Jin Tao, Wu Lei, Wang Jizu, Wang Xingbo, He Zongru, Di Wenfei, Yang Qingshan, Wei Xiaodong
First Clinical Medical College of Gansu University of Traditional Chinese Medicine, Gansu, 730000, PR China; Department of Orthopedics, Gansu Provincial Hospital, Gansu, 730000, PR China.
Department of Neurology, Xuanwu Hospital Capital Medical University, Beijing, 100000, PR China.
Arch Biochem Biophys. 2024 May;755:109960. doi: 10.1016/j.abb.2024.109960. Epub 2024 Mar 19.
Diabetes mellitus (DM) has been demonstrated to accelerate the progression of osteoarthritis (OA) by largely unknown mechanisms. Studies have shown that DM dysfunctional adipocyte-derived exosomes play a crucial role in the pathogenesis of remote organ functions. The present study aimed to clarify whether and how diabetic adipocyte-derived exosomes mediate the pathological regulation of OA. We found that intraarticular injection of DM serum exosomes in the non-diabetic mice significantly exacerbated OA injury as evidenced by a rough and fractured cartilage surface as well as increased chondrocyte apoptosis, decreased mitochondrial membrane potential (△Ψ) and increased expression of cleaved caspase-3. Mechanistic investigation identified that miR-130b-3p was significantly increased in circulating exosomes derived from DM mice and exosomes derived from HG-treated normal adipocytes, and we demonstrated that transfection of miR-130b-3p mimics significantly exacerbated the mitochondrial function of chondrocytes. Our data also indicated that miR-130b-3p impaired the △Ψ, increased cleaved caspase-3 levels, and decreased the expression of 5'-adenosine monophosphate-activated protein kinase α1 (AMPKα1), Silent mating-type information regulation 2 homolog 1 (SIRT1), and peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) in chondrocytes. Pharmacologic activation of AMPKα1 using AICAR reversed the △Ψ and catabolic responses in chondrocytes transfected with miR-130b-3p mimics. Moreover, AICAR decreased the effects of miR-130b-3p mimics on chondrocytes transfected with SIRT1-siRNA or PGC-1α-siRNA. The current study demonstrated that adipocyte-derived exosomal miR-130b-3p under DM conditions suppresses mitochondrial function in chondrocytes through targeting the AMPKα1/SIRT1/PGC1-α pathway, thus exacerbating OA injury.
糖尿病（DM）已被证明可通过 largely 未知的机制加速骨关节炎（OA）的进展。研究表明，糖尿病功能失调的脂肪细胞衍生外泌体在远程器官功能的发病机制中起关键作用。本研究旨在阐明糖尿病脂肪细胞衍生的外泌体是否以及如何介导 OA 的病理调节。我们发现，在非糖尿病小鼠关节内注射 DM 血清外泌体显著加剧了 OA 损伤，表现为软骨表面粗糙和骨折，以及软骨细胞凋亡增加、线粒体膜电位（△Ψ）降低和裂解的 caspase-3 表达增加。机制研究发现，在源自 DM 小鼠的循环外泌体和源自 HG 处理的正常脂肪细胞的外泌体中，miR-130b-3p 显著增加，并且我们证明转染 miR-130b-3p 模拟物显著加剧了软骨细胞的线粒体功能。我们的数据还表明，miR-130b-3p 损害了△Ψ，增加了裂解的 caspase-3 水平，并降低了软骨细胞中 5'-腺苷单磷酸激活蛋白激酶α1（AMPKα1）、沉默交配型信息调节 2 同源物 1（SIRT1）和过氧化物酶体增殖物激活受体γ共激活因子-1α（PGC-1α）的表达。使用 AICAR 对 AMPKα1 进行药理学激活可逆转转染 miR-130b-3p 模拟物的软骨细胞中的△Ψ 和分解代谢反应。此外，AICAR 降低了 miR-130b-3p 模拟物对转染 SIRT1-siRNA 或 PGC-1α-siRNA 的软骨细胞的影响。当前研究表明，DM 条件下脂肪细胞衍生的外泌体 miR-130b-3p 通过靶向 AMPKα1/SIRT1/PGC1-α 途径抑制软骨细胞的线粒体功能，从而加剧 OA 损伤。
