Targeting TFEB for the treatment of Osteoarthritis

Osteoarthritis (OA) is one of the most common forms of arthritis and a leading cause of disability worldwide, with currently no effective therapy.

Accumulating evidence indicates that cartilage degradation which is the main feature of OA is due to cellular senescence.

We recently revealed the role of TFEB, a master regulator of autophagy and lysosomal biogenesis, the main cellular bulk degradation pathway, in immune senescence.

I have shown that TFEB level decrease with age in human peripheral blood mononuclear cells, and TFEB levels can be increased by spermidine (natural polyamine) to reverse the ageing phenotype of these cells (Alsaleh et al, eLife under final revision).

Paralleling the studies mentioned above, my preliminary results show that TFEB protein is decreased, while senescence is increased in chondrocytes and fibroblasts from OA patients. This is in line with reports of an age-related decline in the process of autophagy promoting OA.

Moreover, I found that decreasing TFEB expression by siRNA in OA fibroblasts leads to an increase in senescence-associated markers.

Excitingly, re-establishing TFEB expression prevents cartilage degradation in destabilisation of the medial meniscus (DMM) OA mouse model.

Taken together, I hypothesise that the age-related decrease of TFEB in joint tissues is a major driver of OA development.

To test this, I plan to: (1) Measure TFEB expression and senescence phenotype in OA synovium and cartilage cell subsets. (2) Investigate the impact of TFEB on cellular senescence in chondrocytes and fibroblasts in the joint. (3) Identify novel drug that regulates the expression of TFEB to treat OA.

My proposal will (1) expand our understanding of TFEB expression and senescence phenotypes in joint cell types, (2) determine the role of TFEB in driving senescent changes and (3) identify novel agents targeting TFEB to develop effective new therapeutics for osteoarthritis that will improve patients’ quality of life.