Cuicui Wang, Liang Fang, Meng Shi, Xiangfeng Niu, Tiandao Li, Xiaofei Li, Kevin Cho, Yonghua He, Shuang Liu, Aiwu Lu, Xiaoyun Xing, Jessica Lukowski, Young Ah Goo, John R. Speakman, Di Chen, Regis J. O’Keefe, Gary J. Patti, Michael J. Zuscik, Bo Zhang, Jie Shen
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引用次数: 0
摘要
骨关节炎(OA)是一种关节疾病,其病因部分源于代谢功能障碍,但其潜在机制尚未确定,这限制了开发治疗方法的机会。本研究采用多组学方法,结合RNA测序、ATAC-seq、MRE-seq和代谢组学,揭示了转化生长因子-β (TGF-β)和骨形态发生蛋白(BMP)信号不平衡诱导的OA关节软骨细胞增加了由核因子I a (NFIA)上调调控的脂肪酸合成和氧化过程。抑制NFIA抑制必需代谢酶的基因表达,包括乙酰辅酶A羧化酶A (ACACA)和肉碱棕榈酰基转移酶2 (CPT2),导致小鼠和人OA关节软骨细胞脂肪酸代谢和细胞稳态的恢复。肥胖小鼠表现为代谢应激,关节组织中NFIA、ACACA、CPT2表达升高,同时出现关节损伤后的深度滑膜炎、软骨退变、软骨下骨硬化、疼痛。Nfia抑制和脂肪酸代谢的药理抑制在肥胖小鼠中保持了关节完整性,减轻了损伤性OA环境下的滑膜炎和疼痛。总的来说,这项工作确定了NFIA在脂肪酸代谢和关节软骨细胞稳态调节中的作用,并强调脂肪酸代谢是OA治疗的潜在治疗靶点,特别是在肥胖条件下。
NFIA regulates articular chondrocyte fatty acid metabolism and joint homeostasis
Osteoarthritis (OA) is a joint disease with an etiology partially rooted in metabolic dysfunction, yet the underlying mechanisms in this context are not determined, limiting opportunities to develop therapeutic treatments. In this study, we used a multiomic approach combining RNA sequencing, ATAC-seq, MRE-seq, and metabolomics to reveal that OA articular chondrocytes induced by imbalanced transforming growth factor–β (TGF-β) and bone morphogenetic protein (BMP) signaling have increased fatty acid synthesis and oxidation processes regulated by nuclear factor I A (NFIA) up-regulation. Inhibition of NFIA suppressed the elevated gene expression of essential metabolic enzymes, including acetyl-CoA carboxylase A (ACACA) and carnitine palmitoyltransferase 2 (CPT2), leading to the restoration of fatty acid metabolism and cellular homeostasis in both murine and human OA articular chondrocytes. Obese mice displayed metabolic stress with elevated expression of NFIA, ACACA, and CPT2 in joint tissues, and they simultaneously developed profound synovitis, cartilage degeneration, subchondral bone sclerosis, and pain after joint injury. Both Nfia inhibition and pharmacological suppression of fatty acid metabolism in obese mice preserved joint integrity and mitigated synovitis and pain in the context of injury-induced OA settings. Overall, this work identifies a role for NFIA in the regulation of fatty acid metabolism and articular chondrocyte homeostasis and highlights fatty acid metabolism as a potential therapeutic target for OA treatment, particularly under obesity conditions.
期刊介绍:
Science Translational Medicine is an online journal that focuses on publishing research at the intersection of science, engineering, and medicine. The goal of the journal is to promote human health by providing a platform for researchers from various disciplines to communicate their latest advancements in biomedical, translational, and clinical research.
The journal aims to address the slow translation of scientific knowledge into effective treatments and health measures. It publishes articles that fill the knowledge gaps between preclinical research and medical applications, with a focus on accelerating the translation of knowledge into new ways of preventing, diagnosing, and treating human diseases.
The scope of Science Translational Medicine includes various areas such as cardiovascular disease, immunology/vaccines, metabolism/diabetes/obesity, neuroscience/neurology/psychiatry, cancer, infectious diseases, policy, behavior, bioengineering, chemical genomics/drug discovery, imaging, applied physical sciences, medical nanotechnology, drug delivery, biomarkers, gene therapy/regenerative medicine, toxicology and pharmacokinetics, data mining, cell culture, animal and human studies, medical informatics, and other interdisciplinary approaches to medicine.
The target audience of the journal includes researchers and management in academia, government, and the biotechnology and pharmaceutical industries. It is also relevant to physician scientists, regulators, policy makers, investors, business developers, and funding agencies.