Effect of statin intake on Non-traumatic Generalized Knee Osteoarthritis

他汀类药物摄入量对非创伤性全身性膝骨关节炎的影响

基本信息

批准号：
10280684
负责人：
Shadpour Demehri
金额：
$ 37.45万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-22 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10280684
关键词：
3-Dimensional Address Animals Apolipoprotein E Area Atherosclerosis Biological Markers Blood Vessels Body Weight Bone Marrow C-terminal Cardiovascular Diseases Cartilage Cells Clinical Clinical Trials Collagen Consensus Data Defect Degenerative polyarthritis Diagnostic radiologic examination Disease Dose Dyslipidemias Etiology Genetic Predisposition to Disease Hand Heberden&apos s Node High Fat Diet Human Image Inbred CBA Mice Infarction Intake Investigation Joints Knee Knee Injuries Knee Osteoarthritis Knee joint Lead Lesion Link Lipids Longitudinal cohort Magnetic Resonance Imaging Measurement Measures Medicare claim Modeling Morphology Mus Observational Study Osteogenesis Outcome Pain Participant Patient Self-Report Patients Pharmaceutical Preparations Prevalence Proteins Protocols documentation Publishing Resources Risk Role Serum Structure Subjects Selections Symptoms Testing Therapeutic Effect Time Uncertainty Urine Western Ontario and McMaster Universities Arthritis Index Wild Type Mouse angiogenesis articular cartilage base cartilage degradation clinical examination clinical practice cohort design epidemiology study experimental study follow-up hazard indexing microangiography morphometry mouse model novel protective effect senescence subchondral bone urinary

项目摘要

In this proposal, we will confirm of statins’ protective effects against knee OA progression statins in subjects with non-traumatic generalized OA (GOA) with no/minimal subchondral bone marrow lesions (BMLs) as “potential responders” and investigate the mechanism for statin protective effect on subchondral bone using dyslipidemia- associated non-traumatic OA mice models. While there is no universal consensus on its definition, GOA is commonly described as familial with polyarticular involvement and Heberden's nodes (HNs) in hand joints. Epidemiologic studies have shown that dyslipidemia and atherosclerosis are more prevalent among non- traumatic GOA (HN+) patients than non-OA subjects. Atherosclerosis may accelerate the GOA (HN+) through the ischemic effect on subchondral bone. A high-fat diet can also lead to OA-related subchondral bone damage both in humans and mice. Besides, OA-related bone marrow lesions (BMLs) detected by MRI are strongly associated with dyslipidemia. Experimental studies using dyslipidemia mice models (e.g., Apolipoprotein E- deficient (ApoE-/-) mice) have suggested a protective role for statins, first-line lipid-lowering drugs, on subchondral bone. While experimental animal studies have demonstrated a DMOAD role for statins, the overall observational clinical evidence for the protective effects of statins on OA outcomes have been inconsistent, which could be due to: 1) perhaps most importantly, heterogeneous subject selection with regard to OA etiology and baseline stage; 2) insufficient follow-up time; 3) use of only plain radiographs for OA progression rather than MRI. Our recently published results showed that only subjects with the presence of HN as the hallmark of non- traumatic GOA (HN+), but not HN– patients, show the lower hazard of radiographic OA progression compared to statins nonusers. In our further preliminary analysis of semiquantitative MRI BML measurements, only non- traumatic GOA (HN+) statin users with no/minimal BML demonstrated a lower risk of BML worsening at a 2-year follow-up MRI. Based on these results, we hypothesize that statin use has a protective effect on subchondral bone in non-traumatic GOA (HN+) subjects with no/minimal baseline BML, as “potential responders." Using per- protocol and incident user design and propensity score (PS) matching for potential confounding by indication variables (OA and statin indications), a selected subset of OAI participants with non-traumatic GOA (HN+) with no/minimal BMLs will be used. We further investigate the underlying mechanism in dyslipidemia-associated non- traumatic OA mice models through inhibiting subchondral bone vascular defects and associated subchondral bone marrow deformation. We will pursue the following aims: 1) Determine the association between statin use and protection against MRI, serum, urine biomarkers of cartilage loss, and pain worsening in "potential responders." 2) Examine the role of MRI-based OA-related subchondral bone changes as intermediary variables for the protective effect of statins in “potential responders.” 3) Determine the mechanism for statin protective effect on early subchondral bone change in dyslipidemia-associated early OA mice models.

在本提案中，我们将确认他汀类药物对膝关节 OA 进展的保护作用无/极少软骨下骨髓病变 (BML) 的非创伤性全身性 OA (GOA) 作为“潜在的反应者”并利用血脂异常研究他汀类药物对软骨下骨的保护作用机制- 相关的非创伤性 OA 小鼠模型虽然对其定义尚未达成普遍共识，但 GOA 是通常被描述为家族性多关节受累和手关节赫伯登结节 (HN)。流行病学研究表明，非正常人群中血脂异常和动脉粥样硬化更为普遍。创伤性GOA（HN+）患者比非OA受试者可能加速GOA（HN+）的通过。高脂肪饮食也会导致骨关节炎相关的软骨下骨损伤。此外，MRI 检测到的与 OA 相关的骨髓病变 (BML) 也很明显。与血脂异常相关的实验研究使用血脂异常小鼠模型（例如载脂蛋白E-）缺陷（ApoE-/-）小鼠）表明他汀类药物（一线降脂药物）对虽然实验动物研究已经证明他汀类药物具有 DMOAD 作用，但总体而言他汀类药物对 OA 结局的保护作用的观察性临床证据并不一致，这可能是由于：1）也许最重要的是，关于 OA 病因学的异质受试者选择和基线阶段；2) 随访时间不足；3) 仅使用 X 线平片来判断 OA 进展情况我们最近发表的结果表明，只有以 HN 为标志的受试者才具有非 HN 的特征。相比之下，创伤性 GOA (HN+)（而非 HN– 患者）的放射学 OA 进展风险较低在我们对半定量 MRI BML 测量的进一步初步分析中，只有非他汀类药物使用者。没有/极少 BML 的创伤性 GOA (HN+) 他汀类药物使用者在 2 年中表现出 BML 延长的风险较低基于这些结果，我们推测他汀类药物的使用对软骨下有保护作用。没有/最低基线 BML 的非创伤性 GOA (HN+) 受试者的骨骼，作为“潜在反应者”。协议和事件用户设计和倾向评分 (PS) 匹配，以消除指示中潜在的混淆变量（OA 和他汀类药物适应症），选定的患有非创伤性 GOA (HN+) 的 OAI 参与者子集我们将进一步研究血脂异常相关的非相关的潜在机制。通过抑制软骨下骨血管缺陷和相关软骨下骨损伤小鼠模型我们将追求以下目标：1）确定他汀类药物使用之间的关联。以及针对“潜在”软骨损失和疼痛恶化的 MRI、血清、尿液生物标志物的保护 2) 检查基于 MRI 的 OA 相关软骨下骨变化作为中介变量的作用确定他汀类药物对“潜在反应者”的保护作用。3) 确定他汀类药物的保护机制对血脂异常相关的早期 OA 小鼠模型早期软骨下骨变化的影响。