昼夜节律紊乱通过 GSK3β/β-CATENIN 通路上调髁突软骨细胞中 Per1 介导颞下颌关节骨关节炎。
Circadian rhythm disruption upregulating Per1 in mandibular condylar chondrocytes mediating temporomandibular joint osteoarthritis via GSK3β/β-CATENIN pathway.
机构信息
Department of Stomatology, The Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Guangzhou, 500630, China.
Department of Stomatology, Shenzhen Sixth People's Hospital (Nanshan Hospital), Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, China.
出版信息
J Transl Med. 2024 Jul 15;22(1):662. doi: 10.1186/s12967-024-05475-2.
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.
背景
颞下颌关节骨关节炎（TMJOA）发病率较高，但发病机制尚不清楚。昼夜节律是人体的重要波动，影响各种生物活动。然而，昼夜节律是否影响 TMJOA 的发生和发展尚不清楚。
方法
我们打乱大鼠的正常节律，检测颌骨髁突软骨中核心时钟基因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，上调或下调时钟基因 Per1，检测软骨基质降解酶的表达，检测 GSK3β/β-CATENIN 通路的激活，并使用激动剂和抑制剂进行验证。最后，下调时差大鼠髁突软骨中 Per1 的表达后，检测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出现 TMJOA 样病变，髁突软骨中时钟基因 Per1 及软骨基质降解酶表达增加。下调或上调下颌髁突软骨细胞中 Per1 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，GSK3β/β-CATENIN 通路的激动剂和抑制剂可挽救这种情况。此外，体内下调髁突软骨中 Per1 的表达后，可明显缓解时差引起的软骨降解、软骨丢失、软骨下骨丢失，并抑制 GSK3β/β-CATENIN 信号通路。昼夜节律紊乱可导致 TMJOA。时钟基因 Per1 可通过激活 GSK3β/β-CATENIN 通路，促进软骨基质降解酶的表达，促进 TMJOA 的发生。时钟基因 Per1 是 TMJOA 防治的靶点。
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