Interleukin-6 signaling mediates cartilage degradation and pain in posttraumatic osteoarthritis in a sex-specific manner.
Interleukin-6 signaling mediates cartilage degradation and pain in posttraumatic osteoarthritis in a sex-specific manner.
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DOI：
10.1126/scisignal.abn7082
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发表时间：
2022-07-26
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
--
作者：
骨关节炎(OA)和创伤后骨关节炎(PTOA)是由关节软骨的分解代谢和合成代谢过程的失衡和整个关节的促炎变化引起的，导致关节退变和疼痛。我们研究了白细胞介素6(IL-6)信号是否与PTOA的软骨退化和疼痛有关。在雄性小鼠中，IL6的基因消融减少了PTOA相关的软骨分解代谢、膝关节的神经支配和伤害性信号，但没有改善PTOA相关的软骨下骨硬化或软骨细胞的凋亡。在雌性IL6−/−小鼠身上没有观察到这些影响。与野生型小鼠相比，雄性IL6−/−小鼠膝关节损伤后膝关节和背根神经节中IL-6下游调节因子STAT3和ERK的活性降低。Janus激酶(JAK)在软骨分解代谢的STAT和ERK信号以及组织外植体中的DRG疼痛信号中起关键作用。STAT3信号在软骨分解代谢中起重要作用，ERK信号则介导轴突生长和伤害性神经元的激活。这些数据表明，IL-6以性别特异性的方式介导了与PTOA相关的软骨退化和疼痛，并确定了IL-6信号的下游效应物的组织特异性贡献，这是治疗疾病的OA药物的潜在靶点。
Osteoarthritis (OA) and post-traumatic OA (PTOA) are caused by an imbalance in catabolic and anabolic processes in articular cartilage and pro-inflammatory changes throughout the joint, leading to joint degeneration and pain. We examined whether interleukin-6 (IL-6) signaling contributed to cartilage degradation and pain in PTOA. Genetic ablation of Il6 in male mice decreased PTOA-associated cartilage catabolism, innervation of the knee joint, and nociceptive signaling without improving PTOA-associated subchondral bone sclerosis or chondrocyte apoptosis. These effects were not observed in female Il6−/− mice. Compared to wild-type mice, the activation of the IL-6 downstream mediators STAT3 and ERK was reduced in the knees and dorsal root ganglia (DRG) of male Il6−/− mice after knee injury. Janus kinases (JAKs) were critical for STAT and ERK signaling in cartilage catabolism and DRG pain signaling in tissue explants. Whereas STAT3 signaling was important for cartilage catabolism, ERK signaling mediated neurite outgrowth and the activation of nociceptive neurons. These data demonstrate that IL-6 mediates both cartilage degradation and pain associated with PTOA in a sex-specific manner and identify tissue-specific contributions of downstream effectors of IL-6 signaling, which are potential therapeutic targets for disease-modifying OA drugs.
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DOI：
10.1016/j.clim.2012.12.011
发表时间：
2013-03
期刊：
Clinical immunology (Orlando, Fla.)
影响因子：
--
作者：
Haseeb A;Haqqi TM
通讯作者：
Haqqi TM
影响因子：
9.2
作者：
Erta M;Quintana A;Hidalgo J
通讯作者：
Hidalgo J
影响因子：
15.9
作者：
GUERNE, PA;ZURAW, BL;LOTZ, M
通讯作者：
LOTZ, M
影响因子：
7
作者：
Glasson, S. S.;Blanchet, T. J.;Morris, E. A.
通讯作者：
Morris, E. A.
影响因子：
158.5
作者：
Felson, DT
通讯作者：
Felson, DT