背景:颞下颌关节骨关节炎(TMJOA)发病率高,但其发病机制尚不清楚。昼夜节律是人体的重要振荡,影响各种生物活动。然而,目前尚不清楚昼夜节律是否影响TMJOA的发生和发展。
方法:我们打乱了大鼠的正常节律,并检测了核心时钟基因在颌骨髁突软骨中的表达和髁突的组织学变化。分离大鼠下颌髁突软骨细胞后,我们上调或下调时钟基因Per1,检测软骨基质降解酶的表达,测试了GSK3β/β-CATENIN途径的激活,并使用激动剂和抑制剂进行了验证。最后,下调大鼠下颌髁突软骨Per1表达后,我们检查了软骨基质降解酶的表达和髁突的组织学变化。
结果:时差导致大鼠下颌髁突TMJOA样病变,时钟基因Per1和软骨基质降解酶在大鼠髁突软骨中的表达增加。当Per1在下颌髁突软骨细胞中下调或上调时,GSK3β/β-CATENIN通路被抑制或激活,软骨基质降解酶的表达减少或增加,可以通过GSK3β/β-CATENIN途径的激活剂和抑制剂来挽救。此外,体内下颌髁突软骨中Per1下调后,显著缓解软骨退化,软骨损失,时差引起的软骨下骨丢失,并观察到GSK3β/β-CATENIN信号通路的抑制。昼夜节律中断可导致TMJOA。时钟基因Per1可通过激活GSK3β/β-CATENIN通路并促进软骨基质降解酶的表达来促进TMJOA的发生。时钟基因Per1是TMJOA防治的靶点。
BACKGROUND: Temporomandibular joint osteoarthritis (TMJOA) has a high incidence rate, but its pathogenesis remains unclear. Circadian rhythm is an important oscillation in the human body and influences various biological activities. However, it is still unclear whether circadian rhythm affects the onset and development of TMJOA.
METHODS: We disrupted the normal rhythm of rats and examined the expression of core clock genes in the mandibular condylar cartilage of the jaw and histological changes in condyles. After isolating rat mandibular condylar chondrocytes, we upregulated or downregulated the clock gene Per1, examined the expression of cartilage matrix-degrading enzymes, tested the activation of the GSK3β/β-CATENIN pathway and verified it using agonists and inhibitors. Finally, after downregulating the expression of Per1 in the mandibular condylar cartilage of rats with jet lag, we examined the expression of cartilage matrix-degrading enzymes and histological changes in condyles.
RESULTS: Jet lag led to TMJOA-like lesions in the rat mandibular condyles, and the expression of the clock gene Per1 and cartilage matrix-degrading enzymes increased in the condylar cartilage of rats. When Per1 was downregulated or upregulated in mandibular condylar chondrocytes, the GSK3β/β-CATENIN pathway was inhibited or activated, and the expression of cartilage matrix-degrading enzymes decreased or increased, which can be rescued by activator and inhibitor of the GSK3β/β-CATENIN pathway. Moreover, after down-regulation of Per1 in mandibular condylar cartilage in vivo, significant alleviation of cartilage degradation, cartilage loss, subchondral bone loss induced by jet lag, and inhibition of the GSK3β/β-CATENIN signaling pathway were observed. Circadian rhythm disruption can lead to TMJOA. The clock gene Per1 can promote the occurrence of TMJOA by activating the GSK3β/β-CATENIN pathway and promoting the expression of cartilage matrix-degrading enzymes. The clock gene Per1 is a target for the prevention and treatment of TMJOA.