Hypertension fuels osteoarthritis through neuroendocrine signaling.

Osteoarthritis (OA) is a degenerative joint disease, the progression of which is accelerated by systemic metabolic stress. Here, we identified a neuroendocrine pathway through which hypertension accelerates OA pathogenesis in joints predisposed by mechanical injury or aging. Nationwide cohort analyses and hypertensive mouse models demonstrated that elevated blood pressure exacerbates OA pathogenesis. OA-primed chondrocytes up-regulated arginine vasopressin (AVP) receptor 1A (AVPR1A), rendering them responsive to hypertension-associated circulating AVP. AVP-AVPR1A signaling enhanced catabolic signaling while suppressing anabolic regulators, thereby promoting cartilage catabolism. Genetic deletion or pharmacological inhibition of AVPR1A protected against hypertension-driven OA acceleration. Transcriptomic profiling and gene-silencing analyses identified NR4A3 as the principal downstream transcriptional mediator. Collectively, these findings establish the AVP-AVPR1A axis as a mechanistic link between systemic hypertensive stress and joint degeneration.