探討肥胖合併類風溼性關節炎中27-羥基膽固醇對骨侵蝕的影響

Abstract

類風溼性關節炎（Rheumatoid arthritis, RA）是一種慢性自體免疫疾病，其主要病理特徵包括骨侵蝕。RA的病程受多種因素影響，其中肥胖已被證實與其發展及嚴重程度相關。根據先前的研究顯示，肥胖症中的代謝產物——27-羥基膽固醇（27-Hydroxycholesterol, 27HC）可能是影響兩者關聯的重要因子。因此，本研究旨在探討肥胖合併類風溼性關節炎時，27HC對骨侵蝕的影響，並提出其可能透過肝X受體（Liver X receptor, LXR）參與調控。 細胞實驗結果顯示，在27HC的刺激下，破骨細胞生成的相關分子訊號表現增加，確認27HC會誘導破骨細胞生成作用。此外，LXR拮抗劑的預處理可降低27HC促進破骨細胞生成的效果，表明LXR可能在其中發揮關鍵調控功能。而動物實驗則利用膠原誘導性關節炎大鼠模型，發現接受高油脂高膽固醇飲食的大鼠關節骨組織出現嚴重的發炎與骨吸收現象，且免疫組織化學染色分析顯示與破骨細胞生成相關的分子訊號表現增加，恰巧呼應細胞實驗結果，表示在肥胖合併RA的狀況下會進一步加劇骨侵蝕。 本研究證實27HC可促進破骨細胞生成作用，進一步加劇RA的骨侵蝕現象，並提出LXR可能在其中發揮關鍵調控功能。未來或許能透過更深入的機制探討，進一步釐清27HC與LXR於RA病理環境中的交互作用，以期發展針對肥胖合併RA的潛在治療方法。

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized primarily by bone erosion. The progression of RA is influenced by various factors, among which obesity has been confirmed to be related to its development and severity. Previous studies have indicated that a metabolic product associated with obesity—27-hydroxycholesterol (27HC)—may be an important factor affecting the relationship between the two. Therefore, this study aims to investigate the impact of 27HC on bone erosion in individuals with both obesity and rheumatoid arthritis, proposing that it may be regulated through the liver X receptor (LXR). Cellular experimental results show that under the stimulation of 27HC, the expression of signaling molecules related to osteoclastogenesis increases, confirming that 27HC induces osteoclast formation. Furthermore, pretreatment with an LXR antagonist can reduce the effect of 27HC in promoting osteoclastogenesis, indicating that LXR may play a key regulatory role in this process. In vivo studies utilizing a collagen-induced arthritis rat model further validated these findings. Rats subjected to a high-fat and high-cholesterol diet exhibited exacerbated joint inflammation and severe bone resorption. Immunohistochemical staining analysis showed an increase in the expression of signaling molecules related to osteoclastogenesis, which aligns with the cellular experimental results, indicating that the combination of obesity and RA further intensifies bone erosion. This study confirms that 27HC can promote osteoclastogenesis, further exacerbating bone erosion in RA, and suggests that LXR might be a crucial regulatory factor in this process. Future investigations into the mechanisms involved could shed light on the relationship between 27HC and LXR in the pathological context of RA, potentially leading to new treatment options for individuals with both obesity and RA.