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: 9116034
• 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/9116034
• 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; TNF gene; Testing; Time; X-Ray Computed Tomography; anterior cruciate ligament rupture; articular cartilage; bone; bone epiphysis; bone loss; bone mass; bone metabolism; career; cartilage degradation; 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.

描述(申请人提供)：创伤后骨关节炎(PTOA)的特征是关节软骨和软骨下骨的退化，通常是创伤性关节损伤的长期后果，大约50%的前十字韧带(ACL)断裂或半月板切除术的患者在10-20年内发展为PTOA。在我们的实验室中，我们开发了一种新型的膝关节损伤小鼠模型，它使用非侵入性机械载荷来诱导前交叉韧带断裂，产生与人类PTOA相关的关节损伤反应。使用该模型的初步研究表明，在非侵袭性膝关节损伤后，软骨下骨迅速(在1周内)大量丢失，然后在损伤后4周骨量迅速部分恢复。我们假设，损伤诱导的炎症作为骨重建的大量激活事件，随后驱动这些实质性的短期骨改变。抑制损伤诱导的炎症反应可以有效地阻止这些短期的结构变化，并可能防止软骨下骨和关节软骨的长期退化，但损伤诱导的炎症在PTOA发展中的作用和治疗的机会窗尚未确定。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进展的时间进程，并确定损伤诱导的炎症反应对PTOA发展的影响。在目标1中，我们将确定损伤诱导炎症反应的具体机制和时间进程，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进程有关。在目标2中，我们将评估抑制炎性细胞因子肿瘤坏死因子-�(肿瘤坏死因子-�)、白介素1(IL-1)和白介素6(IL-6)的治疗方法预防非侵袭性膝关节损伤引发的结构性软骨和骨骼改变的能力。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学过程的理解，并可能导致人类受试者创伤性关节损伤的治疗方式发生根本变化。这个导师职业发展奖将为我提供资源，在我的导师团队的指导下进行专业的研究和发展。在指导期间，我将成功地从职业生涯的指导阶段过渡到一名独立的调查员。

项目成果

Effect of alendronate on post-traumatic osteoarthritis induced by anterior cruciate ligament rupture in mice.

丙膦酸盐对小鼠前交叉韧带破裂引起的创伤后骨关节炎的影响。

• DOI: 10.1186/s13075-015-0546-0
• 发表时间: 2015-02-16
• 期刊: Arthritis research & therapy
• 影响因子: 4.9
• 作者: Khorasani MS;Diko S;Hsia AW;Anderson MJ;Genetos DC;Haudenschild DR;Christiansen BA
• 通讯作者: Christiansen BA

Comparison of loading rate-dependent injury modes in a murine model of post-traumatic osteoarthritis.

• DOI: 10.1002/jor.22480
• 发表时间: 2014-01
• 期刊: JOURNAL OF ORTHOPAEDIC RESEARCH
• 影响因子: 2.8
• 作者: Lockwood, Kevin A.;Chu, Bryce T.;Anderson, Matthew J.;Haudenschild, Dominik R.;Christiansen, Blaine A.
• 通讯作者: Christiansen, Blaine A.

Comparison of knee injury threshold during tibial compression based on limb orientation in mice.

• DOI: 10.1016/j.jbiomech.2018.04.014
• 发表时间: 2018-06-06
• 期刊: Journal of biomechanics
• 影响因子: 2.4
• 作者: Hsia AW;Tarke FD;Shelton TJ;Tjandra PM;Christiansen BA
• 通讯作者: Christiansen BA

Cyclin-dependent kinase 9 inhibition protects cartilage from the catabolic effects of proinflammatory cytokines.

• DOI: 10.1002/art.38378
• 发表时间: 2014-06
• 期刊: ARTHRITIS & RHEUMATOLOGY
• 影响因子: 13.3
• 作者: Yik, Jasper H. N.;Hu, Zi'ang;Kumari, Ratna;Christiansen, Blaine A.;Haudenschild, Dominik R.
• 通讯作者: Haudenschild, Dominik R.

Effect of micro-computed tomography voxel size and segmentation method on trabecular bone microstructure measures in mice.

• DOI: 10.1016/j.bonr.2016.05.006
• 发表时间: 2016-12-01
• 期刊: Bone reports
• 影响因子: 2.5
• 作者: Christiansen, Blaine A