Raloxifene減緩肥胖與停經狀態下牙周疾病進展:作用機轉與治療潛能

Abstract

研究背景 牙周疾病是世界口腔疾病中發生率僅次於蛀牙的疾病，在台灣有高達99.2%的成人有程度不一的牙周病。肥胖讓身體呈現慢性低度的發炎，導致巨噬細胞浸潤，如同牙周病一般。停經會增加骨質疏鬆的發生率，和牙周病都是骨頭代謝疾病。肥胖與停經都已經證實會增加牙周病發病率，但相關的機制卻尚未清楚了解，因此本論文主要研究膽固醇代謝產物27-hydroxycholesterol (27HC)對於停經與肥胖狀態下牙周病的致病機轉，以及骨質疏鬆症藥物Raloxifene對於牙周病治療之潛能。 研究方法 利用J774細胞實驗與大鼠牙周誘導實驗搭配肥胖與停經模擬，探討27HC和Raloxifene對於牙周疾病之影響。 結果 細胞實驗結果顯示膽固醇能夠透過27HC刺激J774細胞內CCL2及COX-2發炎因子的表現，而牙周發炎區域的促發炎因子TNF-α具有加強27HC的生成。給予Raloxifene後，J774細胞內的CCL2及COX-2則會顯著下降。動物實驗方面，高脂飼料或卵巢摘除手術的大鼠，其血清膽固醇會顯著上升，但對血清27HC沒有影響。當兩個因子合併時，肝臟27HC與牙齦27HC的表現有上升的趨勢，並對齒槽骨破壞達顯著上的差異。而給予Raloxifene的大鼠組別，非酒精性脂肪肝病活性指數(NAFLD activity score, NAS)有下降趨勢，對於齒槽骨破壞也會有顯著的降低。 總結 本研究嘗試以27HC來闡述肥胖與停經對牙周病的影響，雖然有相關的趨勢存在，但詳細的機制還需要進一步的研究。而實驗的結果顯示Raloxifene未來具有發展成牙周病治療輔助藥物之潛能。

Background Periodontal disease is the second most common oral disease in the world after tooth decay. In Taiwan, up to 99.2% of adults have periodontal disease of varying degrees, and the treatment and subsequent rehabilitation cost occupy a great deal of National Health Insurance and social resources. Obesity presents chronic low-grade inflammation in the body, leading to infiltration of macrophages, as in periodontal disease. Menopause increases the incidence of osteoporosis and is a metabolic disease of the bonelike periodontal disease. Both obesity and menopause have been proven to promote the periodontal disease, but the relevant mechanisms are not yet clearly understood. Therefore, this research mainly focuses on the effect of cholesterol metabolite 27-hydroxycholesterol (27HC) on the progression of periodontal disease in postmenopausal and obese status and the mechanism and therapeutic potential of Raloxifene, a drug for the prevention and treatment of osteoporosis, for periodontal disease. Method Using J774 cell line and periodontitis induction experiment in vivo with obesity and menopause simulation to explore the effect of 27HC and Raloxifene on periodontal disease. Result The results showed that the level of proinflammatory cytokine CCL2 and COX-2can be stimulated by 27HCin J774cell and TNF-α which is common in inflamed periodontal tissue enhanced more 27HC production. Oppositely, Raloxifene dropped CCL2 and COX-2 significantly. In animal model, high fat diet and ovariectomy caused the obvious elevation of serum cholesterol but no change in serum 27HC. Combination of obesity and menopause leaded to the trend of increasing 27HC in liver and gingiva and promoted the alveolar bone destruction. While the group given Raloxifene showed a downward trend for non-alcoholic fatty liver disease activity score(NAS) and alleviated the alveolar bone destruction statically. Conclusion This study attempts to elucidate the effect of obesity and menopause on periodontal disease through 27HC. Although it may be relevant, the mechanism needs more research to uncover. The results show that Raloxifene has the potential to be an adjuvant drug for periodontal disease treatment in the future.