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

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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.

Original languageEnglish
Article numbere18168
JournalPloS one
Volume6
Issue number3
DOIs
Publication statusPublished - 2011

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Won, H. Y., Lee, J. A., Park, Z. S., Song, J. S., Kim, H. Y., Jang, S. M., Yoo, S. E., Rhee, Y., Hwang, E. S., & Bae, M. A. (2011). Prominent bone loss mediated by RANKL and IL-17 produced by CD4+ T cells in tallyho/JngJ mice. PloS one, 6(3), [e18168]. https://doi.org/10.1371/journal.pone.0018168