The effect of immune abnormality on bone and joint disorder and the exploration of potential drug - The role of interleukin 17 (IL-17)

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With the ageing of Taiwanese population in recent future, these age-related osteoporotic fractures, associated with high percentage of functional impairment and mortality, will cause tremendous economic burdens for our society. Osteoporosis is characterized by low bone mass and microarchitectural deterioration and result in bone fragility and fracture. Impaired bone remodeling which is stimulated by numerous inflammatory cytokines in association with abnormal activation of immune system will be detrimental to bone micro-structure. IL-17, production by Th17 cells, induced progressive bone loss after estrogen deficiency in women and considered a novel potential therapeutic target for rheumatoid arthritis (RA) and osteoporosis. However, to date, few data addressed on the osteoporotic therapy targeting to IL-17/Th17. In addition, the paucity of researches addressed on the correlation and potential mechanism of teriparatide [rhPTH (1−34)], a potent anabolic bone agent for osteoporosis, on IL-17/Th17 axis. Herein, we would like to elucidate what the role of IL-17/Th17 is and how PTH(1-34) work on this axis in OVX animal model and screen the potential agents with the inhibitory properties targeting to IL-17 using RA animal model. In future, we will examine the effect of the selected anti-inflammatory and anti-IL-17 compounds on OVX model and develop alternative agents based on the modulation of IL-17/Th17 axis for osteoporosis treatment. We performed the first part experiment to elucidate the effect of teriparatide, ether intermittent or continuous administration, on IL-17 in OVX animal model and explored its underlying mechanism. We evaluated the efficacy of teriparatide in vivo via ELISA for CTx, and IL-17 in serum, Quantitative Real-Time-PCR for mRNA of IL-17 and osteoprotegerin (OPG) and Th17 differentiating factors(ROR-α, RORγt) in isolated CD4+ T cells selected by FACS from bone marrow and spleen cell. From the results of the part 1 experiment, we found elevated CTx and IL-17 production in serum, activation of Th17 cell and their transcript factors after estrogen deprivation and all of them were suppressed by teriparatide administration. This finding supported estrogen-deficiency osteoporosis is an inflammatory disorder and the efficacy of teriparatide on bone turnover via regulating immune system. In the 2nd part of our experiment, we plan to recognize the efficacy of the anti-arthritis and bone erosion as well as the effects on proinflammatory cytokines including IL-17 of phoreltin on RA murine model with collagen-induced arthritis (CIA) immunized by bovine collagen II(CII). Different dosage of Phloretin (50 and 100 mg/kg) was orally administered once a day to CIA mice. Histological analysis confirmed phloretin suppressed joint inflammation and inhibited cartilage and bone destruction, compared to the CIA group. Phloretin also reduced the production of proinflammtory cytokines, TNF