CK2.1, a novel peptide for cartilage repair

骨性关节炎是一种主要的衰弱疾病，由软骨的逐渐丧失引起，主要影响 膝盖、臀部、手、脚和脊椎。办公自动化使医疗保健总支出增加186美元 每年10亿美元。疾病控制和预防中心(CDC)估计有2700万 美国人患有骨性关节炎。据估计，到2030年，20%的美国成年人口， 或者说近6700万人，将患有医生诊断的关节炎。OA治疗重点放在 减少炎症和疼痛症状，同时关节退化仍在继续。缺乏修缮 这种机制最终会导致一种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。骨性关节炎软骨细胞异常肥大 并主动产生软骨降解酶。不幸的是，新的治疗方法 发展，如重组BMP2，诱导软骨细胞肥大，进一步激怒 问题就在这里。因此，虽然它们在诱导ECM分泌和刺激方面非常有效 软骨形成，它们对骨关节炎的治疗没有用处。 我们建议使用新肽CK2.1来治疗骨性关节炎。CK2.1是一种模拟骨骼的肽 形态发生蛋白受体(BMPRIa)。该肽结合了磷酸化位点，可用于 BMPRIa(Syed，AA475-479)的酪蛋白激酶II(CK2)，包含触角 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，而不诱导 肥大。我们还证明了CK2.1在DMM小鼠模型中修复了软骨。 我们进一步将CK2.1偶联到水凝胶颗粒上，使CK2.1能够在体内持续释放 关节腔内可持续数天释放多肽。虽然我们先导研究的结果 目前尚不清楚我们的新肽是否会长期诱导软骨细胞肥大。 学期。此外，目前还不清楚这种多肽作用于哪个细胞群体，扩散到什么程度。 软骨，以及它激活的信号通路。这项提案将回答这些关键问题 在CK2.1可以进一步发展之前必须回答的问题。这个提议太高了 风险和高额回报。CK2.1可能是第一个可以在没有软骨的情况下再生软骨的多肽 促使软骨细胞进入凋亡或成骨细胞。如果是这样的话，我们的研究将带来革命性的变化 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.