Metabolic reprogramming: Targeting inhibition of osteoarthritis-induced pyruvate dehydrogenase kinase expression preserves mitochondrial respiration
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ABSTRACT: Fibroblast-like synoviocytes (FLS) maintain the structural and dynamic integrity of joints. Additionally, FLS have been identified as key drivers of joint destruction in osteoarthritis (OA). Pathogenic THY1+ FLS are classified as invasively proliferative cells. However, little is known about the metabolic changes of FLS in the pathogenesis of OA. Here, we demonstrate functional, proteomic, and metabolic characteristics of inflammation-exposed FLS compared with unexposed fibroblast-like mesenchymal stromal cells (MSCs) from patients with OA. Analysis of FLS and MSC proteomes revealed 592 differentially expressed proteins. Although both cell types were indistinguishable according to classical markers, pathway analysis revealed that pyruvate dehydrogenase kinase (PDK) 3 is highly expressed only in proliferative FLS. Inhibition of PDKs by dichloroacetate significantly shifted glycolysis to oxidative phosphorylation while reducing proliferation without causing cell death. Therefore, reprogramming FLS metabolism from glycolysis to mitochondrial respiration by inhibiting PDK isoforms might be a new approach to treat transformed FLS in OA
INSTRUMENT(S): Q Exactive Plus
ORGANISM(S): Homo Sapiens (human)
TISSUE(S): Mesenchymal Cell, Fibroblast, Bone Marrow, Synovium
DISEASE(S): Osteoarthritis
SUBMITTER: Marieluise Kirchner
LAB HEAD: Philipp Mertins
PROVIDER: PXD027215 | Pride | 2022-03-31
REPOSITORIES: Pride
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