Cellular senescence is a specific phenotypic state that serves both beneficial (e.g. tumor suppression) and harmful functions (e.g. excessive inflammation). The accumulation of senescent chondrocytes likely contributes to the increased risk of OA in older individuals. The use of “senolytic” compounds that specifically target senescent cells for apoptosis has strong potential to mitigate OA, as this would permanently remove the source of inflammatory and matrix-degrading molecules produced by senescent cells. The design of effective strategies for targeting these cells would benefit from a better understanding of the mechanisms by which chondrocytes initiate the senescence program. We have specifically focused on the accumulation of DNA damage with aging and the specific environmental conditions (such as the presence of growth factors) that trigger the induction of senescence in these damaged cells.
Copp ME, Flanders MC, Gagliardi R, Gilbertie JM, Sessions GA, Chubinskaya S, Loeser RF, Schnabel LV, Diekman BO#. The combination of mitogenic stimulation and DNA damage induces chondrocyte senescence. Osteoarthritis Cartilage. 2020 Nov 20:S1063-4584(20)31172-9. PMC7925350, doi: 10.1016/j.joca.2020.11.004. #corresponding author
Sessions GA, Copp ME, Liu JY, Sinkler MA, D’Costa S, Diekman BO. Controlled induction and targeted elimination of p16INK4a-expressing chondrocytes in cartilage explant culture. FASEB J. 2019 Nov;33(11):12364-12373. PMC6988852, PMID 31408372, doi: 10.1096/fj.201900815RR.
Diekman BO, Collins JA, Sessions GA, Strum S, Knecht A, Mitin N, Carlson C, Loeser RF, Sharpless NE. Expression of p16INK4a is a biomarker of chondrocyte aging but does not cause osteoarthritis. Aging Cell. 2018 Aug;17(4):e12771. PMC6052464, doi: 10.1111/acel.12771.
NIH R56 (National Institute on Aging): 1R56AG066911-01A1
Additional support from NC TraCS, UNC Office of Research, UNC Office of the Executive Vice Chancellor and Provost, Comparative Medicine Institute, Department of Biomedical Engineering, Thurston Arthritis Research Center