Mechanometabolism in osteoarthritis (OA): Does mechanical stress affect the metabolism of human fibroblast-like synoviocytes and contribute to stromal memory driving OA?

• Applicant: Dr. Alexandra Damerau
• Subject Area: Orthopaedics, Traumatology, Reconstructive Surgery ; Rheumatology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 530960394

Osteoarthritis (OA) is the most common form of arthritis and one of the leading causes of age-related disability, affecting millions of individuals and costing billions of dollars annually. Fibrosis, a typical feature of OA, is characterised by prolonged and exaggerated activation of fibroblasts due to chronic tissue injury, mechanical stress, and low-grade inflammation. These stimuli activate tissue repair mechanisms, a key feature of which is the transition of fibroblasts into myofibroblasts, central effectors of appropriate repair mechanisms. Based on transcriptional and functional differences, several groups have determined that synovial fibroblasts exist in different subpopulations or states of activation. There is growing evidence that myofibroblasts, which are distinguishable from FLS subsets by the expression of α-smooth muscle actin, collagen type I, and CD82, play an essential role in the progression and maintenance of fibrosis. This raises the question from which specific FLS subpopulation the myofibroblasts are derived. Moreover, the pro-fibrotic agonist TGF-β can be activated through exposure to specific physical or chemical conditions, such as low pH, heat, shear stress, and generation of reactive oxygen species. However, whether pathways or metabolic stressors such as the nuclear factor-κB pathway in liver fibrosis or hypoxia-induced epigenetic changes associated with cardiac fibrosis are part of the fibrotic changes of the OA synovium remains to be elucidated. Based on the crucial effects of mechanical overload on the onset and progression of OA, we hypothesize that altered cellular metabolism, particularly in the lining layer, is induced by mechanosensing in OA, leading to stromal imprinting that causes the transition from fibroblasts to myofibroblast subpopulations and thus causes disease persistence in OA. This study focuses on identifying physiological and pathological mechanotransduction events via fluidic shear stress (FSS), their signal transduction and their effects on metabolism and expression of epigenetic cellular memory. Therefore, we will first identify myofibroblast subsets by comparing synovial tissue from trauma and OA patients at the transcriptomic and proteomic single cell level. Secondly, we will apply pathological FSS with our bioreactor platform and analyse the effects on metabolism with seahorse technology and on epigenetic histone acetylation with ChIP approaches. These analyses will allow us to better understand the underlying processes of OA and thus identify potential therapeutic targets.

• DFG Programme: Research Grants