EP6.2 Molecular and Pharmacological Targets for Cartilage Regeneration in Osteoarthritis: A Systematic Review

Abstract

Abstract Osteoarthritis (OA) affects over 500 million individuals worldwide and lacks an approved disease-modifying therapy. This systematic review aimed to characterize the current landscape of molecular and pharmacological targets studied for cartilage regeneration in OA, evaluate the strength of current evidence, and identify gaps limiting clinical translation. PubMed/MEDLINE, Embase, Cochrane Library, and Web of Science were systematically searched from inception through February 2026. Studies evaluating molecular or pharmacological interventions with an explicitly regenerative or chondroprotective mechanism were included. Two independent reviewers extracted data on study design, molecular targets, intervention type and delivery method, structural and functional outcomes, and mechanistic markers.Risk of bias was assessed using SYRCLE for animal studies and RoB2/ROBINS-I for clinical studies. 62 studies published between 2010 and 2026 met inclusion criteria. Growth factors (27%) and signaling pathways (19%) were the dominant molecular target classes, with TGF-β isoforms representing the most studied axis (30%). Interventions fell into five principal categories: biomaterial and nanodrug delivery platforms (24%), gene therapy (21%), small molecules (24%), biologics (10%), and cell-based/derived therapies (13%). Structural cartilage improvement was reported in 92% of studies, with 97% achieving statistical significance; however, hyaline-like cartilage regeneration was confirmed in only 26% of studies. Upregulation of anabolic extracellular matrix markers including COL2A1, SOX9, and aggrecan, was observed in 95% of studies. Catabolic marker suppression, including downregulation of MMP-13 and ADAMTS5, was reported in 85% of studies, with both anabolic and anti-catabolic responses co-occurring in 81%. Senescence or inflammatory pathway modulation, most commonly via NF-kB suppression and macrophage M1-to-M2 polarisation, was reported in 73% of studies. Functional outcomes were reported in only 19% of studies, all reporting improvement; the remainder provided no functional data. Preclinical evidence for molecular and pharmacological OA regenerative targets is extensive but methodologically limited. The disconnection between near-universal ECM synthesis responses and confirmed hyaline-like regeneration, combined with uniformly positive structural and functional outcomes, raises substantial concern for publication bias. Clinical translation remains limited to a small number of early-phase trials. Advancing candidate targets toward clinical application will require large-animal validation, hyaline-specific structural endpoints, functional primary outcomes, and standardized preclinical reporting.