C10orf10/DEPP activates mitochondrial autophagy and maintains chondrocyte viability in the pathogenesis of osteoarthritis
C10orf10/DEPP activates mitochondrial autophagy and maintains chondrocyte viability in the pathogenesis of osteoarthritis
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DOI：
10.1096/fj.202100896r
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发表时间：
2022-02-01
期刊：
影响因子：
4.8
通讯作者：
Nakashima, Yasuharu
中科院分区：
文献类型：
--
作者：
Kuwahara, Masanari;Akasaki, Yukio;Nakashima, Yasuharu
骨关节炎（OA）是最常见的关节疾病，其特征在于关节软骨的进行性丧失。自噬是一种溶酶体降解途径，维持细胞内环境稳定，软骨细胞自噬功能障碍是OA发病机制的标志。然而，OA软骨细胞自噬功能障碍的原因仍不完全清楚。最近的研究报道，孕激素诱导的蜕膜蛋白（C10 orf 10/DEPP）正调控自噬功能。在这项研究中，我们发现DEPP参与软骨细胞的线粒体自噬功能，以及在OA的发病机制。DEPP的表达下降，在人类OA软骨细胞中的促炎细胞因子的存在或不存在，并诱导饥饿，过氧化氢（H2 O2），和缺氧（氯化钴）。对于功能研究，DEPP敲低降低H2 O2诱导的自噬通量，而DEPP过表达增加H2 O2处理后的自噬通量并维持细胞活力。DEPP通过敲低FOXO类转录因子下调，并调节FOXO 3调节的自噬功能。在通过内侧半月板不稳定的OA小鼠模型中，DEPP敲除小鼠加剧了软骨降解的进展，TUNEL阳性细胞，并且从敲除小鼠中分离的软骨细胞在H2 O2处理后自噬通量降低和细胞死亡增加。亚细胞分级分离分析表明，DEPP通过BCL 2相互作用蛋白3激活线粒体自噬。总之，我们的数据表明，DEPP是一个主要的应力诱导基因参与激活软骨细胞中的线粒体自噬，并保持软骨细胞的活力在OA发病过程中。DEPP代表了增强OA患者自噬的潜在治疗靶点。
Osteoarthritis (OA), the most prevalent joint disease, is characterized by the progressive loss of articular cartilage. Autophagy, a lysosomal degradation pathway, maintains cellular homeostasis, and autophagic dysfunction in chondrocytes is a hallmark of OA pathogenesis. However, the cause of autophagic dysfunction in OA chondrocytes remains incompletely understood. Recent studies have reported that decidual protein induced by progesterone (C10orf10/DEPP) positively regulates autophagic functions. In this study, we found that DEPP was involved in mitochondrial autophagic functions of chondrocytes, as well as in OA pathogenesis. DEPP expression decreased in human OA chondrocytes in the absence or presence of pro-inflammatory cytokines, and was induced by starvation, hydrogen peroxide (H2O2), and hypoxia (cobalt chloride). For functional studies, DEPP knockdown decreased autophagic flux induced by H2O2, whereas DEPP overexpression increased autophagic flux and maintained cell viability following H2O2 treatment. DEPP was downregulated by knockdown of forkhead box class O (FOXO) transcription factors and modulated the autophagic function regulated by FOXO3. In an OA mouse model by destabilization of the medial meniscus, DEPP-knockout mice exacerbated the progression of cartilage degradation with TUNEL-positive cells, and chondrocytes isolated from knockout mice were decreased autophagic flux and increased cell death following H2O2 treatment. Subcellular fractionation analysis revealed that mitochondria-located DEPP activated mitochondrial autophagy via BCL2 interacting protein 3. Taken together, our data demonstrate that DEPP is a major stress-inducible gene involved in the activation of mitochondrial autophagy in chondrocytes, and maintains chondrocyte viability during OA pathogenesis. DEPP represents a potential therapeutic target for enhancing autophagy in patients with OA.