Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Rheumatology and Clinical Immunology, Berlin, Germany; German Rheumatism Research Centre (DRFZ) Berlin, a Leibniz Institute, Berlin, Germany.
Berlin Institute of Health and Max-Delbrück-Centrum for Molecular Medicine, Germany.
Metab Eng. 2022 Jul;72:116-132. doi: 10.1016/j.ymben.2022.03.006. Epub 2022 Mar 13.
Osteoarthritis (OA) is the most common degenerative joint disease and a major cause of age-related disability worldwide, mainly due to pain, the disease's main symptom. Although OA was initially classified as a non-inflammatory joint disease, recent attention has been drawn to the importance of synovitis and fibroblast-like synoviocytes (FLS) in the pathogenesis of OA. FLS can be divided into two major populations: thymus cell antigen 1 (THY1)- FLS are currently classified as quiescent cells and assumed to destroy bone and cartilage, whereas THY1+ FLS are invasively proliferative cells that drive synovitis. Both THY1- and THY1+ FLS share many characteristics with fibroblast-like progenitors - mesenchymal stromal cells (MSC). However, it remains unclear whether synovitis-induced metabolic changes exist in FLS from OA patients and whether metabolic differences may provide a mechanistic basis for the identification of approaches to precisely convert the pathologically proliferative synovitis-driven FLS phenotype into a healthy one. To identify novel pathological mechanisms of the perpetuation and manifestation of OA, we analyzed metabolic, proteomic, and functional characteristics of THY1+ FLS from patients with OA. Proteome data and pathway analysis revealed that an elevated expression of pyruvate dehydrogenase kinase (PDK) 3 was characteristic of proliferative THY1+ FLS from patients with OA. These FLS also had the highest podoplanin (PDPN) expression and localized to the sublining but also the lining layer in OA synovium in contrast to the synovium of ligament trauma patients. Inhibition of PDKs reprogrammed metabolism from glycolysis towards oxidative phosphorylation and reduced FLS proliferation and inflammatory cytokine secretion. This study provides new mechanistic insights into the importance of FLS metabolism in the pathogenesis of OA. Given the selective overexpression of PDK3 in OA synovium and its restricted distribution in synovial tissue from ligament trauma patients and MSC, PDKs may represent attractive selective metabolic targets for OA treatment. Moreover, targeting PDKs does not affect cells in a homeostatic, oxidative state. Our data provide an evidence-based rationale for the idea that inhibition of PDKs could restore the healthy THY1+ FLS phenotype. This approach may mitigate the progression of OA and thereby fundamentally change the clinical management of OA from the treatment of symptoms to addressing causes.
骨关节炎（OA）是最常见的退行性关节疾病，也是全球与年龄相关残疾的主要原因，主要是由于疼痛，这是该病的主要症状。尽管 OA 最初被归类为非炎症性关节疾病，但最近人们越来越关注滑膜炎和成纤维样滑膜细胞（FLS）在 OA 发病机制中的重要性。FLS 可分为两个主要群体：胸腺细胞抗原 1（THY1）-FLS 目前被归类为静止细胞，被认为破坏骨和软骨，而 THY1+FLS 是侵袭性增殖细胞，驱动滑膜炎。THY1-FLS 和 THY1+FLS 都与成纤维样祖细胞-间充质基质细胞（MSC）有许多共同特征。然而，目前尚不清楚 OA 患者的 FLS 是否存在滑膜诱导的代谢变化，以及代谢差异是否可以为精确转换病理性增殖的滑膜炎驱动的 FLS 表型为健康表型提供机制基础。为了确定 OA 持续和表现的新的病理机制，我们分析了来自 OA 患者的 THY1+FLS 的代谢、蛋白质组学和功能特征。蛋白质组数据和途径分析表明，丙酮酸脱氢酶激酶（PDK）3 的表达升高是 OA 患者增殖性 THY1+FLS 的特征。与韧带创伤患者的滑膜相比，这些 FLS 还具有最高的 podoplanin（PDPN）表达，并定位于滑膜衬里层，但也定位于滑膜衬里层。PDK 抑制可将代谢从糖酵解重新编程为氧化磷酸化，减少 FLS 增殖和炎性细胞因子分泌。这项研究为 FLS 代谢在 OA 发病机制中的重要性提供了新的机制见解。鉴于 PDK3 在 OA 滑膜中的选择性过表达及其在韧带创伤患者和 MSC 滑膜组织中的受限分布，PDK 可能代表 OA 治疗的有吸引力的选择性代谢靶点。此外，靶向 PDK 不会影响处于稳态、氧化状态的细胞。我们的数据为这样一种观点提供了循证依据，即抑制 PDK 可以恢复健康的 THY1+FLS 表型。这种方法可能会减缓 OA 的进展，从而从治疗症状到解决病因根本改变 OA 的临床管理。
