The role of the inflammatory response in bone and cartilage changes following non

描述（由申请人提供）：外伤性骨关节炎（PTOA）以关节软骨和软骨下骨退变为特征，通常是外伤性关节损伤的长期后果，大约50%的前交叉韧带（ACL）断裂或半月板切除术患者在10-20年内发展为PTOA。在我们的实验室中，我们开发了一种新的小鼠膝关节损伤模型，该模型使用非侵入性机械载荷诱导前交叉韧带断裂，产生与人类上睑下垂相关的关节损伤反应。使用该模型的初步研究表明，非侵入性膝关节损伤后，软骨下骨迅速（1周内）大量流失，损伤后4周骨量快速部分恢复。我们假设损伤引起的炎症作为骨重塑的大规模激活事件，随后驱动这些实质性的短期骨变化。抑制损伤诱导的炎症反应可能有效地阻止这些短期结构变化，并可能防止软骨下骨和关节软骨的长期退变，然而，损伤诱导的炎症在上睑下垂发展中的作用以及治疗的机会窗口尚未确定。在这项研究中，我们将使用我们的新型小鼠膝关节损伤模型来确定PTOA进展的时间过程，并确定损伤诱导的炎症反应对PTOA发展的影响。在Aim 1中，我们将确定损伤诱导的炎症反应的具体机制和时间过程，以及这种反应是否与膝关节损伤后软骨下骨和关节软骨变化的时间过程有关。在目的2中，我们将评估抑制炎症细胞因子肿瘤坏死因子- (TNF-)、白细胞介素-1 （IL-1）和白细胞介素-6 （IL-6）的治疗方法的能力，以防止非侵入性膝关节损伤引起的软骨和骨结构变化。这些研究的结果将有助于建立旨在减缓或预防PTOA发病的治疗的“机会之窗”，并将建立与损伤诱导的炎症反应相关的治疗靶点。这项研究将极大地扩展我们对关节损伤后生物过程的理解，并可能导致人类受试者创伤性关节损伤治疗方式的根本改变。这个导师职业发展奖将为我在导师团队的指导下进行研究和专业发展提供资源。在指导期间，我将成功地从我的职业生涯的指导阶段过渡到一个独立的调查员。

DESCRIPTION (provided by applicant): Post-traumatic osteoarthritis (PTOA) is characterized by degeneration of articular cartilage and subchondral bone, and is commonly a long-term consequence of traumatic joint injury, with approximately 50% of individuals with anterior cruciate ligament (ACL) rupture or meniscectomy developing PTOA within 10-20 years. In our lab we have developed a novel mouse model of knee injury that uses non-invasive mechanical loading to induce rupture of the ACL, creating a joint injury response that is relevant to PTOA in humans. Preliminary studies using this model indicate that there is rapid (within 1 week) and considerable subchondral bone loss following non-invasive knee injury, followed by a rapid partial recovery of bone mass by 4 weeks post-injury. We hypothesize that injury-induced inflammation acts as a mass activation event for bone remodeling, which subsequently drives these substantial short-term bone changes. Inhibiting the injury-induced inflammatory response may effectively stop these short-term structural changes, and may prevent longer-term degeneration of subchondral bone and articular cartilage, however the role of injury-induced inflammation in PTOA development, and the window of opportunity for treatment have not been defined. In this study we will use our novel mouse model of knee injury to determine the time course of PTOA progression, and determine the effect of the injury-induced inflammatory response on PTOA development. In Aim 1 we will determine the specific mechanisms and time course of the injury-induced inflammatory response, and whether this response is associated with the time course of subchondral bone and articular cartilage changes following knee injury. In Aim 2 we will assess the ability of treatments that inhibit the inflammatory cytokines tumor necrosis factor-¿ (TNF-¿), interleukin-1 (IL-1), and interleukin-6 (IL-6) to prevent structural cartilage and bone changes initiated by non-invasive knee injury. Results from these studies will help establish the "window of opportunity" for treatments aimed at slowing or preventing the onset of PTOA, and will establish therapeutic targets associated with the injury-induced inflammatory response. This research will greatly expand our understanding of biological processes following joint injuries, and could lead to a fundamental change in the way traumatic joint injuries are treated in human subjects. This mentored career development award will provide me with resources to conduct research and develop professionally under the guidance of my mentoring team. During the mentored period I will successfully transition from the mentored stage of my career to an independent investigator. PUBLIC HEALTH RELEVANCE: Traumatic joint injuries such as anterior cruciate ligament (ACL) rupture often lead to post-traumatic osteoarthritis (PTOA), which is associated with cartilage and bone degeneration, as well as significant joint pain. In this study we investigate th role of injury-induced inflammation on the development of PTOA, and establish a "window of opportunity" for treatments aimed at preventing or slowing the onset of PTOA. This research will greatly expand our understanding of biological processes following joint injuries, and could lead to a fundamental change in the way traumatic joint injuries are treated in human subjects.