Drug-induced modulation of gp130 signalling prevents articular cartilage degeneration and promotes repair.
Drug-induced modulation of gp130 signalling prevents articular cartilage degeneration and promotes repair.
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DOI：
10.1136/annrheumdis-2017-212037
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发表时间：
2018-05
影响因子：
27.4
通讯作者：
Evseenko D
中科院分区：
文献类型：
--
作者：
Shkhyan R;Van Handel B;Bogdanov J;Lee S;Yu Y;Scheinberg M;Banks NW;Limfat S;Chernostrik A;Franciozi CE;Alam MP;John V;Wu L;Ferguson GB;Nsair A;Petrigliano FA;Vangsness CT;Vadivel K;Bajaj P;Wang L;Liu NQ;Evseenko D
成人关节软骨（AC）修复能力差，关节表面损伤常导致骨关节炎（OA），其特征为基质丢失、肥大和软骨细胞凋亡。由白细胞介素（IL）-6家族细胞因子介导的炎症已被鉴定为小鼠和人关节中的关节炎前变化的关键驱动因素，导致前馈过程驱动基质降解酶和IL-6本身的表达。在这里，我们表明，通过糖蛋白130（gp 130），IL-6家族细胞因子的共同受体的信号，可以有上下文特异性和精氨酸特异性的影响关节软骨细胞和小分子gp 130调制器可以偏向抗炎和抗退行性输出信号。对170 000种化合物的高通量筛选鉴定出一种称为软骨生长和分化调节剂（RCGD 423）的小分子gp 130调节剂，其在不存在细胞因子配体的情况下促进非典型同源二聚体信号传导，驱动MYC和pSTAT 3的瞬时增加，同时通过直接竞争gp 130占用抑制制瘤素M和IL-6介导的ERK和NF-κB活化。这种小分子增加增殖，同时减少体外成人软骨细胞的凋亡和肥大反应。在大鼠部分椎间盘切除术模型中，RCGD 423大大减少了软骨细胞肥大、损失和变性，同时增加了软骨细胞增殖，超过了对损伤的反应。此外，RCGD 423改善了大鼠全层骨软骨缺损模型中的软骨愈合，增加了缺损中间充质细胞的增殖，并且还抑制了从头产生的软骨中软骨基质的分解。这些结果确定了一种新的策略，通过小分子介导的调节gp 130信号AC补救。
Human adult articular cartilage (AC) has little capacity for repair, and joint surface injuries often result in osteoarthritis (OA), characterised by loss of matrix, hypertrophy and chondrocyte apoptosis. Inflammation mediated by interleukin (IL)-6 family cytokines has been identified as a critical driver of proarthritic changes in mouse and human joints, resulting in a feed-forward process driving expression of matrix degrading enzymes and IL-6 itself. Here we show that signalling through glycoprotein 130 (gp130), the common receptor for IL-6 family cytokines, can have both context-specific and cytokine-specific effects on articular chondrocytes and that a small molecule gp130 modulator can bias signalling towards anti-inflammatory and antidegenerative outputs. High throughput screening of 170 000 compounds identified a small molecule gp130 modulator termed regulator of cartilage growth and differentiation (RCGD 423) that promotes atypical homodimeric signalling in the absence of cytokine ligands, driving transient increases in MYC and pSTAT3 while suppressing oncostatin M- and IL-6-mediated activation of ERK and NF-κB via direct competition for gp130 occupancy. This small molecule increased proliferation while reducing apoptosis and hypertrophic responses in adult chondrocytes in vitro. In a rat partial meniscectomy model, RCGD 423 greatly reduced chondrocyte hypertrophy, loss and degeneration while increasing chondrocyte proliferation beyond that observed in response to injury. Moreover, RCGD 423 improved cartilage healing in a rat full-thickness osteochondral defect model, increasing proliferation of mesenchymal cells in the defect and also inhibiting breakdown of cartilage matrix in de novo generated cartilage. These results identify a novel strategy for AC remediation via small molecule-mediated modulation of gp130 signalling.
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影响因子：
4.9
作者：
Moran EM;Mullan R;McCormick J;Connolly M;Sullivan O;Fitzgerald O;Bresnihan B;Veale DJ;Fearon U
通讯作者：
Fearon U
影响因子：
21.3
作者：
Flores A;Schell J;Krall AS;Jelinek D;Miranda M;Grigorian M;Braas D;White AC;Zhou JL;Graham NA;Graeber T;Seth P;Evseenko D;Coller HA;Rutter J;Christofk HR;Lowry WE
通讯作者：
Lowry WE
影响因子：
--
作者：
Livshits, Gregory;Zhai, Guangju;Hart, Deborah J.;Kato, Bernet S.;Wang, Huizhong;Williams, Frances M. K.;Spector, Tim D.
通讯作者：
Spector, Tim D.
影响因子：
15.9
作者：
LOTZ, M;MOATS, T;VILLIGER, PM
通讯作者：
VILLIGER, PM
影响因子：
4.5
作者：
Hall MD;Murray CA;Valdez MJ;Perantoni AO
通讯作者：
Perantoni AO