Osteoarthritis (OA) is a debilitating degenerative joint disease causing chronic joint pain and disability in 54 million adults in the US. OA can result from either chronic joint use (degenerative or age-related) or from trauma (post- traumatic). At present, there is no disease modifying agent to cure or treat the disease. Clinical management focuses on weight loss, NSAIDs, corticosteroids or HA injections, and other alternative therapies aimed at reducing joints pain and immobility. The final treatment, arthroplasty, is irreversible and requires revisional surgery in 10-15 years. Together, surgical and non-surgical treatments generate $27billion in healthcare costs per year. These socioeconomic burdens highlight the critical need for novel treatments to prevent or delay the cartilage damage caused by OA. Here, we propose a novel therapeutic candidate, osteoactivin (Gpnmb), a type I transmembrane glycoprotein expressed in various cell types with anti-inflammatory and chondroprotective properties. Preliminary studies presented in this application show Gpnmb is highly expressed in high-grade human osteoarthritic cartilage. When human HTB-94 chondrocytes were treated with recombinant Gpnmb protein (rGpnmb) followed by IL-1b stimulation, treated cells demonstrated reduced expression of catabolic markers MMP-9, MMP-13, and IL-6. Furthermore, rGpnmb treatment inhibited matrix degradation ex vivo in human cartilage explants. In vivo, intra-articular injection of rGpnmb in C57BL/6 mouse joints mitigated and prevented cartilage loss in an induced post-traumatic model of OA (destabilization of the medial meniscus, DMM). We determined that Gpnmb acts via interactions in the CD44 receptor in glial cells, macrophages and chondrocytes and that CD44-null mice (CD44-/-) developed severe joint damage using the DMM model compared to WT littermates. Finally, we present that Gpnmb assists in slowing the progression of age-related murine OA. Our lab recently identified a small Gpnmb peptide (Gpnmb-p) with the same anti-inflammatory and biologic properties as rGpnmb. This is significant since peptides are highly selective, potent, and cheaper to produce. Peptides also decrease the potential for toxicity and accumulative problems than the whole protein. Therefore, in this Phase-I SBIR, we propose to evaluate efficacy and safety of rGpnmb and Gpnmb-p to mitigate and treat inflammation and articular cartilage degradation and loss in OA. In aim one, we will assess the safety and efficacy of rGpnmb and Gpnmb- p for the treatment of induced post-traumatic osteoarthritis (PT-OA) induced via the DMM model. In aim two, we will assess the efficacy of rGpnmb and Gpnmb-p for the treatment of age-induced (degenerative) osteoarthritis in mice. For both aims, we will evaluate articular cartilage and matrix degradation using histological and imaging analyses. Successful completion of this work will demonstrate the potential therapeutic value of Gpnmb for the OA treatment with possibl...