Background

The heterogeneity of osteoarthritis (OA) significantly limits the effectiveness of pharmacological treatments in an unselected patient population. In this context, the identification of OA subtypes is meaningful for the development of therapies that target specific types of OA pathogenesis.

Methods

Expression array profiles of 70 OA and 36 control synovial samples were extracted from the GEO database. Unsupervised consensus clustering was performed based on the most variable genes to identify OA subclusters. Next, Joint samples from OA patients were obtained. We divided the OA patient into two subpopulations according to synovial ADCY7 levels. Synovium and cartilage samples from different OA subpopulations were evaluated. In addition, we established a high-fat diet (HFD)-induced rat OA model. We evaluated OA progression, lipid metabolism, synovitis and fibroblast-like synoviocytes (FLS) function in this HFD-induced OA model.

Results

70 OA patients were categorized into three distinct subclusters. We noted that one subcluster was characterized by synovial lipid metabolism disorder GO terms. We further identified the most noticeable KEGG pathway “Regulation of lipolysis in adipocytes” in this subcluster as well as the most significantly differentially expressed gene, ADCY7. We found that the ADCY7 high expressing group (32.6%) exhibited features of synovial inflammatory lipolysis epithelial-mesenchymal transition (EMT) tendency, as well as faster join space narrowing. The HFD induced OA-like degeneration in rat joints. We observed similar synovial inflammatory lipolysis and EMT in FLS, characterized by higher proliferative and invasive activity and elevated proinflammatory and procatabolic properties. ADCY7 was highly expressed in the synovium of the HFD-OA model rats and the inhibition of ADCY7 effectively attenuated these HFD-induced degenerative changes as well as synovial inflammatory lipolysis and FLS dysfunction. In HFD-FLSs, ADCY7 promoted the phosphorylation of PKA as well as its downstream lipid droplet-associated protein PLIN1 and hormone-sensitive lipase (HSL). The inhibition of PKA largely alleviated ADCY7-mediated HFD-FLS dysfunction.

Conclusions

We described a synovial EMT and lipid metabolism disorder in the pathogenesis of OA. This novel mechanism may represent a currently undefined OA subtype. ADCY7 is a potential molecular marker of this pathomechanism.

The Translational potential of this article

Utilizing synovial samples from OA patients, we identified a subpopulation with high ADCY7 expression. This may represent a currently undefined OA subtype and explain the clinical phenomenon of more severe synovial inflammation in obese OA patients. In addition, we established an HFD-induced OA rat model and found an upregulation of ADCY7 in the synovium. We confirmed that the inhibition of ADCY7 could effectively attenuate HFD-induced degenerative changes as well as the inflammatory lipolysis and FLS dysfunction observed in the rat model. This suggests that ADCY7 and its downstream pathways are potential pharmacological targets for treating this lipid-metabolism-disorder-related OA mechanism.

中文翻译：

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一种以滑膜脂质代谢紊乱和成纤维细胞样滑膜细胞功能障碍为特征的骨关节炎亚型

背景

骨关节炎 (OA) 的异质性显着限制了药物治疗在未经选择的患者群体中的有效性。在这种情况下，OA 亚型的鉴定对于开发针对特定类型 OA 发病机制的疗法具有重要意义。

方法

从 GEO 数据库中提取了 70 个 OA 和 36 个对照滑膜样品的表达阵列谱。基于可变性最大的基因进行无监督共识聚类，以识别 OA 亚群。接下来，获得了来自 OA 患者的关节样本。我们根据滑膜 ADCY7 水平将 OA 患者分为两个亚群。评估了来自不同 OA 亚群的滑膜和软骨样本。此外，我们建立了高脂饮食（HFD）诱导的大鼠OA模型。我们在这种 HFD 诱导的 OA 模型中评估了 OA 进展、脂质代谢、滑膜炎和成纤维细胞样滑膜细胞 (FLS) 功能。

结果

70 名 OA 患者被分为三个不同的亚群。我们注意到一个亚群的特征是滑膜脂质代谢障碍 GO 术语。我们进一步确定了该亚群中最显着的 KEGG 途径“脂肪细胞中脂解的调节”以及最显着差异表达的基因 ADCY7。我们发现 ADCY7 高表达组 (32.6%) 表现出滑膜炎症性脂解上皮间质转化 (EMT) 趋势的特征，以及更快的连接空间变窄。HFD 在大鼠关节中诱导 OA 样变性。我们在 FLS 中观察到类似的滑膜炎症脂解和 EMT，其特征是具有更高的增殖和侵袭活性以及升高的促炎和促分解代谢特性。ADCY7 在 HFD-OA 模型大鼠的滑膜中高表达，ADCY7 的抑制有效地减弱了这些 HFD 诱导的退行性变化以及滑膜炎症性脂肪分解和 FLS 功能障碍。在 HFD-FLSs 中，ADCY7 促进 PKA 及其下游脂滴相关蛋白 PLIN1 和激素敏感性脂肪酶 (HSL) 的磷酸化。PKA 的抑制在很大程度上减轻了 ADCY7 介导的 HFD-FLS 功能障碍。

结论

我们描述了 OA 发病机制中的滑膜 EMT 和脂质代谢紊乱。这种新机制可能代表当前未定义的 OA 亚型。ADCY7 是这种病理机制的潜在分子标志物。

本文的转化潜力

利用来自 OA 患者的滑膜样本，我们确定了一个具有高 ADCY7 表达的亚群。这可能代表了目前未定义的 OA 亚型，并解释了肥胖 OA 患者更严重的滑膜炎症的临床现象。此外，我们建立了 HFD 诱导的 OA 大鼠模型，发现滑膜中 ADCY7 上调。我们证实，ADCY7 的抑制可以有效地减轻 HFD 诱导的退行性变化以及在大鼠模型中观察到的炎症性脂解和 FLS 功能障碍。这表明 ADCY7 及其下游通路是治疗这种脂质代谢紊乱相关 OA 机制的潜在药理学靶点。