Endothelial dysfunction induces joint aging and osteoarthritis in hypertensive rats

The intricate relationship between hypertension and knee osteoarthritis (OA) has sparked intense debate, with recent studies suggesting a complex interplay between these two conditions. Systolic and pulse pressures are correlated with an increased incidence of radiographic knee OA. The data implies that hypertension may not only contribute to chronic joint pain but also exacerbate structural damage in the knee joint, potentially through hemodynamic shear stress. However, a large-scale Mendelian Randomization study involving nearly 385,000 participants from the UK Biobank revealed a paradoxical inverse correlation between systolic blood pressure and knee and hip OA, hinting that genetic predisposition to hypertension may unexpectedly lower OA risk. This unexpected finding highlights the need for further investigation into the bidirectional relationship between hypertension and OA, including the cellular and molecular mechanisms that underlie this complex interaction. By elucidating the underlying mechanisms, we can develop more effective therapeutic strategies to mitigate the impact of hypertension on OA and improve patient outcomes. To study the effects of hypertension on joints, we utilized two hypertensive rat models. In Chapter 2, the deoxycorticosterone acetate (DOCA)-induced hypertension model was employed, while in Chapter 3, we used the spontaneously hypertensive rat (SHR) model. In Chapter 4, OA was induced in hypertensive rats to assess whether hypertension exacerbates OA. In Chapter 5, we used a human cell model to investigate the crosstalk between endothelial cells and chondrocytes. Blood pressure and joint oxygen saturation levels were monitored, and at 9 – 10 months of age, rats were sacrificed for aortic and leg tissue analysis. CT scans of the legs and histological staining of aortic and joint tissues were performed to evaluate structural changes. The antihypertensive drug captopril was administered to examine pre- and post-treatment effects on vascular and joint health. To study hypertension’s impact on OA, hypertensive rats underwent ACLT surgery, followed by two months of monitoring before histological analysis. Statistical comparisons were performed using one-way ANOVA with Tukey's test. In Chapters 2 and 3, both DOCA-induced hypertensive rats and SHR models exhibited significant vascular and joint aging, reduced chondrocyte proteoglycan levels, elevated cartilage degradation marker MMP-13, and bone loss compared to controls. SHR rats showed reduced joint oxygen saturation, increased vascular oxidative stress, and accumulation of senescent cells with proteoglycan loss in joints. Captopril demonstrated anti-senescent and chondroprotective effects in SHR and aged chondrocytes but did not prevent bone loss. In Chapter 4, hypertensive OA models did not show worsened blood pressure but indicated increased cardiovascular burden and more severe joint dysfunction. In Chapter 5, co-culture systems revealed that IGFBP6 mediated biochemical crosstalk between endothelial dysfunction and chondrocyte aging. Our findings demonstrate that hypertension induces vascular dysfunction and endothelial cell senescence, leading to chondrocyte aging and degradation. This study reveals hypertension-induced vascular and joint changes, providing evidence for the impact of vascular health on joint integrity. In the captopril treatment group, both vascular and joint phenotypes improved, suggesting that antihypertensive drugs may offer a novel therapeutic strategy for OA by addressing endothelial dysfunction. These findings underscore the need for further exploration into the vascular-joint connection, potentially broadening therapeutic approaches for patients with co-existing hypertension and OA.