Novel Early Intervention to Prevent Post-Traumatic Osteoarthritis

预防创伤后骨关节炎的新型早期干预措施

• 批准号: 8360907
• 负责人: Dominik R Haudenschild
• 金额: $ 20.79万
• 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: 2012-08-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8360907
• 关键词: Acute; Acute-Phase Reaction; Age; Antineoplastic Agents; Apoptosis; Arthritis; Athletic; Bone remodeling; CDK9 Protein Kinase; Cartilage; Cells; Chondrocytes; Clinical Trials; Complex; Contralateral; Data; Degenerative polyarthritis; Development; Early treatment; Effectiveness; Enzymes; Event; Foundations; Future; GAG Gene; Gene Activation; Gene Expression; Genes; Genetic Transcription; Goals; Hour; Human; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Injury; Interleukin-1; Joints; Knee; Mechanics; Meniscus structure of joint; Minor; Modeling; Molecular Target; Mus; Nature; Patients; Peptide Hydrolases; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Phosphotransferases; Physicians; Plants; Population; Prevention; Production; Repression; Research; Saline; Serum; Swelling; Testing; Therapeutic Intervention; Time; Tissues; Transcription Elongation; Transcriptional Activation; Translations; Trauma; Treatment Effectiveness; Vision; Visit; anterior cruciate ligament rupture; base; bone; clinical care; cytokine; in vivo; inhibitor/antagonist; injured; joint injury; kinase inhibitor; mouse model; novel; osteochondral tissue; patient population; prevent; response; response to injury; therapeutic target; treatment strategy

DESCRIPTION (provided by applicant): Joint injuries such as ACL ruptures or meniscal tears typically occur in a young athletic population. Physicians acknowledge that even such relatively minor joint traumas ultimately progress to osteoarthritis in a majority of patients. Despite this, current clinical care does nothing at the time of injury to prevent the future onset of post-traumatic osteoarthritis (PTOA). Our global hypothesis is that PTOA begins at the cellular level just after joint injury occurs. The optimal time frame for effective therapeutic intervention is immediately after the injury, and the optimal therapeutic target will reduce the acute cellular response to the injury. We have developed a novel whole-joint injury model to initiate PTOA in mice. A single non-invasive mechanical load applied to the knee induces ACL rupture. Comparable to human ACL injuries, we observe an acute inflammatory response and joint swelling that resolves in a few days, extensive remodeling of subchondral bone, meniscus and cartilage, and OA (within 12 weeks in our model). The non-surgical nature of our injury model uniquely allows us to focus on the natural early events of joint injury that initiate the subsequen progression of OA. Joint trauma almost immediately triggers an acute cellular response. The acute response phase is characterized by the transcriptional activation of primary response genes and the release of inflammatory cytokines from joint tissues, which stimulates production of degradative enzymes involved with OA. Very recent evidence demonstrates that primary response genes are regulated at the transcription elongation step, with the rate-limiting step being the recruitment of cyclin-dependent kinase-9 (cdk9) to the transcription complex by NF?B. Thus, cdk9 kinase activity represents a new molecular target to inhibit the acute inflammatory response after joint injury. Specific cdk9 kinase inhibitors are readily available, an are currently in phase II clinical trials as anti-cancer drugs. Preliminary data support our hypothesis. We demonstrate that: 1) the acute cellular response in primary human chondrocytes is almost completely abolished by ckd9 inhibitor, with >90% repression of 37 different IL-1? induced genes, 2) these cell-based results were reproducible in cultured human osteochondral explants, in which cdk9 inhibitor also inhibits GAG release and decreases apoptosis; and 3) the treatment window to inhibit the acute cellular response is at least 3 hours in vitro. Our research strategy is to determine the time course of cdk9-dependent gene transcription immediately following joint injury, and then to assess the ability of cdk9 inhibitors to alter OA progression. Successful completion of this study will define a new class of PTOA prevention drugs based on inhibition of primary response inflammatory gene transcription. It will establish an early treatment window for joint injuries to prevent or delay the onset of PTOA. Translation to human clinical trials will follow. PUBLIC HEALTH RELEVANCE: Joint injuries such as ACL ruptures or meniscal tears typically happen in a young and active patient population. Physicians acknowledge the fact that even these relatively minor joint traumas ultimately progress to PTOA in a majority of patients after a 10- to 20-year lag phase. Despite this, current clinical care does nothing at the time of injury to prevent the future onset of PTOA. Our global hypothesis is that PTOA actually begins at the cellular level just after an injury occurs, and thus the optimal time frame for therapeutic intervention is also just after the injury. The goal of this proposal is to develop an early treatmnt strategy, administered just after a joint injury, which will prevent the future onset of PTOA. Join trauma almost immediately triggers an acute cellular response. This acute cellular response then activates many genes that promote joint degradation and arthritis progression. Recent studies have identified that a single enzyme is an absolute requirement during the acute cellular response. We propose a treatment strategy to specifically inhibit this critical enzyme shortly after a joint is injured, and thereby prevent the acute cellular response from occurring. Our hypothesis is that this will delay or even prevent the future onset of PTOA. We will test this hypothesis in a mouse model of ACL rupture, and this will lay the foundation for human clinical trials. Our vision is to provide clinicians with a treatment option that they can prescribe to join injury patients during their first visit to delay or prevent the onset of PTOA. This will reduce th future burden of PTOA for today's young and active population.

