The Requirement of ADAMTS5-mediated Cleavage of Aggrecan in Temporomandibular Joint Development

ADAMTS5 介导的聚集蛋白聚糖裂解在颞下颌关节发育中的要求

• 批准号: 10202461
• 负责人: Alexandra Rogers
• 金额: $ 5.13万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10202461
• 关键词: Affect; American; Anabolism; Architecture; Area; Biology; Biomechanics; CD44 gene; Cartilage; Cartilage Matrix; Cells; Chondrocytes; Chondrogenesis; Coupled; Coupling; Critical Thinking; Data; Degenerative polyarthritis; Dentists; Development; Diet; Discipline of Nursing; Disease; Disintegrins; Embryo; Extracellular Matrix; Extracellular Matrix Degradation; Fellowship; Fibrocartilages; Food; Foundations; Goals; Hip region structure; Homeostasis; Hyaline Cartilage; Hypertrophy; Incisor; Joints; Knee; Link; Mandible; Mandibular Condyle; Mediating; Metalloproteases; Modeling; N-terminal; Natural regeneration; Occlusal Splints; Osteogenesis; Pathway interactions; Patients; Peptide Hydrolases; Phase I Clinical Trials; Physiological; Proteoglycan; Regenerative Medicine; Regulation; Reporting; Research; Role; Scientist; Signal Transduction; Soft Diet; Solid; Technical Expertise; Techniques; Temporomandibular Joint; Temporomandibular Joint Disorders; Temporomandibular joint osteoarthritis; Testing; Thrombospondins; Time; Tissues; Treatment Cost; aggrecan; aggrecanase; bone erosion; career; cartilage degradation; cell behavior; design; effective therapy; experimental study; in vivo; inhibitor/antagonist; joint destruction; joint loading; mechanical load; mouse model; notch protein; novel; phase I trial; postnatal; protective effect; regenerative; regenerative therapy; subchondral bone; theories; training opportunity; young adult

PROJECT SUMMARY/ABSTRACT The goal of this proposal is to understand the role of ADAMTS5 during temporomandibular joint (TMJ) development. TMJ disorders afflict over 20 million Americans, yet they are an understudied area. Specifically, TMJ osteoarthritis (TMJOA) is of particular concern because it disrupts extracellular matrix (ECM) homeostasis leading to cartilage degradation and subchondral bone erosion. Upregulated A Disintegrin And Metalloproteinase with ThromboSpondin motifs (ADAMTS)-5 cleavage of aggrecan, the most abundant TMJ proteoglycan, has been considered a hallmark of TMJOA. However, the majority of research on ADAMTS5- ECM turnover has focused on hyaline cartilage, not fibrocartilage, which comprises the TMJ. Additionally, our preliminary data demonstrates that ADAMTS5 proteolytic activity is required for establishment of the fibrocartilage cell zones in the young adult TMJ. Therefore, this fellowship proposal tests the hypothesis that ADAMTS5-mediated aggrecan cleavage is vital for the development of the mandibular condyle in the TMJ. To study this hypothesis, three specific aims are proposed. Specific Aim 1 will investigate the consequence of ADAMTS5 deficiency during embryonic and early postnatal fibrocartilage cell layer development. Specific Aim 2 will elucidate the mechanistic requirement of ADAMTS5-mediated aggrecan cleavage for chondrocyte hypertrophy and subchondral bone formation. Finally, Specific Aim 3 will determine the role of mechanical load on the developing mandibular condyle in combination with ADAMTS5 deficiency. This proposal is calling into question the existing theory that ADAMTS activity is primarily destructive to cartilage. Our preliminary data indicate a critical role for ADAMTS5-mediated aggrecan cleavage in chondrocyte maturation and mandibular condylar development. In addition these experiments investigate the requirement for coupling of extracellular matrix turnover with mechanical loading to promote normal TMJ development and homeostasis. Results from this study will provide a more thorough understanding of fibrocartilage biology for the development of regenerative techniques in the treatment of TMJ disorders.

项目概要/摘要 该提案的目标是了解 ADAMTS5 在颞下颌关节 (TMJ) 过程中的作用 发展。颞下颌关节紊乱症困扰着超过 2000 万美国人，但这一领域的研究尚未充分。具体来说， 颞下颌关节骨关节炎 (TMJOA) 特别值得关注，因为它会破坏细胞外基质 (ECM) 稳态 导致软骨退化和软骨下骨侵蚀。上调解整合素和 具有 ThromboSpondin 基序 (ADAMTS)-5 的金属蛋白酶可切割最丰富的 TMJ 聚集蛋白聚糖 蛋白多糖被认为是 TMJOA 的标志。然而，大多数关于 ADAMTS5 的研究 ECM 的更新主要集中在透明软骨上，而不是构成颞下颌关节的纤维软骨上。此外，我们的 初步数据表明 ADAMTS5 蛋白水解活性是建立 年轻成人颞下颌关节内的纤维软骨细胞区。因此，该奖学金提案检验了以下假设： ADAMTS5 介导的聚集蛋白聚糖裂解对于 TMJ 中下颌骨髁的发育至关重要。到 研究这一假设，提出了三个具体目标。具体目标 1 将调查以下后果： ADAMTS5 在胚胎和产后早期纤维软骨细胞层发育过程中缺乏。具体目标 2 将阐明 ADAMTS5 介导的软骨细胞聚集蛋白聚糖裂解的机制要求 肥大和软骨下骨形成。最后，具体目标 3 将确定机械的作用 发育中的下颌髁突的负荷与 ADAMTS5 缺陷相结合。这个提案正在呼吁 ADAMTS 活动主要破坏软骨的现有理论受到质疑。我们的初步数据 表明 ADAMTS5 介导的聚集蛋白聚糖裂解在软骨细胞成熟和下颌骨发育中起关键作用 髁突发育。此外，这些实验还研究了细胞外偶联的要求 基质周转与机械负荷促进正常的颞下颌关节发育和稳态。结果来自 这项研究将为纤维软骨生物学的发展提供更全面的了解 再生技术治疗颞下颌关节紊乱。