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.

Type 1 diabetic bone loss is prevented by novel osteogenic factors

“…The genetic background is mixed, but is 86% homologous with SWR mice. TallyHo mice are fatter and weigh more than controls by 4 weeks of age [47,48]. Body weight continues to increase with age, but obesity in these mice is less severe than some other diabetic models [49].…”

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“…[46] It shows therapeutic effect when administer via intravenous and show low oral bioavailability. [11] Petroleum ether, chloroform, and methanol root extracts of C. zedoaria Rosc (Family: Zingiberaceae) showed significant recovery on behavioral and radiology aspects of FCA-induced monoarthritis in left ankle joint of rats using open-field test. Traditionally, C. zedoaria root has been used as anti-inflammatory and antiarthritic drug.…”

“…[10] RA, induced by the prolonged inappropriate inflammatory responses, is one of the most prevalent of all chronic inflammatory joint diseases. [11] Bone erosion is a central feature of RA. It begins in the joints with the inflammation of the synovium.…”

“…[46] CM has various pharmacological activities against many chronic diseases and acts by inhibiting cell proliferation and metastasis and downregulating various factors, including NFκB, IL-1β, and TNF alpha. [11] It shows anti-inflammatory, antiarthritic and antioxidant properties. [46] It shows therapeutic effect when administer via intravenous and show low oral bioavailability.…”

HIV infection and osteoporosis

“…Chronic immune reconstitution may also have a role in bone loss associated with ART initiation, as a result of increased circulating levels of proinflammatory, proresorptive cytokines. 34,35 Interestingly, there is emerging evidence that adverse effects on bone may be reduced or absent with one class of ART drugs: the integrase inhibitors. In an open-label study of participants randomized to lopinavir/ritonavir þ raltegravir or lopinavir/ ritanovir þ 2-3 nucleoside/nucleotide reverse transcriptase inhibitors as second-line therapy, bone loss in the spine and hip over 48 weeks was significantly less in those in the treatment arm containing the integrase inhibitor raltegravir.…”