描述（由申请人提供）：关节损伤，如ACL断裂或踝关节撕裂，通常发生在年轻的运动人群中。医生们承认，即使是这种相对较小的关节创伤，在大多数患者中最终也会发展为骨关节炎。尽管如此，目前的临床护理在受伤时并没有预防创伤后骨关节炎（PTOA）的未来发作。我们的总体假设是PTOA在关节损伤发生后立即在细胞水平开始。有效治疗干预的最佳时间范围是在损伤后立即进行，并且最佳治疗靶点将减少对损伤的急性细胞反应。我们已经开发了一种新的全关节损伤模型，在小鼠中启动PTOA。对膝关节施加单一非侵入性机械载荷会导致ACL断裂。与人类ACL损伤相比，我们观察到急性炎症反应和关节肿胀在几天内消退，软骨下骨、半月板和软骨的广泛重塑以及OA（在我们的模型中在12周内）。我们的损伤模型的非手术性质使我们能够专注于关节损伤的自然早期事件，这些事件引发了OA的快速进展。关节创伤几乎立即引发急性细胞反应。急性反应期的特征在于初级反应基因的转录激活和炎性细胞因子从关节组织的释放，其刺激与OA相关的降解酶的产生。最近的证据表明，主要的反应基因在转录延伸的步骤进行调节，与限速步骤是招聘的细胞周期蛋白依赖性激酶-9（cdk 9）的转录复合物的NF？B。因此，cdk 9激酶活性代表了抑制关节损伤后急性炎症反应的新分子靶点。特异性cdk 9激酶抑制剂是容易获得的，并且目前作为抗癌药物处于II期临床试验中。初步数据支持我们的假设。我们证明：1）原代人软骨细胞中的急性细胞反应几乎被ckd 9抑制剂完全消除，37种不同的IL-1？诱导的基因，2）这些基于细胞的结果在培养的人骨软骨细胞外植体中是可再现的，其中cdk 9抑制剂还抑制GAG释放并减少细胞凋亡;和3）抑制急性细胞应答的治疗窗口在体外为至少3小时。我们的研究策略是确定关节损伤后cdk 9依赖性基因转录的时间进程，然后评估cdk 9抑制剂改变OA进展的能力。这项研究的成功完成将定义一类新的基于抑制原发性反应炎症基因转录的PTOA预防药物。它将为关节损伤建立一个早期治疗窗口，以预防或延迟PTOA的发作。随后将进行人体临床试验。 公共卫生相关性：关节损伤，如ACL断裂或踝关节撕裂，通常发生在年轻和活跃的患者人群中。医生们承认，即使是这些相对较小的关节创伤，在10- 20年的滞后期后，大多数患者最终也会进展为PTOA。尽管如此，目前的临床护理在受伤时对 防止未来PTOA的发生。我们的总体假设是，PTOA实际上是在损伤发生后立即在细胞水平开始的，因此治疗干预的最佳时间范围也是在损伤后。该提案的目标是开发一种早期治疗策略，在关节损伤后立即实施，这将防止PTOA未来的发作。创伤几乎立即引发急性细胞反应。这种急性细胞反应然后激活许多促进关节退化和关节炎进展的基因。最近的研究已经确定，在急性细胞反应期间，单一酶是绝对需要的。我们提出了一种治疗策略，在关节受伤后不久特异性抑制这种关键酶，从而防止急性细胞反应的发生。我们的假设是，这将延迟甚至防止PTOA的未来发作。我们将在ACL断裂的小鼠模型中测试这一假设，这将为人类临床试验奠定基础。我们的愿景是为临床医生提供一种治疗选择，他们可以在首次就诊时与受伤患者一起开处方，以延迟或预防PTOA的发生。这将减少PTOA对当今年轻和活跃人口的未来负担。