Mechanisms of inflammation and associated tissue damage in musculoskeletal diseases

Mechanobiology in arthritic disease.

The reason why inflammation homes to joints in arthritic diseases have been a longstanding mystery. We reasoned that mechanical loading may be a key factor in the events leading to joint inflammation. We, therefore, performed an unbiased screen for novel mechanotransduction targets in stromal cells from joints. Based on our exciting preliminary data we aim to study the functional implications of one of these candidates in arthritic disease.

The project will involve the use of human primary cells exposed to mechanical forces in vitro, organoid models from synovial cells which we will expose to in vitro forces, the use of candidate small molecules to interfere with these and genetic knockdown approaches. This will be combined with molecular and functional profiling including but not limited to RNA sequencing, and chemotaxis assays.

In vitro data will be coupled to suitable preclinical models of arthritis (passive transfer models such as serum transfer model, cytokine-dependent models of inflammatory (both TNF dependent and independent), or tendon injury. Readouts include histology, microCT to monitor erosions, femur bending tests (bone strength), electron-microscopy of tendons, tendon strength measurements, etc. Collectively, this project will provide a novel unprecedented view of the mechanisms driving the onset of joint and tendon inflammation, an important medical health problem with a broad impact on our society.

Current therapeutic strategies to combat arthritis in the clinic focus on affecting the immune system. Here we aim to interfere with tissue resident function supported by our preliminary data that tissue resident cells are crucial in the onset of arthritis (see also Cambré et al. Nature Communications 2018; Cambré Ann Rheum Dis 2019, Gracey et al. Nat Rev Rheumatol 2020). This novel approach has the potential to change our current view to tackle joint inflammation. We identified a key transcription factor and will delineate upstream regulators leading to activation thereof; this will involve also the use of small-molecule inhibitors.

Experience in clinical or translational research in the field of inflammation. Experience or keen interest in exploring novel wet-lab technologies, animal work and exploring databases.

Medical background or training in the field of RA or inflammation will accelerate the integration of the MD in the project.