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

项目摘要/摘要 本研究的目的是了解ADAMTS5在颞下颌关节(TMJ)中的作用。 发展。TMJ障碍困扰着2000多万美国人，但他们是一个研究不足的领域。具体来说， TMJ骨关节炎(TMJOA)特别令人担忧，因为它扰乱了细胞外基质(ECM)的动态平衡 导致软骨退化和软骨下骨质侵蚀。上调的A去整合素和 最丰富的TMJ--聚集素-5裂解的具有凝血酶反应蛋白基序的金属蛋白酶 蛋白多糖，一直被认为是TMJOA的标志。然而，大多数关于ADAMTS5的研究- ECM的营业额主要集中在透明软骨上，而不是组成TMJ的纤维软骨上。此外，我们的 初步数据表明，ADAMTS5蛋白降解活性是建立 青壮年TMJ的纤维软骨细胞带。因此，这个奖学金提案检验了这样一个假设： ADAMTS5介导的aggrecan卵裂对于TMJ中下颌骨的发育至关重要。至 研究这一假设，提出了三个具体目标。特定目标1将调查以下事件的后果 胚胎和出生后早期纤维软骨细胞层发育过程中ADAMTS5缺乏。特定目标 2将阐明ADAMTS5介导的聚集素切割对软骨细胞的机制要求 肥大和软骨下骨形成。最后，具体目标3将决定机械的作用 ADAMTS5缺乏症对发育期下颌骨髁突的影响。这项提案是在呼吁 质疑ADAMTS活性主要是对软骨破坏的现有理论。我们的初步数据 提示ADAMTS5介导的聚集素切割在软骨细胞成熟和下颌骨中起关键作用 髁状突发育。此外，这些实验还探讨了细胞外偶联的要求 基质周转配合机械负荷，促进TMJ正常发育和动态平衡。结果来自 本研究将为更深入地了解纤维软骨生物学的发展提供参考。 再生技术在颞下颌关节紊乱病治疗中的应用

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.