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

项目总结/摘要 本研究的目的是了解ADAMTS 5在颞下颌关节（TMJ） 发展颞下颌关节紊乱困扰着超过2000万美国人，但他们是一个研究不足的领域。具体地说， 颞下颌关节骨关节炎（TMJOA）是特别关注的，因为它破坏了细胞外基质（ECM）的稳态 导致软骨退化和软骨下骨侵蚀。上调的A去整合素和 具有血栓蛋白基序的金属蛋白酶（ADAMTS）-5切割聚集蛋白聚糖，最丰富的TMJ 蛋白聚糖被认为是TMJOA的标志。然而，大多数关于ADAMTS 5- ECM的周转集中在透明软骨，而不是纤维软骨，它构成了颞下颌关节。此外，我们的 初步数据表明，ADAMTS 5蛋白水解活性是建立 纤维软骨细胞带在年轻的成年人颞下颌关节。因此，本研究金提案检验了以下假设： ADAMTS 5介导的聚集蛋白聚糖裂解对TMJ中下颌髁突的发育至关重要。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： 胚胎和出生后早期纤维软骨细胞层发育过程中的ADAMTS 5缺陷。具体目标 2将阐明ADAMTS 5介导的软骨细胞聚集蛋白聚糖切割的机制要求。 肥大和软骨下骨形成。最后，具体目标3将确定机械的作用 对发育中的下颌骨髁突施加的负荷与ADAMTS 5缺陷的组合。这项提案呼吁 质疑现有的理论，即ADAMTS活动主要是破坏软骨。我们的初步数据 表明ADAMTS 5介导聚集蛋白聚糖切割在软骨细胞成熟和下颌骨发育中的关键作用 髁突发育此外，这些实验研究了偶联细胞外蛋白的要求。 基质周转与机械负荷，以促进正常的颞下颌关节发育和稳态。结果 这项研究将为纤维软骨生物学的发展提供更深入的了解， 再生技术在颞下颌关节紊乱病的治疗。

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.