Department of Spinal Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China.
Curr Med Chem. 2024;31(27):4392-4405. doi: 10.2174/0109298673287134231121050158.
Osteoarthritis (OA) represents a persistent degenerative joint ailment. As OA advances, profound joint pain coupled with diminished joint function inflicts substantial physical distress and psychological strain on patients. Presently, pharmacological solutions for arthritis remain limited, primarily encompassing analgesics and joint replacement surgical procedures. Hence, non-operative strategies to mitigate osteoarthritis progression have captured significant attention in orthopedic research.
This study aims to discern a definitive causal linkage between ADAMTS-4/5 and osteoarthritis through Mendelian randomization analysis. Moreover, it seeks to anticipate the therapeutic efficacy of a suite of emergent hydroxyquinolines for osteoarthritis using the Quantitative Structure-Activity Relationship (QSAR) methodology.
Within this study, genetic variants specific to knee osteoarthritis were procured as exposure variables from a genome-wide association study (GWAS). Genetic variant data for ADAMTS-4/5 served as the endpoint to evaluate the causal nexus employing univariate Mendelian randomization. This analysis underpins the hypothesis that ADAMTS-4/5 presents a promising therapeutic target for osteoarthritis management. The suppressive properties of novel hydroxyquinolines against ADAMTS-4/5 were subsequently examined through conformational analyses, underscoring the potential of these compounds as therapeutic candidates for osteoarthritis.
IVW outcomes from the Mendelian randomization revealed a significant association of KOA (OR: 1.1675, 95% CI: 1.0003-1.3627, P = 0.0495) with ADAMTS-5. However, KOA (OR: 1.0801, 95% CI: 0.9256-1.2604, P = 0.3278) displayed no evident connection with ADAMTS-4. Notably, the instrumental variables manifested neither heterogeneity nor horizontal pleiotropy. In this research endeavor, 16 pharmacological models were formulated via the CoMSIA method within 3D conformational relationship evaluations. A synergistic interplay of hydrophobic, spatial, and hydrogen-bonded receptor domains emerged as the most predictively potent. The cross-validation coefficient q2 for the optimum model stood at 0.716, with a principal component score of 5, a regression coefficient r2 of 0.971, a standard estimation error of 0.351, and an f-value of 156.951. Such metrics intimate the commendable predictive prowess of our devised CoMSIA models.
The research unearthed a robust causal interrelation between ADAMTS-5 and osteoarthritis via Mendelian randomization. Furthermore, a credible drug model targeting ADAMTS-5 was constructed. Collectively, these findings illuminate a path forward in the pursuit of target-specific drugs for osteoarthritis management in subsequent investigations.
骨关节炎（OA）是一种持续的退行性关节疾病。随着 OA 的发展，严重的关节疼痛加上关节功能下降，给患者带来了巨大的身体痛苦和心理压力。目前，关节炎的药物治疗仍然有限，主要包括镇痛药和关节置换手术。因此，减轻骨关节炎进展的非手术策略在骨科研究中引起了广泛关注。
本研究旨在通过孟德尔随机分析确定 ADAMTS-4/5 与骨关节炎之间的明确因果关系。此外，还使用定量构效关系（QSAR）方法预测一系列新型羟基喹啉类化合物对骨关节炎的治疗效果。
在本研究中，作为暴露变量，从全基因组关联研究（GWAS）中获取了特定于膝关节骨关节炎的遗传变异。ADAMTS-4/5 的遗传变异数据作为终点，通过单变量孟德尔随机分析评估因果关系。该分析支持 ADAMTS-4/5 作为骨关节炎管理的有前途的治疗靶点的假设。通过构象分析研究了新型羟基喹啉类化合物对 ADAMTS-4/5 的抑制作用，强调了这些化合物作为骨关节炎治疗候选物的潜力。
孟德尔随机分析的 IVW 结果显示，KOA（OR：1.1675，95%CI：1.0003-1.3627，P=0.0495）与 ADAMTS-5 显著相关。然而，KOA（OR：1.0801，95%CI：0.9256-1.2604，P=0.3278）与 ADAMTS-4 没有明显联系。值得注意的是，工具变量既没有表现出异质性，也没有表现出水平的多效性。在这项研究中，通过 3D 构象关系评估，共建立了 16 个基于 CoMSIA 方法的药理学模型。最具预测能力的是疏水性、空间性和氢键受体域的协同相互作用。最佳模型的交叉验证系数 q2 为 0.716，主成分得分 5，回归系数 r2 为 0.971，标准估计误差为 0.351，f 值为 156.951。这些指标表明，我们设计的 CoMSIA 模型具有令人称赞的预测能力。
通过孟德尔随机分析发现了 ADAMTS-5 与骨关节炎之间的稳健因果关系。此外，构建了针对 ADAMTS-5 的可信药物模型。总的来说，这些发现为后续研究中针对骨关节炎管理的靶向药物的探索指明了方向。
