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.
Highlights
Bone tissue continuously undergoes remodeling through mechanical coupling of osteoclastic bone resorption and osteoblastic bone formation
We demonstrated that male TH mice as a polygenic diabetes model developed an osteoporotic phenotype with decreased bone density and increased osteoclastogenic factors, such as IFN-c, IL-6, and RANK ligand (RANKL), in the blood and bone marrow
RANKL was prominently increased in CD4+ T cells, which were biased towards differentiation into IL-17producing Th17 cells in TH mice
Summary
Bone tissue continuously undergoes remodeling through mechanical coupling of osteoclastic bone resorption and osteoblastic bone formation. Insulin-like growth factor (IGF), transforming growth factor (TGF) and parathyroid hormone (PTH) stimulate the production of bone collagen and matrix proteins in osteoblasts and increase osteoclast apoptosis, resulting in increased bone formation [1,2,3,4,5,6]. Inflammatory cytokines, including IL-1, IL-6, and TNF-a, enhance osteoclastic bone resorption, further inducing bone destruction [7,8,9,10]. Other cytokines produced by T cells such as IL-4, IL-13, IFN-c, and TGF-b induce OPG expression and interfere with the RANKL-RANK signaling pathway, suppressing osteoclastogenesis [18,19]
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