髌下脂肪垫来源sIL-6R激活反式信号通路致膝关节骨关节炎软骨退变的机制及干预研究

膝关节骨关节炎(OA)的主要病理特征为软骨退变，髌下脂肪垫通过炎症参与软骨退变机制尚不明确。申请者前期研究证实，髌下脂肪垫可分泌IL-6加速离体创伤软骨退变，且OA患者髌下脂肪垫分泌游离型IL-6受体(sIL-6R)增多。已知IL-6结合膜型IL-6受体(mIL-6R)可激活抗炎经典信号通路，结合sIL-6R可激活促炎反式信号通路，而sgp130中和sIL-6R可抑制反式信号通路。因此申请人假设：OA髌下脂肪垫存在sIL-6R/sgp130分泌失衡，sIL-6R增多可导致反式信号通路异常激活，从而加速软骨退变。为验证假设，该项目采用细胞组织共培养、基因沉默探讨过量sIL-6R引发软骨退变的机制，并通过动物模型结合B超引导穿刺将sgp130类似物sgp130fc脂肪垫内注射，以特异性阻滞反式信号通路观察疗效。本项目对阐明OA发病机制具有重要基础理论价值，并可为后期开发精准治疗药物提供思路。

The main pathologic feature of knee osteoarthritis is cartilage degeneration. How infrapatellar fat pad is involved in cartilage degeneration through inflammation is not clear. Our previous studies revealed that infrapatellar fat pad aggravated ex vivo cartilage degeneration through interleukin-6 (IL-6). We also found osteoarthritis patients’ infrapatellar fat pad released more soluble type interleukin-6 receptor (sIL-6R). It is well known that when IL-6 binds membrane type interleukin-6 receptor (mIL-6R), anti-inflammatory classical-signaling pathway will be activated, however, when it binds sIL-6R, pro-inflammatory trans-signaling pathway will be activated. While, sgp130 inhibits trans-signaling pathway by neutralizing sIL-6R. Therefore, it is hypothesized that increased sIL-6R and reduced sgp130 secreted by infrapatellar fat pad activate trans-signaling pathway, thus inducing cartilage degeneration. To confirm the hypothesis, cell-tissue co-culture and gene silencing techniques will be used to investigate the mechanisms of cartilage degeneration induced by sIL-6R. Then, sgp130 analog sgp130fc will be injected into infrapatellar fat pad of osteoarthritis animal model guided by ultrasound to specifically block trans-signaling pathway for treating osteoarthritis. The project is important for elucidating the pathogenesis of osteoarthritis, and could give clues to developing precise therapeutic drugs in the future.