机械应力通过 Wnt/β-连环蛋白信号通路减少分泌卷曲相关蛋白表达并促进颞下颌关节骨关节炎。

Mechanical stress reduces secreted frizzled-related protein expression and promotes temporomandibular joint osteoarthritis via Wnt/β-catenin signaling.

机构信息

Department of Orthodontics, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, China; Fujian Key Laboratory of Oral Diseases, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, China.

Fujian Key Laboratory of Oral Diseases, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, China.

出版信息

Bone. 2022 Aug;161:116445. doi: 10.1016/j.bone.2022.116445. Epub 2022 May 16.

DOI:10.1016/j.bone.2022.116445

PMID:35589066

Abstract

AIMS

Mechanical stress overload in the temporomandibular joint (TMJ) is an important cause of TMJ osteoarthritis (TMJOA). Whether secreted frizzled-related proteins (SFRPs) play important roles in the development of mechanical stress-induced TMJOA remains controversial. In this study, we investigated the roles of the Wnt/β-catenin signaling and SFRPs in the progression of mechanical stress-induced TMJOA.

METHODS

We investigated the progression of mechanical stress-induced TMJOA using an in vivo model via modified increased occlusal vertical dimension (iOVD) malocclusion and an in vitro model in which isolated chondrocytes were subjected to mechanical stress. The effects of inhibition of Wnt/β-catenin signal on TMJOA induced by mechanical stress were studied by in vitro drug added and in vivo intra-articular injection of XAV-939. TMJOA progression, Wnt/β-catenin signaling and SFRPs was assessed by Cone beam computed tomography (CBCT) analysis, histochemical and immunohistochemical (IHC) staining, quantitative real-time PCR (qRT-PCR), Western blotting (WB), and immunofluorescence (IF) staining.

RESULTS

Our in vivo results showed that iOVD-induced mechanical stress in the TMJ disrupted mandible growth, induced OA-like changes in TMJ cartilage, and increased OA-related cytokine expression. In addition, iOVD activated Wnt/β-catenin signaling and suppressed Sfrp1, Sfrp3, and Sfrp4 expression in condylar cartilage. Moreover, our in vitro study showed that stress disrupted homeostasis, activated Wnt/β-catenin signaling and inhibited SFRP3 and SFRP4 expression in chondrocytes. Suppression of Wnt/β-catenin signaling with XAV-939 promoted SFRP3 and SFRP4 expression and rescued mechanical stress-induced cartilage degeneration in vivo and in vitro.

CONCLUSIONS

Our work suggests that mechanical stress reduces SFRPs expression both in vivo and in vitro and promotes TMJOA via Wnt/β-catenin signaling. Suppression of Wnt/β-catenin signaling promotes SFRPs expression, especially SFRP3 and SFRP4 expression, and rescues mechanical stress-induced cartilage degeneration. Wnt/β-catenin signaling and SFRPs may represent potential therapeutic targets for TMJOA.

摘要

目的

颞下颌关节（TMJ）的机械应力过载是 TMJ 骨关节炎（TMJOA）的重要原因。分泌卷曲相关蛋白（SFRPs）是否在机械应力诱导的 TMJOA 发展中起重要作用仍存在争议。在这项研究中，我们研究了 Wnt/β-连环蛋白信号和 SFRPs 在机械应力诱导的 TMJOA 进展中的作用。

方法

我们通过改良的增加咬合垂直距离（iOVD）错合畸形建立体内模型，通过分离的软骨细胞受到机械应力建立体外模型，研究机械应力诱导的 TMJOA 的进展。通过体外药物添加和关节内注射 XAV-939 研究抑制 Wnt/β-连环蛋白信号对机械应力诱导的 TMJOA 的影响。通过锥形束 CT（CBCT）分析、组织化学和免疫组织化学（IHC）染色、实时定量 PCR（qRT-PCR）、Western blot（WB）和免疫荧光（IF）染色评估 TMJOA 进展、Wnt/β-连环蛋白信号和 SFRPs。

结果

我们的体内结果表明，TMJ 中的 iOVD 诱导的机械应力破坏了下颌骨的生长，诱导了 TMJ 软骨的 OA 样变化，并增加了 OA 相关细胞因子的表达。此外，iOVD 激活了髁突软骨中的 Wnt/β-连环蛋白信号，并抑制了 Sfrp1、Sfrp3 和 Sfrp4 的表达。此外，我们的体外研究表明，应激破坏了软骨细胞的内稳态，激活了 Wnt/β-连环蛋白信号，并抑制了 SFRP3 和 SFRP4 的表达。用 XAV-939 抑制 Wnt/β-连环蛋白信号促进了 SFRP3 和 SFRP4 的表达，并挽救了体内和体外机械应力诱导的软骨退化。

结论

我们的工作表明，机械应力无论是在体内还是体外都降低了 SFRPs 的表达，并通过 Wnt/β-连环蛋白信号促进了 TMJOA。抑制 Wnt/β-连环蛋白信号促进了 SFRPs 的表达，特别是 SFRP3 和 SFRP4 的表达，并挽救了机械应力诱导的软骨退化。Wnt/β-连环蛋白信号和 SFRPs 可能是 TMJOA 的潜在治疗靶点。