Mechanical stability and biological consequences of cracks in articular cartilage

骨关节炎（OA）是关节炎的最常见形式，是一种关节疾病，其特征在于 关节软骨这种疾病是复杂和动态的，经过数年甚至数十年的演变，最终 导致关节疼痛和功能障碍。OA影响美国超过2700万成年人，使其成为导致 残疾。尽管在西方国家是最常见的残疾原因，但OA无法治愈， 诊断或治疗的选择。在寻找治疗方法的过程中，最关键的知识差距包括 了解OA的发病机制，然后才能集中到晚期疾病状态，这是 以疼痛、畸形和功能障碍为特征。事实上，目前的晚期诊断标准 影像学改变和最终通过关节成形术治疗已被证明是一个“解决方案”， 理想.软骨中的裂纹（即基质中的断裂）很有可能成为前OA的一种早期标志物 增加OA风险。裂缝通常在关节创伤后以及疾病晚期观察到。的确， 当对软骨损伤和OA进展进行分级和分类时，经常考虑裂纹。最近 基础科学研究已经定义了裂纹的流行和形态，裂纹的机械阈值 引发和开裂后的生物生理变化。然而，要开发作为前OA的标志物或 为了指导临床决策，必须回答有关裂缝的关键问题。这些问题包括 基础科学研究到临床应用。 这一建议概述了两个基本的科学问题，加强了对自然科学的基本理解。 机械和生物学后果的裂纹软骨，并在这样做，开始测试裂纹作为一个 重要骨科生物标志物。具体来说，它是未知的，如果现有的裂缝不稳定软骨或易患 进一步生物降解。 广义地说，申请人假设裂纹形态可用于区分裂纹， 良性与裂纹，表明可避免地损害软骨。在这项研究中，申请人更具体地说， 假设当负荷超过阈值时，软骨中的裂缝将生长并诱导超急性细胞 恶化为了弥补这些知识差距，本提案有两个具体目标：（1）调查 软骨裂纹的机械稳定性和（2）表征软骨裂纹的急性生物学后果， 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.