CK2.1, a novel peptide for cartilage repair

OA是一种主要的衰弱性疾病，由软骨的逐渐丧失引起，主要影响 膝盖，臀部，手，脚，和脊柱OA使医疗保健总支出增加186美元 每年十亿。美国疾病控制和预防中心（CDC）估计， 美国人患有OA。据估计，到2030年，20%的美国成年人口， 将近六千七百万人将被医生诊断为关节炎。OA治疗的重点是 减少炎症和疼痛症状，同时关节退化继续。年久失修 这种机制最终会导致需要进行全膝关节置换手术的情况。 目前正在开发的治疗方法的主要缺点之一是有可能诱导 软骨细胞肥大OA软骨中的软骨细胞显示异常肥大， 表型和积极产生软骨降解酶。不幸的是， 发育，如重组BMP 2，诱导软骨细胞肥大，进一步加剧 问题所在因此，尽管它们在诱导ECM分泌和刺激ECM分泌方面非常有效， 软骨形成，它们对于OA治疗是无用的。 我们提出使用新型肽CK2.1治疗OA。CK2.1是骨的模拟肽 形态发生蛋白受体（BMPRIa）。该肽结合了磷酸化位点， 酪蛋白激酶II（CK 2）的BMPRIa（SYED，AA 475 -479），并含有 用于细胞摄取的同源结构域信号序列。在我们的初步研究中，我们证明了CK2.1 具有诱导ECM分泌和软骨形成的潜力， 肥厚我们还证明了CK2.1在DMM小鼠模型中修复软骨。 我们进一步将CK2.1缀合至水凝胶颗粒，以使CK2.1能够持续释放到细胞中。 关节腔内释放肽达多天。虽然我们的初步研究结果 是有希望的，目前还不清楚我们的新肽是否会诱导软骨细胞肥大， term.此外，目前还不清楚肽作用于哪个细胞群体，它扩散到多远， 软骨以及它激活的信号通路。该提案将回答这些关键问题。 在进一步开发CK2.1之前必须回答的问题。这一提议很高 风险和高回报。CK2.1可能是第一个可以再生软骨而不需要蛋白质的肽。 驱动软骨细胞凋亡或成骨细胞。如果是这样的话，我们的研究将彻底改变 临床研究。

OA is a major debilitating disease caused by the gradual loss of cartilage, primarily affecting the knees, hips, hands, feet, and spine. OA increases aggregate health care expenditures by $186 billion annually. The Centers for Disease Control and Prevention (CDC) estimates 27 million Americans suffer from OA. Estimates show that by year 2030, 20% of the adult U.S. population, or nearly 67 million people, will have physician-diagnosed arthritis. OA treatments focus on reducing inflammation and pain symptoms while joint degradation continues. The lack of repair mechanism will eventually lead to a condition that necessitates total knee replacement surgery. One of the major drawbacks of current therapeutics being developed is the potential to induce chondrocyte hypertrophy. Chondrocytes in OA cartilage show an aberrant hypertrophic phenotype and actively produce cartilage-degrading enzymes. Unfortunately, new treatments in development, such as recombinant BMP2, induce chondrocyte hypertrophy, further exasperating the problem. Therefore, although they are very potent in inducing ECM secretion and stimulating chondrogenesis, they are not useful for OA treatment. We propose the use of novel peptide CK2.1 to treat OA. CK2.1 is a mimetic peptide of the Bone Morphogenetic Protein receptor (BMPRIa). The peptide incorporates the phosphorylation site for Casein Kinase II (CK2) of the BMPRIa (SYED, AA475–479) and contains the Antennapedia Homeodomain signal sequence for cellular uptake. In our pilot study, we demonstrated that CK2.1 has the potential to induce ECM secretion and chondrogenesis without the induction of hypertrophy. We also demonstrated that CK2.1 repaired the cartilage in a DMM mouse model. We further conjugated CK2.1 to hydrogel particles to enable a sustained release of CK2.1 into the intra articular cavity releasing the peptide for multiple days. While results from our pilot study are promising, it is unclear if our novel peptide will induce chondrocyte hypertrophy in the long- term. Furthermore, it is unclear which cell population the peptide acts on, how far it diffuses into the cartilage, and what signaling pathways it activates. This proposal will answer these critical questions that must be answered before CK2.1 can be further developed. This proposal is high risk and also high reward. CK2.1 may be the first peptide that can regenerate cartilage without driving chondrocytes into apoptosis or osteoblasts. If this is the case our studies will revolutionize the clinical research.