Gene therapy for fat-1 prevents obesity- induced metabolic dysfunction, cellular senescence, and osteoarthritis

• 成果类型: Article
• 署名作者: Tang, Ruhang; Harasymowicz, Natalia S.; Wu, Chia-Lung; Choi, Yun-Rak; Lenz, Kristin; Oswald, Sara J.; Guilak, Farshid
• 署名单位: Utah System of Higher Education; University of Utah; Utah System of Higher Education; University of Utah; University of Rochester; Washington University (WUSTL); Washington University (WUSTL); Yonsei University; Yonsei University Health System
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9495
• DOI: 10.1073/pnas.2402954121
• 发表日期: 2024-10-22
• 关键词: polyunsaturated fatty-acids; adipose-tissue; eicosapentaenoic acid; docosahexaenoic acid; knee osteoarthritis; transgenic mice; expression; cells; omega-3-fatty-acids; inflammation

摘要

Obesity is one of the primary risk factors for osteoarthritis (OA), acting through cross talk among altered biomechanics, metabolism, adipokines, and dietary free fatty acid (FA) composition. Obesity and aging have been linked to cellular senescence in various tissues, resulting in increased local and systemic inflammation and immune dysfunction. We hypothesized that obesity and joint injury lead to cellular senescence that is typically associated with increased OA severity or with aging and that the ratio of omega- 6 (w- 6) to omega- 3 (w- 3) FAs regulates these pathologic effects. Mice were placed on an w- 6- rich high- fat diet or a lean control diet and underwent destabilization of the medial meniscus to induce OA. Obesity and joint injury significantly increased cellular senescence in subcutaneous and visceral fat as well as joint tissues such as synovium and cartilage. Using adeno- associated virus (AAV) gene therapy for fat- 1 , a fatty acid desaturase that converts w- 6 to w- 3 FAs, decreasing the serum w- 6:w- 3 FA ratio had a strong senomorphic and therapeutic effect, mitigating metabolic dysfunction, cellular senescence, and joint degeneration. In vitro coculture of bone marrow- derived macrophages and chondrocytes from control and AAV8- fat1- treated mice were used to examine the roles of various FA mediators in regulating chondrocyte senescence. Our results suggest that obesity and joint injury result in a premature aging of the joint as measured by senescence markers, and these changes can be ameliorated by altering FA composition using fat- 1 gene therapy. These findings support the potential for fat- 1 gene therapy to treat obesity- and/or injury- induced OA clinically.