While a number of risk factors have been associated with osteoarthritis (OAR) – obesity, biological sex, joint injury and genetics – the leading risk factor is still the older age. Even though age is widely recognized as the greatest risk factor for OAR, the biological mechanisms behind this connection remain unclear. Previous work has demonstrated that chondrocytes from older cadaveric donors have elevated levels of DNA damage as compared to chondrocytes from younger donors. Hypo-replicative cell types such as neurons, hematopoietic stem cells, and chondrocytes tend to accumulate sites of persistent DNA damage during aging, due at least in part to the lack of access to repair mechanisms that are only present in S phase (cellular mitosis). Persistent DNA damage is a common feature in numerous contexts that drive cellular senescence and other age-related dysfunction.
A causative role for DNA damage in senescence is supported by studies that apply exogenous DNA damage or disrupt DNA repair pathways; however, the inverse has been more challenging to test experimentally – does enhanced DNA repair efficiency mitigate senescence? In a new study, researchers from University of North Carolina at Chapel Hill, North Carolina State University, Rush University Medical Center and Thomas Jefferson University aimed to determine whether a decline in DNA repair efficiency is one explanation for the accumulation of DNA damage with age, and to quantify the improvement in repair with activation of Sirtuin 6 (SIRT6). Sirtuin 6 is a nuclear-localized NAD-dependent deacetylase that has been shown to play numerous important roles in cellular processes that become dysregulated with aging.
This enzyme quickly localizes to sites of DNA damage and initiates chromatin remodeling to facilitate the recruitment and activity of proteins involved in DNA repair. It works by removing acetyl groups from nuclear proteins, modifying both their function and interaction with other proteins. A preferred substrate of SIRT6 is histone H3 of the core protein that makes up the nucleosome unit of DNA. In this investigation, scientists used irradiation as an acute model of DNA damage to bring the level of damage to equivalent levels across chondrocytes from donors of various ages. After acute damage with irradiation, DNA repair was shown to be more efficient in chondrocytes from young (≤45 years old) as compared to middle-aged (50–65 years old) or older (>70 years old) cadaveric donors.
Activation of SIRT6 with MDL-800 improved the repair efficiency, while inhibition with EX-527 reduced the rate of repair and increased the percentage of cells that retain high levels of damage. In addition to affecting repair after acute damage, treating chondrocytes from older donors with MDL-800 for 48 hours significantly reduced the amount of baseline DNA damage. Chondrocytes isolated from the knees of mice between 4 months and 22 months of age revealed both an increase in DNA damage with aging, and a decrease in DNA damage following MDL-800 treatment. Lastly, treating murine cartilage explants with MDL-800 lowered the percentage of chondrocytes with high p16 cell cycle inhibitor promoter activity. Cellular senescence is a phenotypic state characterized by stable cell cycle arrest in response to intrinsic or extrinsic stress.
One of its main feature is the expression of small proteins blocking cyclins and cyclin-dependent kinases (CDKs), that are encessary to regulate all the steps needed for a regular cell division. Examples are the aforementioned p16/INK4 and another important is p21/Cip1. CDKs inhibition by p16 or p21 avoid cells to re-enter cell cycle when it is genetically forbidden because dictated by yhe differentiation status of the original tissue. The most clear example is given by brain neurons: once differentiated they cannot undergo cell division; forcing them in this task means sure death by a process called catastrophic mitosis. The only way to replace them is to stimulat other neighboring stem cells. Cartilage cells (chondrocytes) are not so inclined to re-enter cell cycle; yet in controlled ways this could be possible avoiding their death.
The only troublesome issue is that senescence is unavoidably linked to collected DNA damages that prevent certain regions of chromatin to be regulated (i.e. positive gene expression). This is mainly due to oxidative stress which gets enhanced with the regular cell aging. Therefore, a strategy to prevent cellular aging in cartilages (meaning a rideuced sìrisk to develop osteoarthritis) could be to enhance DNA repair, along with antioxidant supplementation to scavenge reactive oxidant species responsible for the inderlying genomic damage. This supports the concept that using SIRT6 activation to maintain low levels of DNA damage may prevent the initiation of senescence, at least in cartilages, which is suitable to prevent osteoarthosis.
This could be done in natural ways and even with an aimed nutrition: natural antioxidants like glutathione (GSH) and its precursor N-acetyl-cysteine (NAC; a supplement) are used by condrocytes to replenish their cellular antioxidant potential. Cartilage also need vitamin C (ascorbic acid) non only to modulate collagen synthesis but also to dialogue with GSH and antioxidant proteins (e.g. thioredoxins). Supplementation of higher doses of vitamin C could be another strategy to protect cartilage cells from oxidative stress which, in turn, leads in time to DNA damage. Another nautral substance correlated to GSH is ergothioneine (ETN), which is relatively abundant in red blood cells. Certain foods are also enriched with this compound, like edible mushrooms.
In conclusion, a double strategy to reduce oxidative stress in chondrocytes, in order to enhance their DNA reapiring abilities, could be a suitable oprion to prevent cartilage cell loss, ultimately leading to osteoartrosis.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Scientific references
Copp ME et al. Aging 2023 Dec 9; 15(23):13628-13645.
Wu Y et al. Int Immunopharmacol. 2023; 124(Pt A):110854.
Collins JA et al. Ann Rheum Dis 2023; 82(11):1464-1473.
Chang AR, Ferrer CM et al. Physiol Rev 2020; 100:145–69.