Genome-Wide Association Studies to Drug: Identifying Retinoic Acid Metabolism Blocking Agents to Suppress Mechanoflammation in Osteoarthritis.

IF 2.6 4区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY
DNA and cell biology Pub Date : 2023-09-01 Epub Date: 2023-07-07 DOI:10.1089/dna.2023.0197
Linyi Zhu, Tonia L Vincent
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引用次数: 0

Abstract

Osteoarthritis (OA) is a highly prevalent debilitating joint disease for which there are currently no licensed disease-modifying treatments. The pathogenesis of OA is complex, involving genetic, mechanical, biochemical, and environmental factors. Cartilage injury, arguably the most important driving factor in OA development, is able to activate both protective and inflammatory pathways within the tissue. Recently, >100 genetic risk variants for OA have been identified through Genome Wide Association Studies, which provide a powerful tool to validate existing putative disease pathways and discover new ones. Using such an approach, hypomorphic variants within the aldehyde dehydrogenase 1 family member A2 (ALDH1A2) gene were shown to be associated with increased risk of severe hand OA. ALDH1A2 encodes the enzyme that synthesizes all-trans retinoic acid (atRA), an intracellular signaling molecule. This review summarizes the influence of the genetic variants on expression and function of ALDH1A2 in OA cartilage, its role in the mechanical injury response of cartilage, and its potent anti-inflammatory effect after cartilage injury. In doing so it identifies atRA metabolism-blocking agents as potential treatments for suppressing mechanoflammation in OA.

从全基因组关联研究到药物:鉴定维甲酸代谢阻断剂以抑制骨关节炎的机制性炎症。
骨关节炎(OA)是一种高发的使人衰弱的关节疾病,目前还没有获得许可的改变病情的治疗方法。OA 的发病机制十分复杂,涉及遗传、机械、生化和环境因素。软骨损伤可以说是导致 OA 发生的最重要驱动因素,它能够激活组织内的保护性和炎症性通路。最近,通过全基因组关联研究(Genome Wide Association Studies)发现了超过 100 个 OA 遗传风险变体,这为验证现有的推测疾病通路和发现新通路提供了强有力的工具。利用这种方法,醛脱氢酶1家族成员A2(ALDH1A2)基因中的低形变与严重手部OA风险的增加有关。ALDH1A2编码合成全反式维甲酸(atRA)的酶,atRA是一种细胞内信号分子。本综述总结了遗传变异对 OA 软骨中 ALDH1A2 表达和功能的影响、ALDH1A2 在软骨机械损伤反应中的作用及其在软骨损伤后的强效抗炎作用。因此,它确定了atRA代谢阻断剂作为抑制OA机械炎症的潜在治疗方法。
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来源期刊
DNA and cell biology
DNA and cell biology 生物-生化与分子生物学
CiteScore
6.60
自引率
0.00%
发文量
93
审稿时长
1.5 months
期刊介绍: DNA and Cell Biology delivers authoritative, peer-reviewed research on all aspects of molecular and cellular biology, with a unique focus on combining mechanistic and clinical studies to drive the field forward. DNA and Cell Biology coverage includes: Gene Structure, Function, and Regulation Gene regulation Molecular mechanisms of cell activation Mechanisms of transcriptional, translational, or epigenetic control of gene expression Molecular Medicine Molecular pathogenesis Genetic approaches to cancer and autoimmune diseases Translational studies in cell and molecular biology Cellular Organelles Autophagy Apoptosis P bodies Peroxisosomes Protein Biosynthesis and Degradation Regulation of protein synthesis Post-translational modifications Control of degradation Cell-Autonomous Inflammation and Host Cell Response to Infection Responses to cytokines and other physiological mediators Evasive pathways of pathogens.
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