類風濕性關節炎具有發炎性細胞激素浸潤之特徵，臨床上可導致關節破壞及肌肉質量缺失。肌肉生長抑制素是調節肌肉質量及骨質之重要因子。我們試圖確認肌肉生長抑制素是否能調整類風濕性關節炎之滑液膜纖維母細胞活性以及發炎反應，結果類風濕性關節炎患者之關節液其肌肉生長抑制素和介白素-1β(類風濕性關節炎關鍵發炎性細胞激素)有過度表現的情形且兩者呈現正相關；另外，在細胞實驗中，我們發現肌肉生長抑制素透過ERK, JNK, AP-1之訊息傳導路徑來正向調控介白素-1β的表現。再者，透過電腦分析我們發現標記於介白素-1β的3，端非轉譯區(3′ UTR)之微小RNA(miR-21-5p)；當細胞經肌肉生長抑制素治療顯示它會抑制miR-21-5p表現而miR-21-5p之類似物可阻止肌肉生長抑制素誘發之介白素-1β表現，顯現經肌肉生長抑制素治療後兩者間之負相關性；我們也觀察到類風濕性關節炎(CIA, collagen-induced-arthritis)大鼠動物實驗中，其後腳關節有腫脹之現象，其中組織免疫染色顯現有較高之肌肉生長抑制素及介白素-1β表現。綜合所述，我們證實肌肉生長抑制素調節介白素-1β之表現，而控制肌肉生長抑制素表現可能為治療類風濕性關節炎之重要標的。
Rheumatoid arthritis (RA) is characterized by the infiltration of a number of pro-inflammatory cytokines into synovial fluid and patients with RA often develop joint destruction and deficits in muscle mass. The growth factor myostatin is a key regulator linking muscle mass and bone structure. We sought to determine whether myostatin regulates rheumatoid synovial fibroblast activity and inflammation in RA. We found that levels of myostatin and interleukin (IL)-1β in synovial fluid from RA patients were over-expressed and positively correlated. In in vitro investigations, we found that myostatin dose-dependently regulated IL-1β expression through the ERK, JNK and AP-1 signal-transduction pathways. Computational analysis confirmed that miR-21-5p directly targets the expression of the 3’ untranslated region (3'UTR) of IL-1β. Treatment of cells with myostatin inhibited miR-21-5p expression and miR-21-5p mimic prevented myostatin-induced enhancement of IL-1β expression, showing an inverse correlation between miR-21-5p and IL-1β expression during myostatin treatment. We also found significantly increased paw swelling in an animal model of collagen-induced arthritis (CIA), compared with controls; immunohistochemistry staining revealed substantially higher levels of myostatin and IL-1β expression in CIA tissue. Our evidence indicates that myostatin regulates IL-1β production. Thus, targeting myostatin may represent a potential therapeutic target for RA.
