Potential Methods of Targeting Cellular Aging Hallmarks to Reverse Osteoarthritic Phenotype of Chondrocytes

SIMPLE SUMMARY: Osteoarthritis (OA) is the most common chronic and disabling joint disease worldwide, causing pain and impaired mobility. Currently, no effective disease-modifying drugs are available to treat this disorder. Although not all elderly individuals have osteoarthritis, aging is considered the primary risk factor for this disease. However, the mechanisms by which aging and osteoarthritis correlate are still not completely understood. In this review, we revisit the features of OA chondrocytes and compare them with the cellular hallmarks of aging, including genomic instability, telomere attrition, epigenetic alteration, mitochondrial dysfunction, loss of proteostasis, deregulated nutrient-sensing, cellular senescence, and altered intercellular communication. It is concluded that OA chondrocytes share many similar alterations with cellular aging. Next, based on findings from studies on chondrocytes and other cell types, we propose methods that can potentially reverse the osteoarthritic phenotype of chondrocytes back to a healthier state. Lastly, we discuss the current challenges and future perspectives. Specifically, we need to identify the hub(s) that regulate(s) the most changes observed in OA and aged chondrocytes, which can subsequently assist in the development of the most efficient treatments. In addition, OA chondrocyte-targeting therapeutics may negatively influence other healthy tissues, thus warranting careful examination. ABSTRACT: Osteoarthritis (OA) is a chronic degenerative joint disease that causes pain, physical disability, and life quality impairment. The pathophysiology of OA remains largely unclear, and currently no FDA-approved disease-modifying OA drugs (DMOADs) are available. As has been acknowledged, aging is the primary independent risk factor for OA, but the mechanisms underlying such a connection are not fully understood. In this review, we first revisit the changes in OA chondrocytes from the perspective of cellular hallmarks of aging. It is concluded that OA chondrocytes share many alterations similar to cellular aging. Next, based on the findings from studies on other cell types and diseases, we propose methods that can potentially reverse osteoarthritic phenotype of chondrocytes back to a healthier state. Lastly, current challenges and future perspectives are summarized.