Sunday, May 18, 2025
5/18/2025
The Role of GPNMB in Post-Traumatic Osteoarthritis - Project Summary 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 or from trauma. 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. There is a 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-1ß 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. Preliminary data presented in the application and in support of the proposed studies showed that in vivo, intra-articular injection of rGpnmb in a post-traumatic model of OA (destabilization of the medial meniscus, DMM) mitigated and prevented cartilage loss. We determined that Gpnmb acts via interactions in the CD44 receptor in glial cells, macrophages, and that CD44-null mice (CD44-/-) developed severe joint damage using the DMM model compared to WT littermates. Therefore, we propose to evaluate efficacy of rGpnmb to mitigate and treat inflammation and articular cartilage degradation and loss in OA, with the central hypothesis that Gpnmb inhibits intra-articular inflammation and protects against post-traumatic OA (PT-OA) in a CD44-dependent manner. We will assess the efficacy of rGpnmb for the treatment in PT-OA induced via the DMM model. We will evaluate articular cartilage and matrix degradation using histological and imaging analyses. Behavioral changes will also be assessed. We will then determine if the Gpnmb’s anti-inflammatory response is CD44-dependent in vitro by isolating primary chondrocytes from C57BL/6J (control) and our in-house global CD44 null (CD44-/-) animals and challenging them with inflammation with or without rGpnmb treatment. We will also identify the signaling pathway that contributes to the anti-inflammatory response of Gpnmb via RT-qPCR and immunoblotting. In vivo, we will determine if the anti-inflammatory effects of Gpnmb occur via a CD44-dependent mechanism through induction of PT-OA in C57BL/6 (control) and CD44-/- mice with/without rGpnmb therapeutic treatment. Successful completion of this work will demonstrate the potential therapeutic value of Gpnmb in the treatment of OA and better elucidate the mechanism by which Gpnmb’s exerts its effect with possible extension to other applications.
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