The joint-local renin–angiotensin system in rheumatoid arthritis and osteoarthritis: mechanistic evidence, disease-specific patterns, and translational perspectives

The renin-angiotensin system (RAS), traditionally regarded as a hormonal cascade regulating cardiovascular and renal homeostasis, is increasingly recognized as a locally active, tissue-specific network within joint structures. Accumulating evidence indicates that synovial tissue, synovial fluid, and articular cartilage harbor a functionally active joint-local renin-angiotensin system that operates partially autonomously from the systemic RAS circulation and is implicated in the pathogenesis of both arthritis (RA) and osteoarthritis (OA). This narrative review integrates human, animal, and in vitro evidence to examine the dual-axis organization of the joint RAS, comprising a pathogenic angiotensin-converting enzyme (ACE)/Angiotensin II (Ang II)/ Angiotensin II type 1 receptor (AT1R) axis and a counter-regulatory ACE2/Angiotensin-(1-7) (Ang-(1-7))/Mas receptor-Mas related G protein-coupled receptor D (Mas-MrgD) axis, and to explore how imbalance between these pathways may differentially influence inflammatory and degenerative joint diseases. In RA, experimental and translational studies suggest that enhanced activity of the classical axis within synovial tissue is associated with synovial inflammation, fibroblast-like synoviocyte survival, angiogenesis, and bone erosion through pathways involving nuclear factor kappa B (NF-kB), mitogen-activated protein kinase (MAPK), and receptor activator of nuclear factor kB ligand (RANKL)/Wingless-related integration site (Wnt) signaling pathway. In OA, available data indicate that chondrocyte expression of AT1R/Angiotensin II type 2 receptor (AT2R), together with cytokine-induced receptor upregulation, may sensitize cartilage to Ang II-mediated effects, contributing to matrix metalloproteinase-13 (MMP-13)-mediated matrix degradation and activation of interleukin-6 (IL-6)/janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling. Genetic studies support disease-specific patterns, with the ACE insertion/deletion polymorphism showing a more consistent association with RA susceptibility than with knee OA, although findings vary across populations and do not consistently correlate with disease severity. From a therapeutic perspective, modulation of the joint-local RAS is currently supported mainly by preclinical evidence. Experimental models suggest that classical RAS inhibitors and emerging strategies targeting the protective axis-such as putative ACE2 activators, AT2R agonists, and bone-targeted peptide delivery can influence inflammatory and structural pathways within the joint, while direct clinical evidence remains limited. Overall, current data support the biological relevance of a local joint RAS in arthritis pathophysiology and highlight key gaps between experimental findings and clinical translation.