Novel Early Intervention to Prevent Post-Traumatic Osteoarthritis

描述（由申请人提供）：关节损伤如前交叉韧带断裂或半月板撕裂通常发生在年轻的运动人群中。医生承认，即使是这种相对较小的关节创伤最终也会在大多数患者中发展为骨关节炎。尽管如此，目前的临床护理并没有在受伤时预防创伤后骨关节炎（pta）的未来发作。我们的总体假设是，在关节损伤发生后的细胞水平上，pta开始发生。有效治疗干预的最佳时间框架是在损伤后立即进行，最佳治疗目标将减少对损伤的急性细胞反应。我们开发了一种新的全关节损伤模型来启动小鼠的PTOA。单次非侵入性机械负荷作用于膝关节导致前交叉韧带破裂。与人类前交叉韧带损伤相比，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引发骨性关节炎随后进展的关节损伤的自然早期事件。关节创伤几乎会立即引发急性细胞反应。急性反应期的特点是主要反应基因的转录激活和关节组织中炎症细胞因子的释放，这刺激了与OA相关的降解酶的产生。最近的证据表明，主要应答基因在转录延伸阶段受到调控，而限速阶段是NF - B向转录复合体募集周期蛋白依赖性激酶-9 （cdk9）。因此，cdk9激酶活性是抑制关节损伤后急性炎症反应的一个新的分子靶点。特异性cdk9激酶抑制剂很容易获得，目前作为抗癌药物正在进行II期临床试验。初步数据支持我们的假设。我们证明：1)原发性人软骨细胞的急性细胞反应几乎完全被ckd9抑制剂所消除，其中>抑制了37种不同的IL-1？2)这些基于细胞的结果在体外培养的人骨软骨外植体中可重复，cdk9抑制剂也能抑制GAG释放并减少细胞凋亡；3)体外抑制急性细胞反应的治疗窗口期至少为3小时。我们的研究策略是确定关节损伤后cdk9依赖性基因转录的时间过程，然后评估cdk9抑制剂改变OA进展的能力。本研究的成功完成将定义一类新的基于抑制初级反应炎症基因转录的pta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pta的发作。随后将转化为人体临床试验。

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.