骨關節炎 (Osteoarthritis, OA) 為最常發生的退化性關節炎疾病，其危險因子如老化、肥胖、性別、工作、飲食及關節中磷酸鈣 (BCP) 晶體累積等，造成關節過度負荷或損傷，使得骨頭表面的磨損、軟骨細胞外基質的流失和侵蝕，導致軟骨細胞死亡及滑膜炎的產生。在OA的發生時，軟骨細胞和滑膜細胞會過度分泌各種發炎細胞因子如IL-1β、TNF-α、IL-6，而誘導相關因子特別是基質金屬蛋白酶 (MMP)、含Ⅰ型血小板结合蛋白基序的解聚蛋白樣金屬蛋白酶 (ADAMTS)，導致細胞外基質 (Extracellular Matrix, ECM) 如第二型膠原蛋白 (Collagen II)及聚集蛋白聚醣(Aggrecan)分解代謝和合成代謝之間的失衡而降解。
OA主要病徵為過度發炎造成的組織損傷，近年來，NLRP3發炎體　(Inflammasome) 已被證實涉及OA的發病機制，NLRP3發炎體為NLRP3蛋白結合ASC及pro-caspase1之複合蛋白體，其活化之後caspase-1促使細胞因子IL-1β、IL-18成熟並釋放，造成軟骨的發炎和變性。而NLRP3發炎體參與OA疾病機制仍不清楚，但有潛力成為治療OA之新穎標的。過去研究指出，紫檀芪 (Pterostilbene, PT) 及硫酸軟骨素 (Chondroitin sulfate, CS) 可以透過抑制發炎反應來減緩OA。然而，天然物調控NLRP3 發炎體以治療OA的功效及機制仍不清楚，因此，本研究欲使用紫檀芪以及將硫酸軟骨素經小分子處理之硫酸軟骨素寡聚醣 (Oligo-chondroitin sulfate, Oligo-CS)，探討是否能透過抑制NLRP3發炎體活化，降低OA之發炎機轉，進而減緩OA的功效。
在動物實驗之安全性評估的部分，給予管餵PT、Oligo-CS後並不會對小鼠造成不良副作用，肝腎生化指標分析及組織染色並無顯著的變化。而在OA動物模式結果發現，透過番紅O-固綠染色觀察膝關節，施打鹼性磷酸鈣之磷酸八鈣 (Octacalcium phosphate, OCP) 組關節間隙明顯變窄，其表面蛋白多醣及細胞的損失，而給予PT、Oligo-CS後有效保護了軟骨表面的完整性，減緩了軟骨基質的侵蝕。腸道菌相的分析結果顯示，相較於OCP組，給予PT、Oligo-CS後增加了擬桿菌門並減少了厚壁菌門的產生，顯示天然物會促使小鼠腸道微生物的改變，並往好的方向改變。細胞實驗結果顯示，人類軟骨肉瘤SW1353細胞在OCP處理後，會導致ROS的上升並使細胞存活率的下降；而人類單核球細胞THP-1細胞在LPS/ATP的刺激下使NLRP3發炎體相關蛋白的活化，啟動NF-κB路徑並造成發炎細胞因子IL-1β、IL-6的產生。發炎細胞因子的分泌也使SW1353細胞中軟骨分解代謝指標MMP-13, ADAMTS-5的表達升高，造成細胞外基質Collagen II的流失，然而合併處理PT和Oligo-CS，有效抑制了THP-1細胞中NLRP3發炎體的活化，進而阻斷NF-κB路徑及後續發炎因子的產生，從而預防了細胞外基質的降解，減緩OA的發生。
因此，我們推測天然物PT和Oligo-CS能透過抑制NLRP3發炎體的活化進而預防了OA的發生。

Osteoarthritis (OA) is the most common degenerative arthritis disease, usually associated with aging, obesity, diet, and deposition of basic calcium phosphate crystals in the joints. Recently, the focus on the mechanism of OA has been aimed to inflammation and the apoptosis of chondrocytes. The inflammatory cytokines such as IL-1β and TNF-α would induce activation of matrix metalloproteinase13 (MMP13) and aggrecanase (ADAMTS5) leading to degradation of the cartilage matrix. Recent studies have indicated that NLRP3 inflammasome could involve in the pathogenesis of arthritis. When it is activatied, caspase-1 triggers the maturation of IL-1β to degenerate of cartilage. In this context, recent studies indicated that natural products such as oligo-chondroitin sulfate (Oligo-CS) or pterostilbene (PT) has anti-inflammatory effects could alleviate OA through inhibition of inflammation. Therefore, we aim to evaluate the protective effects of PT and Oligo-CS against OA by downregulation of NLRP3 inflammasome-mediated inflammation. In in vivo study, C57BL/6 mice are injected with OCP in right knee and treated with PT, Oligo-CS by gavage for 28 days. The morphology of cartilage showed that the joint space of OCP groups was significantly narrowed and the loss of chondrocytes while PT and Oligo-CS groups effectively maintained the cartilage surface. Compared to OCP groups, the gut microbiota of Firmicutes/Bacteroidetes ratio were decreased in PT and Oligo-CS groups. In the in vitro study, stimulation of OCP or LPS/ATP increased the expression of NLRP3 inflammasome and initiate the NF-κB pathway and cause the production of inflammatory cytokines IL-1β, IL-6 and the metabolic index MMP-13, ADAMTS-5. It also cause the degradation of the cartilage matrix.When treated with PT or Oligo-CS, It indicated that PT and Oligo-CS significantly reduced inflammation. We suggest that the protective effects of PT and Oligo-CS against OA could be dependent on inactivation of NLRP3 Inflammasome.

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