A New Insight on Targeting SDF-1 As an Emerging Therapeutic Potential Target Against Osteoarthritis

Osteoarthritis (OA), a primary contributor to musculoskeletal disability, remains without disease-modifying therapies despite extensive investigation into inflammation and catabolism over the years. Stromal cell-derived factor-1 (SDF-1/CXCL12) has been identified as a significant therapeutic target, playing a crucial role in cartilage degradation, synovial inflammation, osteoclast recruitment, and subchondral bone remodelling through CXCR4/CXCR7 signalling pathways. This review consolidates recent findings indicating that increased levels of synovial and serum SDF-1 are associated with the severity of OA. Additionally, mechanistic studies have shown that SDF-1 induces MMP-3/9/13, ADAMTS-4/5, and COX-2 in chondrocytes via the PI3K/AKT, MAPK/ERK, and JAK/STAT pathways. SDF-1 enhances the infiltration of CD4+ T-cells and macrophages, stimulates angiogenesis through VEGF, and facilitates osteoclastogenesis, thereby creating a pathological interaction among cartilage, synovium, and bone. The use of CXCR4 antagonists (AMD3100 analogues), SDF-1 neutralizing agents, and miR-146a-5p modulation in preclinical settings demonstrates a reduction in matrix degradation, maintenance of aggrecan/collagen II levels, and inhibition of bone sclerosis in ACLT/DMM models. CXCR7-biased signalling and SDF-1-guided MSC homing offer regenerative potential when combined with catabolic suppression. The results indicate that modulating the SDF-1/CXCR4/CXCR7 axis represents a complex strategy for disease-modifying osteoarthritis drugs, highlighting the need for clinical translation via targeted nanoparticles and the selection of patients guided by biomarkers.