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

非手术后炎症反应在骨和软骨变化中的作用

• 批准号: 8280849
• 负责人: Blaine A. Christiansen
• 金额: $ 11.38万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-10 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8280849
• 关键词: Acute; Animal Model; Arthralgia; Arthritis; Biological; Biological Markers; Biological Process; Bone Resorption; Bone remodeling; Cartilage; Degenerative polyarthritis; Deterioration; Development; Event; Goals; Human; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Injection of therapeutic agent; Injury; Interleukin-1; Interleukin-6; K-Series Research Career Programs; Knee; Knee Injuries; Lead; Ligaments; Mechanics; Mentors; Methods; Modeling; Mus; Operative Surgical Procedures; Osteitis; Osteoblasts; Osteoclasts; Osteogenesis; Patients; Proteoglycan; Research; Research Personnel; Resources; Rheumatism; Risk Factors; Role; Serum; Staging; Symptoms; Testing; Time; Tumor Necrosis Factor-alpha; X-Ray Computed Tomography; anterior cruciate ligament rupture; articular cartilage; bone; bone epiphysis; bone loss; bone mass; bone metabolism; career; clinically relevant; collagenase; cytokine; effective therapy; human subject; in vivo; inhibitor/antagonist; injured; joint injury; longitudinal analysis; malformation; mouse model; novel; optical imaging; partial recovery; prevent; response; response to injury; substantia spongiosa; therapeutic target

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.

描述（由适用提供）：创伤后骨关节炎（PTOA）的特征是关节软骨和软骨下骨变性，通常是创伤性关节损伤的长期后果，大约50％的人患有前十字韧带（ACL）破裂或Meniscecture copture或Meniscecture copture copture或Meniscecture copture copture或Meniscecture copture cortipure或Meniscecture copture copture cortimencecture或Meniscecture copture cotecture或Meniscepture pttoa in 10-20年。在我们的实验室中，我们开发了一种新型的膝盖损伤小鼠模型，该模型使用非侵入性机械载荷诱导ACL破裂，从而产生了与人类PTOA相关的关节损伤反应。使用该模型的初步研究表明，无创膝关节损伤后有很快（在1周内）和大量的软骨下骨质流失，随后在伤害后4周迅速部分骨骼骨骼的部分恢复。我们假设受伤诱导的感染是骨重塑的质量激活事件，随后驱动了这些实质性的短期骨变化。抑制损伤引起的炎症反应可能有效地阻止了这些短期结构变化，并可能防止软骨下骨和关节软骨的长期变性，但是损伤诱导的感染在PTOA发育中的作用，并且尚未确定治疗机会窗口。在这项研究中，我们将使用新型的膝关节损伤小鼠模型来确定AIM 1中PTOA的时间过程，我们将确定损伤引起的炎症反应的特定机制和时间过程，以及这种反应是否与膝盖损伤后的下骨和关节软骨的时间过程有关。在AIM 2中，我们将评估抑制炎症性细胞因子肿瘤坏死因子（TNF- - ），白介素-1（IL-1）和白介素6（IL-6）的治疗能力，以防止通过非侵入性膝盖受伤引发的结构软骨和骨变化。这些研究的结果将有助于建立旨在减慢或防止PTOA发作的治疗方法的“机会之窗”，并将建立与损伤引起的炎症反应相关的治疗靶标。这项研究将大大扩展我们对联合伤害后生物过程的理解，并可能导致人类受试者对创伤性关节损伤的根本变化。这个修订的职业发展奖将为我提供资源，以在我的心理团队的指导下进行研究和专业发展。在修订时期，我将成功从职业的修订阶段过渡到独立调查员。 公共卫生相关性：创伤性关节损伤，例如前交叉韧带（ACL）破裂通常会导致创伤后骨关节炎（PTOA），这与软骨和骨变性有关，以及严重的关节疼痛。在这项研究中，我们研究了损伤引起的感染对PTOA发展的作用，并为旨在防止或减慢PTOA发作的治疗范围建立了“机会之窗”。这项研究将大大扩展我们对联合损伤后生物过程的理解，并可能导致人类受试者对创伤性关节损伤的根本变化。