CK2.1, a novel peptide for cartilage repair

CK2.1，一种用于软骨修复的新型肽

• 批准号: 10053849
• 负责人: ANJA G NOHE
• 金额: $ 20.76万
• 依托单位: UNIVERSITY OF DELAWARE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-14 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10053849
• 关键词: Acute; Adult; Affect; Age; Aging; American; Animal Model; Apoptosis; Architecture; Arthritis; Automobile Driving; Behavior; Bone Density; Bone Development; C57BL/6 Mouse; Cartilage; Cartilage Matrix; Cells; Centers for Disease Control and Prevention (U.S.); Chondrocytes; Chondrogenesis; Clinical Research; Collagen Type II; Collagen Type X; Data; Degenerative polyarthritis; Development; Diagnosis; Diffuse; Disease; Enzymes; Exposure to; Extracellular Matrix; Friction; Gait; Generations; Goals; Hand; Health Expenditures; Hip region structure; Human; Hydrogels; Hypertrophy; Impairment; Inflammation; Injectable; Injections; Joints; Knee; Lead; Measures; Medial meniscus structure; Meniscus structure of joint; Modeling; Mus; Natural regeneration; Operative Surgical Procedures; Osteoblasts; Osteocalcin; Osteogenesis; Pathway interactions; Patients; Peptide Hydrolases; Peptide Signal Sequences; Peptides; Phenotype; Phosphorylation Site; Physicians; Pilot Projects; Play; Population; Process; Production; Property; Proteins; Publishing; Quality of life; RNA; Recombinants; Reporting; Risk Factors; Signal Pathway; Signal Transduction; Structure; Synovial Membrane; System; Testing; Therapeutic; Time; Tissues; Vertebral column; bone morphogenetic protein 2; bone morphogenetic protein receptors; cartilage repair; casein kinase II; cell type; design; foot; high reward; high risk; homeodomain; improved; joint destruction; joint function; knee replacement arthroplasty; laser capture microdissection; mouse model; novel; novel therapeutics; pain symptom; particle; peptidomimetics; prevent; receptor; repaired; tissue repair; transcriptome sequencing; type IA bone morphogenetic protein receptor; uptake

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.

OA 是一种由软骨逐渐丧失引起的严重衰弱性疾病，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 每年亿。美国疾病控制与预防中心 (CDC) 估计有 2700 万人 美国人患有骨关节炎。据估计，到 2030 年，20% 的美国成年人 或近 6700 万人将患有医生诊断的关节炎。 OA治疗重点 减少炎症和疼痛症状，同时关节继续退化。缺乏修复 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可能诱发 软骨细胞肥大。 OA 软骨中的软骨细胞显示异常肥大 表型并积极产生软骨降解酶。不幸的是，新的治疗方法 重组 BMP2 等开发会诱导软骨细胞肥大，进一步加剧 问题。因此，尽管它们在诱导 ECM 分泌和刺激 软骨形成，它们对于 OA 治疗没有用处。 我们建议使用新型肽 CK2.1 来治疗 OA。 CK2.1是骨的模拟肽 形态发生蛋白受体（BMPRIa）。该肽包含磷酸化位点 BMPRIa (SYED, AA475–479) 的酪蛋白激酶 II (CK2) 并包含触角足 用于细胞摄取的同源域信号序列。在我们的试点研究中，我们证明了 CK2.1 具有诱导 ECM 分泌和软骨形成的潜力，而无需诱导 肥大。我们还证明 CK2.1 可以修复 DMM 小鼠模型中的软骨。 我们进一步将 CK2.1 与水凝胶颗粒结合，使 CK2.1 能够持续释放到 关节腔内释放肽持续多天。虽然我们的试点研究结果 是有希望的，目前还不清楚我们的新肽是否会在长期内诱导软骨细胞肥大 学期。此外，尚不清楚该肽作用于哪些细胞群，以及它扩散到多远。 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。这个提议很高 风险也高，回报也高。 CK2.1可能是第一个无需人工干预即可再生软骨的肽 驱动软骨细胞凋亡或成骨细胞。如果是这样的话，我们的研究将发生革命性的变化 临床研究。