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: 8507602
• 负责人: Dominik R Haudenschild
• 金额: $ 16.46万
• 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 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8507602
• 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 Intervention; 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.

描述（由申请人提供）：年轻的运动人群中通常发生联合伤害，例如ACL破裂或半月板眼泪。医师承认，即使如此相对较小的关节创伤最终会发展为大多数患者的骨关节炎。尽管如此，当前的临床护理在受伤时没有任何作用，以防止未来的创伤后骨关节炎（PTOA）发作。我们的全球假设是，PTOA在关节损伤发生后始于细胞水平。有效治疗干预的最佳时间框架是在受伤后立即进行的，最佳治疗靶标将减少对损伤的急性细胞反应。我们已经开发了一种新型的全关节损伤模型来启动小鼠PTOA。施加在膝盖上的单个非侵入性机械负荷会引起ACL破裂。与人类ACL损伤相当，我们观察到急性炎症反应和关节肿胀在几天内消失，对软骨下骨，弯月面和软骨进行了广泛的重塑，以及OA（在我们的模型12周内）。我们的伤害模型的非手术性质使我们能够专注于启动OA随后进展的关节损伤的自然早期事件。关节创伤几乎立即触发急性细胞反应。急性反应阶段的特征是主要反应基因的转录激活以及关节组织中炎症细胞因子释放，这刺激了与OA有关的降解酶的产生。最近的证据表明，主要反应基因在转录伸长步骤中受到调节，而限制步骤是通过NF？b募集细胞周期蛋白依赖性激酶-9（CDK9）对转录复合物的募集。因此，CDK9激酶活性代表了一个新的分子靶标，可抑制关节损伤后急性炎症反应。特定的CDK9激酶抑制剂很容易获得，目前正在作为抗癌药物中的II期临床试验。初步数据支持我们的假设。我们证明：1）CKD9抑制剂几乎完全废除了原代人软骨细胞中的急性细胞反应，> 90％的抑制作用37个不同的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外植体中可重现，其中CDK9抑制剂还抑制了GAG释放并减少凋亡。 3）抑制急性细胞反应的治疗窗口至少在体外3小时。我们的研究策略是在关节损伤后立即确定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。这项研究的成功完成将根据抑制原发性反应炎症基因转录来定义一类新的PTOA预防药物。它将建立一个早期的治疗窗口，以防止或延迟PTOA发作。将随后转化为人类临床试验。

项目成果

Articular Cartilage Injury and Potential Remedies.

• DOI: 10.1097/bot.0000000000000462
• 发表时间: 2015-12
• 期刊: Journal of orthopaedic trauma
• 影响因子: 2.3
• 作者: Chubinskaya S;Haudenschild D;Gasser S;Stannard J;Krettek C;Borrelli J Jr
• 通讯作者: Borrelli J Jr

Bromodomain-containing-protein-4 and cyclin-dependent-kinase-9 inhibitors interact synergistically in vitro and combined treatment reduces post-traumatic osteoarthritis severity in mice.

• DOI: 10.1016/j.joca.2020.07.012
• 发表时间: 2021-01
• 期刊: Osteoarthritis and cartilage
• 影响因子: 7
• 作者: Fukui T;Yik JHN;Doyran B;Davis J;Haudenschild AK;Adamopoulos IE;Han L;Haudenschild DR
• 通讯作者: Haudenschild DR

Reply: To PMID 24470357.

回复：PMID 24470357。

• DOI: 10.1002/art.38817
• 发表时间: 2014
• 期刊: Arthritis & rheumatology (Hoboken, N.J.)
• 作者: Haudenschild,DominikR;Yik,JasperHN
• 通讯作者: Yik,JasperHN

In-vitro and in-vivo imaging of MMP activity in cartilage and joint injury.

• DOI: 10.1016/j.bbrc.2015.03.100
• 发表时间: 2015-05-08
• 期刊: BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
• 影响因子: 3.1
• 作者: Fukui, Tomoaki;Tenborg, Elizabeth;Yik, Jasper H. N.;Haudenschild, Dominik R.
• 通讯作者: Haudenschild, Dominik R.