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

• 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
• 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' 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

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，我们将证实他汀类药物在以下受试者中对膝关节OA进展的保护作用： 无/极轻微软骨下骨髓病变（BML）的非创伤性全身性OA（果阿）为“潜在” 反应者”，并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。虽然对它的定义没有普遍的共识，但果阿是 常被描述为家族性的多关节受累和手部关节中的Heberden淋巴结（HN）。 流行病学研究表明，血脂异常和动脉粥样硬化在非肥胖人群中更为普遍。 创伤性果阿（HN+）患者比非OA受试者。动脉粥样硬化可通过以下途径加速果阿（HN+） 对软骨下骨的缺血作用。高脂肪饮食也会导致OA相关的软骨下骨损伤 在人类和老鼠身上都是如此。此外，MRI检测到的OA相关骨髓病变（BML）也很明显 与血脂异常有关。使用血脂异常小鼠模型的实验研究（例如，载脂蛋白E- ApoE缺陷（ApoE-/-）小鼠）的研究表明，一线降脂药物他汀类药物对 软骨下骨虽然实验动物研究已经证明了他汀类药物的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不一致， 这可能是由于：1）可能最重要的是，关于OA病因的异质性受试者选择 和基线阶段; 2）随访时间不足; 3）仅使用普通X线片检查OA进展，而不是 核磁共振我们最近发表的结果表明，只有存在HN作为非- 创伤性果阿（HN+），而不是HN-患者，显示放射学OA进展的风险较低， 他汀类药物非使用者。在我们对半定量MRI BML测量的进一步初步分析中，只有非 无/极轻微BML的创伤性果阿（HN+）他汀类药物使用者在2年时BML恶化的风险较低， 后续MRI。基于这些结果，我们假设他汀类药物的使用对软骨下炎有保护作用， 无/极轻微基线BML的非创伤性果阿（HN+）受试者的骨，作为“潜在缓解者”。“使用每- 方案和事件用户设计以及适应症潜在混杂的倾向评分（PS）匹配 变量（OA和他汀类药物适应症），一个选定的非创伤性果阿（HN+）OAI参与者子集， 将不使用/使用最少的BML。我们进一步研究了与血脂异常相关的非肥胖症的潜在机制， 通过抑制软骨下骨血管缺损和相关软骨下骨形成的创伤性OA小鼠模型 骨髓变形我们将追求以下目标：1）确定他汀类药物使用与 并防止MRI、血清、尿液中软骨损失的生物标志物和“潜在”疼痛恶化。 响应者。“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 他汀类药物在“潜在反应者”中的保护作用。3)确定他汀类药物保护的机制 对血脂异常相关早期OA小鼠模型中早期软骨下骨变化的影响。