Effect of statin intake on Non-traumatic Generalized Knee Osteoarthritis

在这项建议中，我们将确认他汀类药物对膝关节骨关节炎进展的保护作用。 无/轻度软骨下骨髓损害的非创伤性全身性骨性关节炎(GOA) 并研究他汀类药物通过血脂异常对软骨下骨的保护作用机制- 相关的非创伤性骨性关节炎小鼠模型。虽然对它的定义没有普遍的共识，但果阿是 通常被描述为有多关节受累和手关节赫伯登结节(HN)的家族性疾病。 流行病学研究表明，血脂异常和动脉粥样硬化在非 创伤性骨质疏松症(HN+)患者明显多于非骨性关节炎患者。动脉粥样硬化可能通过以下途径加速GOA(HN+) 对软骨下骨的缺血影响。高脂肪饮食也会导致骨性关节炎相关的软骨下骨损伤 在人类和老鼠身上都是如此。此外，MRI检测到的骨关节炎相关骨髓病变(BML) 与血脂异常有关。脂代谢紊乱小鼠模型的实验研究(如载脂蛋白E- (ApoE-/-)缺陷小鼠提示他汀类药物具有保护作用，他汀类药物是一线降脂药物 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，但总体来说 关于他汀类药物对骨性关节炎预后的保护作用的观察临床证据一直不一致， 这可能是由于：1)也许最重要的是，关于骨性关节炎病因的不同主题选择 和基线阶段；2)随访时间不足；3)仅使用平片进行骨关节炎进展，而不是 核磁共振检查。我们最近发表的结果表明，只有存在HN的受试者才是非 与创伤性骨性关节炎(HN+)相比，创伤性骨性关节炎(HN+)而不是HN-患者表现出较低的放射性骨关节炎进展风险 给他汀类药物的非使用者。在我们进一步的半定量MRI BML测量的初步分析中，只有非 创伤性GoA(HN+)他汀类药物没有/最小BML患者在2年内BML恶化的风险较低 复查核磁共振。根据这些结果，我们假设他汀类药物对软骨下骨具有保护作用。 无/最低基线BML的非创伤性骨质疏松症(HN+)受试者的骨骼，作为“潜在的响应者”。 协议和事件用户设计和倾向得分(PS)匹配，以根据指示进行潜在混淆 变量(OA和他汀类药物适应症)，OAI参与者中选择的一组非创伤性GoA(HN+)患者， 不使用/最小BMLS。我们进一步探讨与血脂异常相关的非高脂血症的潜在机制。 抑制软骨下骨血管缺损及相关软骨下组织的创伤性骨性关节炎小鼠模型 骨髓变形。我们将追求以下目标：1)确定他汀类药物使用之间的关联 以及对MRI、血清、尿液中软骨丢失的生物标志物和潜在的疼痛恶化的保护 2)检查基于MRI的骨关节炎相关软骨下骨改变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)确定他汀类药物的保护机制 对血脂异常相关的早期骨关节炎小鼠模型早期软骨下骨改变的影响。

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.