The Therapeutic Role of GPNMB in Osteoarthritis

骨关节炎是一种衰弱的退行性关节疾病，导致5400万人慢性关节疼痛和残疾 美国的成年人。骨性关节炎可由慢性联合使用(退行性或年龄相关性)或创伤(后遗症)引起。 创伤)。目前，还没有疾病改良剂来治愈或治疗这种疾病。临床管理重点 关于减肥、非甾体抗炎药、皮质类固醇或HA注射，以及其他旨在减轻关节疼痛的替代疗法 和静止不动。最后的治疗是关节成形术，这是不可逆转的，需要在10-15年内进行修复手术。 手术和非手术治疗每年总共产生270亿美元的医疗成本。这些社会经济问题 负担突出了迫切需要新的治疗方法来预防或延缓由骨关节炎引起的软骨损伤。这里, 我们提出了一种新的治疗候选药物，骨活素(GPNMB)，一种表达于 多种细胞类型，具有抗炎和软骨保护作用。在这篇文章中提出的初步研究 应用表明，GPNMB在人高级别骨关节软骨中高表达。当人类HTB-94 用重组GPNMB蛋白(RGpnmb)处理软骨细胞，然后再用IL-1b刺激处理细胞 显示分解代谢标记物MMP9、MMP13和IL6的表达减少。此外，rGpnmb治疗 抑制人软骨移植体内基质的体外降解。C57BL/6小鼠关节内注射rGpnmb的体内实验研究 小鼠关节在诱导的创伤后骨性关节炎模型中减轻和防止软骨丢失(关节不稳定) 内侧半月板(DMM)。我们确定GPNMB通过胶质细胞中CD44受体的相互作用发挥作用， 巨噬细胞和软骨细胞以及CD44缺失小鼠(CD44-/-)使用DMM产生严重的关节损伤 模型与WT窝产仔进行比较。最后，我们提出了GPNMB有助于减缓与年龄相关的进展 小鼠骨质疏松症。我们实验室最近发现了一种具有相同抗炎和生物活性的小肽(GPNMB-p) 属性为rGpnmb。这一点意义重大，因为多肽具有高度的选择性、效力，而且生产成本更低。肽类 与整个蛋白质相比，还可以减少潜在的毒性和蓄积问题。因此，在这一阶段-I SBIR，我们建议评估rGpnmb和GPNMB-p缓解和治疗炎症和 关节软骨在骨性关节炎中的降解和丢失。在目标一中，我们将评估rGpnmb和GPNMB的安全性和有效性。 P用于治疗DMM模型诱导的创伤后骨关节炎(PT-OA)。在目标二中，我们将 评价rGpnmb和GPNMB-p治疗增龄性(退行性)小鼠骨关节炎的疗效。 对于这两个目标，我们将使用组织学和影像分析来评估关节软骨和基质的降解。 这项工作的成功完成将展示GPNMB在治疗骨性关节炎中的潜在治疗价值 可能扩展到其他应用程序。

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 possible extension to other applications.