INTRODUCTION
Osteoarthritis (OA), the leading cause of disability among older adults, has long been considered a disease driven primarily by mechanical wear and tear. However, accumulating evidence indicates that OA is also influenced by systemic metabolic, endocrine, and vascular factors. Hypertension, which is highly prevalent in aging populations, is associated with an increased OA risk and greater severity. However, the mechanisms linking elevated blood pressure to impaired cartilage homeostasis remain undefined.

RATIONALE
Transcriptomic analyses in mice identified Avpr1a, which encodes the receptor for the neuroendocrine hormone arginine vasopressin (AVP), as one of the most strongly up-regulated genes in OA chondrocytes. Further screening revealed that Avpr1a is the only AVP receptor gene that is up-regulated in articular cartilage. Because the AVP-AVPR1A axis plays a central role in blood pressure regulation, its dysregulation within cartilage suggests a direct molecular link between hypertension and OA. Given that circulating AVP concentration increases under hypertensive conditions, we hypothesized that hypertension-induced elevations in AVP act on OA-primed chondrocytes—sensitized through mechanical injury or aging—that up-regulate AVPR1A, thereby activating catabolic signaling pathways.

RESULTS
We combined human cohort analyses with two hypertensive mouse models to define the mechanistic relationship between hypertension and OA. Logistic regression of population-scale data demonstrated that hypertension was independently associated with OA prevalence, with progressively stronger associations observed in advanced structural disease. In both mouse models, hypertension markedly exacerbated experimental OA, increasing cartilage erosion and subchondral bone plate thickening without affecting synovitis or osteophyte maturity. We further demonstrated that AVP is not synthesized locally within joint tissues but instead reaches the synovial fluid through the systemic circulation. AVPR1A expression was increased in OA cartilage but remained low in healthy, young cartilage. Both mechanical wear and tear and natural aging acted as priming factors by up-regulating basal AVPR1A expression. Consequently, this priming, rather than hypertension alone, was required to activate the AVP-AVPR1A signaling axis. Activation of this pathway promoted catabolic signaling while suppressing anabolic signaling without inducing cellular senescence. Cartilage destruction required concurrent elevation of both AVP and AVPR1A. Genetic deletion or local intra-articular pharmacological antagonism of AVPR1A prevented hypertension-induced cartilage degeneration, demonstrating that hypertension-driven OA progression depends specifically on AVP-AVPR1A signaling. Finally, transcriptomic and functional analyses identified NR4A3 as the principal transcriptional effector linking hypertensive endocrine signaling to chondrocyte catabolism, independent of the renin-angiotensin-aldosterone system or oxytocin receptors.

CONCLUSION
These findings establish the AVP-AVPR1A axis as an endocrine-skeletal signaling pathway through which systemic hypertension accelerates OA progression. Hypertension elevates circulating AVP, OA primes chondrocytes to express AVPR1A, and their combined activation drives cartilage matrix breakdown and subchondral bone remodeling. Targeting AVPR1A or its downstream mediators offers a therapeutic strategy to slow OA progression in hypertensive individuals experiencing joint injury or advanced age.