Sirt6 promotes DNA damage repair in osteoarthritis chondrocytes by activating the Keap1/Nrf2/HO-1 signaling pathway

ABSTRACT

The aim of this study was to explore the effect and mechanism of Sirt6 on DNA damage repair in OA chondrocytes. Cartilage tissues were collected from OA patients with knee arthroplasty and traumatic amputation patients without OA. Besides, 7-week-old male C57BL/6 mice were randomly divided into Control and OA groups; CHON-001 cells of corresponding groups were treated with 10 ng/ml interleukin (IL)-1β, respectively. Subsequently, Sirt6 or siNrf2 was over-expressed in CHON-001 cells to observe the effect of Sirt6 on DNA damage and senescence of chondrocytes by IL-1β through the nuclear factor E2-related factor 2 (Nrf2) signaling pathway. The expression level of Sirt6 in human and mouse OA cartilage tissues was significantly decreased. However, 24 h of treatment with IL-1β significantly decreased the expression of Sirt6 in chondrocytes, induced DNA damage, and promoted cellular senescence. In addition, over-expression of Sirt6 promoted DNA damage repair and inhibited cellular senescence in IL-1β-induced chondrocytes. Moreover, the overexpression of Sirt6 activated the Keap1/Nrf2/HO-1 signaling pathway in chondrocytes, while knockdown of Nrf2 expression inhibited the DNA damage repair and anti-senescence effects of Sirt6 on IL-1β-treated chondrocytes. Sirt6 may reduce DNA damage and cellular senescence in OA chondrocytes induced by IL-1β through activating the Keap1/Nrf2/HO-1 signaling pathway.

KEYWORDS:

• Sirt6
• osteoarthritis
• nuclear factor erythroid-2-related factor 2
• DNA damage
• senescence

Disclosure statement

No potential conflict of interest was reported by the author(s).

Author contributions

LM and QJ conceptualized and designed the study, drafted the initial manuscript. NM, LX, QZ and YC collected the data and carried out the initial analyses. LL and LW critically reviewed the manuscript for important intellectual content. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

Availability of data and materials

The data used to support the findings of this study are available from the corresponding author upon request.

Ethics approval and consent to participate

This study and were authorized by the Ethical Committee of The Affiliated People’s Hospital with Jiangsu University. All procedures of animal experiment were performed in accordance with the Guide for the Care and Use of Laboratory Animals. All patients provided written informed consent prior to enrollment in the study.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/15384101.2024.2316493

Additional information

Funding

This study was supported by the Project of Medical Education Collaborative Innovation Fund of Jiangsu University [JDY2022010] and the Science and Technology Planning Social Development Project of Zhenjiang City [SH2023043].