Pyruvate dehydrogenase kinases as a potential novel target to treat osteoarthritis

Introduction Osteoarthritis (OA) is the most common degenerative joint disease and a major cause of age-related disability worldwide, largely due to pain, the main symptom of the 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: THY1- FLS are classified as quiescent cells and assumed to destroy bone and cartilage, whereas THY1+FLS are invasively proliferative cells that drive synovitis. However, it remains unclear whether synovitis-induced metabolic changes exist in FLS from OA patients. Methods To identify novel targets for the diagnosis and treatment of OA, we analyzed FLS isolated from tibial plateau samples collected during knee arthroplasty for OA. FLS from patients with ligament trauma and quiescent non-inflamed fibroblast progenitors – bone marrow-derived mesenchymal stromal cells (MSCs) – served as comparative samples. We performed transcriptomic, proteomic, surface marker and metabolic analyses and measured cytokine/chemokine secretion. Results We observed comparable features of FLS and non-inflamed MSCs with respect to the minimal criteria defining the MSC phenotype and, therefore, confirmed MSCs as a valid fibroblast-like, non-inflammatory control to identify synovitis-mediated alterations in OA FLS. Mapping the distribution of subsets within expanded FLS, we observed that>90% THY1+FLS proliferated faster than MSCs. Proteome data and pathway analysis revealed that an elevated expression of pyruvate dehydrogenase kinase (PDK) 3 was characteristic of pathogenic proliferative THY1+FLS from OA patients. Increased expression of this enzyme is associated with a reduction in glucose oxidation/OXPHOS and an increase in fatty acid oxidation as well as pentose phosphate pathway. These FLS also had the highest PDPN expression and localized to the sublining but also to the lining layer in OA synovium in contrast to the synovium of ligament trauma patients. Selective targeted inhibition of PDKs using dichloroacetate facilitated metabolic reprogramming of THY1+FLS from OA patients by reducing proliferation and inflammatory cytokine/chemokine secretion. Discussion This is the first study to identify PDK isoforms as contributors to the metabolic changes in active proliferative PDPN+THY1+FLS in OA. Given the selective overexpression of PDK3 in OA synovium and its restricted distribution in synovial tissue from ligament trauma patients and MSCs, PDKs represent attractive selective metabolic targets for OA therapy. Moreover, targeting PDKs does not affect cells in a homeostatic, oxidative state such as non-inflammatory MSC or low-grade inflamed FLS from patients with ligament injuries. Our data provide an evidence-based rationale for therapeutic inhibition of PDKs thereby restoring the healthy phenotype.