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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.

Selected Papers:
Copp ME, Shine J, Brown HL, Nimmala KR, Hansen OB, Chubinskaya S, Collins JA, Loeser RF, Diekman BO. Sirtuin 6 activation rescues the age-related decline in DNA damage repair in primary human chondrocytes. Aging (Albany NY). 2023 Dec 9:15.
Copp ME, Chubinskaya S, Bracey DN, Shine J, Sessions G, Loeser RF, Diekman BO. Comet assay for quantification of the increased DNA damage burden in primary human chondrocytes with aging and osteoarthritis. Aging Cell. 2022 Sep;21(9):e13698.
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.
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.
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.

Funding:
NIH R01 (National Institute on Aging): R01AG081734
NIH R56 (National Institute on Aging): R56AG066911

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