Mechanical stability and biological consequences of cracks in articular cartilage

骨关节炎(OA)是最常见的关节炎形式，是一种以关节退行性变为特征的关节疾病 关节软骨。这种疾病是复杂和动态的，经过几年甚至几十年的演变最终 导致关节疼痛和功能障碍。在美国，超过2700万成年人受到骨质疏松症的影响，这使其成为导致癌症的主要原因 残疾。尽管在西方国家，骨性关节炎是导致残疾的最常见原因，但它没有治愈方法，而且很少。 诊断或治疗选项。在寻找治疗方法的过程中，最关键的知识差距包括 了解骨性关节炎的发病机制之前，会聚到晚期的疾病状态，这是 以疼痛、畸形和功能障碍为特征的。的确，目前的诊断标准是晚期 放射学改变和通过关节成形术的最终治疗已被证明是一种远不是 非常理想。软骨破裂(即基质破裂)很有可能成为骨性关节炎前病变的早期标志之一。 并增加了骨性关节炎的风险。骨折常见于关节创伤后和疾病晚期。的确， 在对软骨损伤和骨性关节炎进展进行分级和分类时，通常会考虑骨折。近期 基础科学研究定义了裂纹的流行率和形态，以及裂纹的机械阈值 以及裂解后的生物生理变化。然而，要发展为一个标志，前办公自动化或 指导临床决策，必须回答有关裂缝的关键问题。这些问题包括 基础科学研究向临床应用转变。 这项建议概述了两个基础科学问题，以加强对 软骨裂缝的力学和生物学后果，并在这样做的过程中，开始将裂缝作为一种 重要的骨科生物标志物。具体地说，目前尚不清楚存在的裂缝是否会破坏软骨的稳定或使其易于发生。 这将导致进一步的生物降解。 一般而言，申请者假设裂纹形态可以用来区分 良性的诗句表明软骨受到了不可挽回的损伤。在这项研究中，申请者更具体地 假设，当负荷超过某个阈值时，软骨中的裂缝将会生长并诱导超急性细胞 恶化。为了解决这些知识差距，这项建议有两个具体目标：(1)调查 软骨裂隙的机械稳定性和(2)表征裂隙的急性生物学后果。 软骨。

Osteoarthritis (OA), the most common form of arthritis, is a joint disease characterized by the degradation of articular cartilage. This disease is complex and dynamic, evolving over years or even decades to ultimately cause joint pain and dysfunction. OA affects over 27 million adults in the US, making it a leading cause of disability. Despite being the most common cause of disability in western nations, OA has no cure and few options for diagnosis or treatment. In the search for a treatment, the most critical knowledge gap involves understanding the pathogenesis of OA prior to converging on the late-stage disease state, which is characterized by pain, deformity, and dysfunction. Indeed, the current standard of diagnosis by late-stage radiographic changes and eventual treatment via arthroplasty has proven to be a “solution” that is far from ideal. Cracks in cartilage (i.e. breaks in the matrix) have strong potential to be one such early marker of pre-OA and increased OA risk. Cracks are often observed after joint trauma as well as in late-stage disease. Indeed, cracks are often considered when grading and classifying cartilage damage and OA progression. Recent basic-science studies have defined crack prevalence and morphology, mechanical thresholds for crack initiation, and bio-physiological changes after cracking. However, to be developed as a marker for pre-OA or to guide clinical decision-making, key questions about cracks must be answered. These questions range from basic-science research to clinical application. This proposal outlines two basic-science questions that enhance the fundamental understanding of the mechanical and biological consequences of cracks in cartilage and, in so doing, begin to test cracks as an important orthopedic biomarker. Specifically, it is unknown if existing cracks destabilize cartilage or predispose it to further biological degradation. Broadly, the applicants hypothesize that crack morphology can be used to distinguish between cracks that are benign verses cracks that indicate irrevocably damage cartilage. In this study, the applicants more specifically hypothesize that, when loaded above a threshold, cracks in cartilage will grow and induce peracute cellular deterioration. To address these knowledge gaps, this proposal has two specific aims: (1) Investigate the mechanical stability of cracks in cartilage and (2) Characterize the acute biological consequences of cracks in cartilage.