/blood ; Leptin/pharmacology ; Male ; Mice ; Mice, Inbred C57BL ; Osteoblasts/drug effects ; Osteoblasts/metabolism ; Osteoblasts/pathology ; Osteocalcin/blood ; Osteogenesis/drug effects ; RANK Ligand/metabolism* ; Testosterone/pharmacology
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.
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Rhee, Yumie(이유미) ORCID logo https://orcid.org/0000-0003-4227-5638
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