The Therapeutic Role of GPNMB in Osteoarthritis

骨关节炎（OA）是一种使人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。OA可由慢性关节使用（退行性或年龄相关）或创伤（术后）引起。 创伤）。目前，没有疾病修饰剂来治愈或治疗该疾病。临床管理重点 减肥、NSAID、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 和不动。最后的治疗，关节成形术，是不可逆的，需要在10-15年的修正手术。 手术和非手术治疗每年产生270亿美元的医疗费用。这些社会经济 这些负担突出了对预防或延迟由OA引起的软骨损伤的新型治疗的迫切需要。在这里， 我们提出了一种新的治疗候选药物，骨激活素（Gpnmb），一种I型跨膜糖蛋白，表达于 具有抗炎和软骨保护特性的各种细胞类型。本报告中提出的初步研究 应用显示Gpnmb在高级别人骨关节炎软骨中高度表达。当人类HTB-94 用重组Gpnmb蛋白（rGpnmb）处理软骨细胞，然后用IL-1b刺激，处理的细胞 显示分解代谢标志物MMP-9、MMP-13和IL-6的表达降低。此外，rGpnmb治疗 抑制人软骨外植体中的离体基质降解。在体内，在C57 BL/6中关节内注射rGpnmb 小鼠关节减轻并防止了OA的诱导创伤后模型中的软骨损失（ 内侧半月板，DMM）。我们确定Gpnmb通过与神经胶质细胞中的CD 44受体相互作用起作用， 巨噬细胞和软骨细胞，CD 44-null小鼠（CD 44-/-）使用DMM发生了严重的关节损伤 与WT同窝仔相比的模型。最后，我们提出，Gpnmb有助于减缓与年龄相关的进展， 小鼠OA。我们的实验室最近发现了一种小的Gpnmb肽（Gpnmb-p），具有相同的抗炎和生物活性， 属性为rGpnmb。这是重要的，因为肽是高度选择性的，有效的，并且生产成本更低。肽 也比全蛋白降低了潜在的毒性和累积问题。因此，在第一阶段， SBIR，我们建议评估rGpnmb和Gpnmb-p减轻和治疗炎症的有效性和安全性， OA中的关节软骨退化和损失。目的一，我们将评估rGpnmb和Gpnmb的安全性和有效性- p用于治疗通过DMM模型诱导的诱导的创伤后骨关节炎（PT-OA）。在目标二中，我们将 评估rGpnmb和Gpnmb-p用于治疗小鼠中年龄诱导的（退行性）骨关节炎的功效。 对于这两个目标，我们将使用组织学和成像分析来评估关节软骨和基质降解。 这项工作的成功完成将证明Gpnmb对OA治疗的潜在治疗价值， 可能扩展到其他应用。

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.