Endothelial senescence modulates chondrocyte fate in joint ageing and osteoarthritis

Abstract

Osteoarthritis (OA) is a prevalent joint disease leading to disability. Despite decades of effort in OA research, current treatment for the disease is limited to pain relief. Its complex pathogenesis and aetiology have hindered the therapeutic discovery. Understanding the cellular and molecular perspectives of the disease hence become an urge in the field. Cartilage lesion is the typical hallmark of OA. As the primary constituent of hyaline cartilage, chondrocytes have been of particular interest. Chondrocyte hypertrophy and senescence are two important cellular states that have both been implicated in OA onset and progression. While they co-exist frequently in OA joints, little is known about the relationship between the two cellular processes. This study provides a pioneering idea of the role of chondrocyte fates in joint homeostasis by establishing a novel model to distinct the two cellular states. It has been demonstrated that hypertrophic chondrocytes were more prone to senescence, and could be driven into senescence state under oxidative stress. Hypertrophy also seemed to be a critical stage for oxidative-stress induced senescence. Interference with chondrocyte hypertrophy has been shown to protect cells from becoming senescence. As an age-related degenerative disease, cellular senescence has been targeted for OA therapy. The findings of the transition from hypertrophy to senescence in chondrocytes therefore provided new insight into the anti-senescence strategy in OA. OA is now conceived as a whole-joint disease with the interplay between systemic and local risk factors. Amongst all metabolic conditions, hypertension has been the most prominent comorbidity to knee OA epidemiologically. This study fills the gap of the lack of experimental proof of the causal association between them. We demonstrated that the secretome of senescent endothelial cells could trigger chondrocyte senescence, potentially via hypertrophy. Noticeably, such senescence phenotypes could be alleviated by improving vascular health. Antihypertensive drug, captopril, has exhibited its senolytic effect on vascular ageing. It seemed to mitigate endothelial senescence and its senescence-associated secretory phenotypes. Our findings provided the first experimental evidence of vascular dysfunction-induced cartilage ageing through biochemical crosstalk. The finding has also strengthened the notion of hypertension being a risk factor of OA as observed in clinics. In short, this project has opened up new avenues for OA management strategy. Microscopically, our data has pointed in the direction of targeting chondrocyte hypertrophy for senescence elimination in age-related OA. Macroscopically, we have evidenced the role of vascular health in cartilage homeostasis. We demonstrated the senolytic effect of antihypertensive drug in endothelium and its subsequent beneficial effect on chondrocytes. This work hints at the potential of targeting local joint dysfunction systemically and would thus lay a foundation for upcoming scientific advances in OA management.