Akt2 inhibition alleviates temporomandibular joint osteoarthritis by preventing subchondral bone loss

IF 4.9 2区医学 Q1 Medicine

Arthritis Research & Therapy Pub Date : 2025-02-27 DOI:10.1186/s13075-025-03506-x

Shi-Yang Feng, Meng-Nan Cao, Chen-Chen Gao, Yi-Xin Li, Jie Lei, Kai-Yuan Fu

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Abstract

This study aimed to investigate the role and mechanism of the Akt2 pathway in different stages of anterior disc displacement (ADD)-induced temporomandibular joint osteoarthritis (TMJOA). A rat model for TMJOA that simulates anterior disc displacement was established. For inhibit Akt2 expression in subchondral bone, rats were intravenously injected with adeno-associated virus carrying Akt2 shRNA at a titer of 1 × 1012 transducing units/mL 10 days before the ADD or sham operations. The rats were euthanized and evaluated 1 or 8 weeks after surgery, as these time points represented the early or advanced stage of ADD. Immunostaining was performed to examine the expression and location of phosphorylated Akt2 in different stages of ADD. Microcomputed tomography, hematoxylin and eosin staining, toluidine blue staining, Western blotting, immunohistochemical and immunofluorescence staining were used to elucidate the pathological changes and potential mechanisms underlying ADD-induced TMJOA. In the rat model of ADD-induced TMJOA, rapid condylar bone loss occurred with increased phosphorylation of Akt2 in subchondral bone macrophages within 1 week post-surgery. At 8 weeks after surgery, abnormal remodeling of subchondral bone and degenerative changes in cartilage were observed. Inhibiting Akt2 reduced condylar bone resorption following ADD surgery while improving condylar bone morphology at 8 weeks post-surgery. Additionally, inhibition of Akt2 alleviated cartilage degeneration characterized by a decreased number of apoptotic chondrocytes, reduced expression of matrix metalloproteinases, and increased collagen type II expression in cartilage tissue. The Akt2 pathway is activated mainly in subchondral bone macrophages during the early stage of ADD and plays an important role in regulating subchondral bone remodeling. Inhibition of Akt2 could serve as a prophylactic treatment to slow the progression of ADD-induced TMJOA.

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Akt2抑制通过防止软骨下骨丢失减轻颞下颌关节骨性关节炎

本研究旨在探讨Akt2通路在前椎间盘移位（ADD）诱导的颞下颌关节骨性关节炎（TMJOA）不同阶段中的作用及机制。建立模拟前盘移位的大鼠颞下颌关节关节炎模型。为了抑制Akt2在软骨下骨中的表达，在ADD或假手术前10天静脉注射携带Akt2 shRNA的腺相关病毒，滴度为1 × 1012个转导单位/mL。手术后1周或8周对大鼠实施安乐死并进行评估，因为这些时间点代表了ADD的早期或晚期。免疫染色检测磷酸化Akt2在ADD不同阶段的表达和位置。微计算机断层扫描、苏木精和伊红染色、甲苯胺蓝染色、Western blotting、采用免疫组织化学和免疫荧光染色法分析add诱导TMJOA的病理变化及其潜在机制。在add诱导的TMJOA大鼠模型中，术后1周内，软骨下骨巨噬细胞中Akt2磷酸化水平升高，髁突骨快速丢失。术后8周，观察到软骨下骨异常重塑和软骨退行性改变。抑制Akt2可减少ADD术后髁突骨吸收，同时改善术后8周髁突骨形态。此外，Akt2的抑制减轻了软骨退行性变，其特征是软骨组织中凋亡软骨细胞数量减少，基质金属蛋白酶表达减少，II型胶原表达增加。Akt2通路在ADD早期主要在软骨下骨巨噬细胞中被激活，在调节软骨下骨重塑中起重要作用。抑制Akt2可作为一种预防性治疗，以减缓add诱导的TMJOA的进展。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Arthritis Research & Therapy RHEUMATOLOGY-

CiteScore

8.60

自引率

2.00%

发文量

261

审稿时长

14 weeks

期刊介绍： Established in 1999, Arthritis Research and Therapy is an international, open access, peer-reviewed journal, publishing original articles in the area of musculoskeletal research and therapy as well as, reviews, commentaries and reports. A major focus of the journal is on the immunologic processes leading to inflammation, damage and repair as they relate to autoimmune rheumatic and musculoskeletal conditions, and which inform the translation of this knowledge into advances in clinical care. Original basic, translational and clinical research is considered for publication along with results of early and late phase therapeutic trials, especially as they pertain to the underpinning science that informs clinical observations in interventional studies.