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

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：创伤后骨关节炎 (PTOA) 的特点是关节软骨和软骨下骨退化，通常是创伤性关节损伤的长期后果，大约 50% 的个体患有前十字韧带 (ACL) ）在 10-20 年内发生 PTOA 的破裂或半月板切除术在我们的实验室中，我们开发了一种使用非侵入性机械加载的新型膝关节损伤小鼠模型。诱导 ACL 破裂，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，非侵入性膝关节损伤后会出现快速（1 周内）且大量的软骨下骨丢失。损伤后 4 周骨量迅速部分恢复，我们发现损伤引起的炎症是骨重塑的大量激活事件，随后驱动了这些实质性的短期骨变化，抑制了损伤引起的炎症反应。可以有效地阻止这些短期结构变化，并可以防止软骨下骨和关节软骨的长期退化，但是损伤引起的炎症在 PTOA 发展中的作用以及治疗的机会窗口尚未确定。在研究中，我们将使用我们的新型膝关节损伤小鼠模型来确定 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。在目标 1 中，我们将确定损伤的具体机制和时间过程。诱导的炎症反应，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相关。在目标 2 中，我们将评估抑制炎症细胞因子肿瘤坏死因子-� (TNF-�) 的治疗能力。白细胞介素 1 (IL-1) 和白细胞介素 6 (IL-6) 预防非侵入性膝关节损伤引发的结构性软骨和骨骼变化，这些研究结果将有助于建立“机会之窗”。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，并可能导致创伤性关节方式的根本改变。这个指导性职业发展奖将为我提供在指导团队的指导下进行专业研究和发展的资源。在指导期间，我将成功地从职业生涯的指导阶段过渡到独立研究者。。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Contribution of mechanical unloading to trabecular bone loss following non-invasive knee injury in mice.

机械卸载对小鼠非侵入性膝关节损伤后小梁骨丢失的影响。

DOI：
发表时间：
2016
期刊：
影响因子：
0
作者：
Anderson, Matthew J;Diko, Sindi;Baehr, Leslie M;Baar, Keith;Bodine, Sue C;Christiansen, Blaine A
通讯作者：
Christiansen, Blaine A

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

创伤后骨关节炎小鼠模型中加载率依赖性损伤模式的比较。

DOI：
发表时间：
2014-01
期刊：
影响因子：
0
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.

基于小鼠肢体方向的胫骨压缩过程中膝关节损伤阈值的比较。

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

Trabecular bone loss at a distant skeletal site following noninvasive knee injury in mice.

小鼠非侵入性膝关节损伤后远处骨骼部位的小梁骨丢失。

DOI：
发表时间：
2015-01
期刊：
影响因子：
0
作者：
Christiansen, Blaine A;Emami, Armaun J;Fyhrie, David P;Satkunananthan, Patrick B;Hardisty, Michael R
通讯作者：
Hardisty, Michael R

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

微型计算机断层扫描体素大小和分割方法对小鼠骨小梁微结构测量的影响。