DEVELOPMENT OF NEW THERAPIES FOR EARLY OSTEOARTHRITIS: FROM PATHOLOGY TO SOLUTIONS

Osteoarthritis (OA) is a major clinical challenge, and effective disease-modifying drugs for OA are still lacking due to the complicated pathology and diverse treatment targets. Effective early treatments are urgently needed to prevent OA progression. We aim to manage the synovial fibrosis and subchondral bone sclerosis in the early stage of OA development by targeting the onsite pathologically high expression of transforming growth factor β (TGFβ). We here report a novel strategy of intra-articular (I.A.) sustained-release of pirfenidone (PFD), a clinically-approved TGFβ inhibitor, by using combinations of biodegradable biomaterials, to achieve disease-modifying effects on early OA joints [1] Based on the pathological changes of subchondral bone in early osteoarthritis [2], we designed a comprehensive monthly I.A. injection method using poly lactic-co-glycolic acid (PLGA) microparticles and hyaluronic acid (HA) solution to enable a sustained release of PFD. This strategy was then verified in animal models in medial meniscus (DMM)- induced OA mice (n=6–8/group) and sheep undergoing meniscectomy (n=22). We found that PFD effectively restored the mineralization in bone forming cells in the presence of excessive amount of TGFβ1 (as those levels found in OA patients' synovial fluid) when cultured in vitro. With the establishment and treatment of the monthly I.A. injection strategy (Figure 1), this treatment effectively regulated OA progression in destabilization of the medial meniscus (DMM)- induced OA mice model up to 12 weeks, including preventing subchondral bone loss in early OA and subchondral bone sclerosis in late OA, and reduced synovitis and pain with cartilage preservation effects. Similar results were found in the sheep model, with effects lasting up to 24 weeks This finding suggests the promising clinical application of PFD as a novel disease-modifying OA drug. For any figures or tables, please contact the authors directly.