The activator protein-1 transcription factor component c-Fos may be a new therapeutic target for patients with osteoarthritis, according to preclinical research published by Matsuoka et al in the Annals of the Rheumatic Diseases. Investigators analyzed c-Fos expression in the articular cartilage samples of patients with osteoarthritis and mouse models with c-Fos inactivation and destabilized medial menisci by utilizing histology, immunohistochemistry, RNA sequencing, quantitative reverse transcription polymerase chain reactions, and in situ metabolic enzyme assays. The researchers discovered that c-Fos levels were inversely correlated with disease severity. They noted that chondrocytes without c-Fos proliferated less, had shorter collagen fibers, and had reduced cartilage matrices. Additionally, they discovered that decreased pyruvate dehydrogenase and elevated lactate dehydrogenase enzymatic activities in situ were potentially caused by the higher expression of hypoxia-inducible factor-1a, the LDHA gene, and 3-phosphoinositide dependent protein kinase-1 in the chondrocytes. Compared with wild-type mice, mice with c-Fos inactivation demonstrated increased cartilage destruction. When the researchers treated the mice with the pyruvate dehydrogenase kinase inhibitor dichloroacetic acid, they observed restored pyruvate dehydrogenase and lactate dehydrogenase activity, chondrocyte proliferation, and collagen biosynthesis, as well as decreased cartilage destruction. The researchers emphasized that c-Fos may respond to osteoarthritis signals by modulating cellular bioenergetics in chondrocytes and balancing pyruvate flux between anaerobic glycolysis and the tricarboxylic acid cycle. According to a companion press release from the Medical University of Vienna, the study authors concluded, “Our findings are an important step toward the development of targeted therapies in the form of drugs based on the newly discovered control mechanism of c-Fos expression in cartilage cells.
July 07, 2023