二甲双胍可减轻骨关节炎症状：Bcl2 和 CXCL16 基因多样性在 OA 中的作用。
Metformin attenuates symptoms of osteoarthritis: role of genetic diversity of Bcl2 and CXCL16 in OA.
机构信息
Department of Pharmacology & Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
Bone and Joint Disease Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
出版信息
Arthritis Res Ther. 2023 Mar 7;25(1):35. doi: 10.1186/s13075-023-03025-7.
OBJECTIVE
This study aimed to evaluate the effectiveness of metformin versus placebo in overweight patients with knee osteoarthritis (OA). In addition, to assess the effects of inflammatory mediators and apoptotic proteins in the pathogenesis of OA, the genetic polymorphisms of two genes, one related to apoptosis (rs2279115 of Bcl-2) and the other related to inflammation (rs2277680 of CXCL-16), were investigated.
METHODS
In this double-blind placebo-controlled clinical trial, patients were randomly divided to two groups, one group receiving metformin (n = 44) and the other one receiving an identical inert placebo (n = 44) for 4 consecutive months (starting dose 0.5 g/day for the first week, increase to 1 g/day for the second week, and further increase to 1.5 g/day for the remaining period). Another group of healthy individuals (n = 92) with no history and diagnosis of OA were included in this study in order to evaluate the role of genetics in OA. The outcome of treatment regimen was evaluated using the Knee Injury and Osteoarthritis Outcome Score (KOOS) questionnaire. The frequency of variants of rs2277680 (A181V) and rs2279115 (938C>A) were determined in extracted DNAs using PCR-RFLP method.
RESULTS
Our results indicated an increase in scores of pain (P ≤ 0.0001), activity of daily living (ADL) (P ≤ 0.0001), sport and recreation (Sport/Rec) (P ≤ 0.0001), and quality of life (QOL) (P = 0.003) and total scores of the KOOS questionnaire in the metformin group compared to the placebo group. Susceptibility to OA was associated with age, gender, family history, CC genotype of 938C>A (Pa = 0.001; OR = 5.2; 95% CI = 2.0-13.7), and GG+GA genotypes of A181V (Pa = 0.04; OR = 2.1; 95% CI = 1.1-10.5). The C allele of 938C>A (Pa = 0.04; OR = 2.2; 95% CI = 1.1-9.8) and G allele of A181V (Pa = 0.02; OR = 2.2; 95% CI = 1.1-4.8) were also associated with OA.
CONCLUSION
Our findings support the possible beneficial effects of metformin on improving pain, ADL, Sport/Rec, and QOL in OA patients. Our findings support the association between the CC genotype of Bcl-2 and GG+GA genotypes of CXCL-16 and OA.
目的
本研究旨在评估二甲双胍治疗超重膝骨关节炎（OA）患者的疗效。此外，为了评估炎症介质和凋亡蛋白在 OA 发病机制中的作用，研究了两个基因的遗传多态性，一个与凋亡相关（Bcl-2 的 rs2279115），另一个与炎症相关（CXCL-16 的 rs2277680）。
方法
在这项双盲安慰剂对照临床试验中，患者被随机分为两组，一组接受二甲双胍（n=44），另一组接受相同的惰性安慰剂（n=44），连续治疗 4 个月（起始剂量为 0.5g/天，持续一周，第二周增加至 1g/天，其余时间增加至 1.5g/天）。另一组无 OA 病史和诊断的健康个体（n=92）也纳入本研究，以评估遗传因素在 OA 中的作用。采用 KOOS 问卷评估治疗方案的疗效。使用 PCR-RFLP 法从提取的 DNA 中确定 rs2277680（A181V）和 rs2279115（938C>A）变体的频率。
结果
我们的结果表明，与安慰剂组相比，二甲双胍组的疼痛评分（P≤0.0001）、日常生活活动（ADL）评分（P≤0.0001）、运动和娱乐（Sport/Rec）评分（P≤0.0001）和生活质量（QOL）评分（P=0.003）以及 KOOS 问卷的总分均有所增加。OA 的易感性与年龄、性别、家族史、938C>A 的 CC 基因型（Pa=0.001；OR=5.2；95%CI=2.0-13.7）和 A181V 的 GG+GA 基因型（Pa=0.04；OR=2.1；95%CI=1.1-10.5）有关。938C>A 的 C 等位基因（Pa=0.04；OR=2.2；95%CI=1.1-9.8）和 A181V 的 G 等位基因（Pa=0.02；OR=2.2；95%CI=1.1-4.8）也与 OA 有关。
结论
我们的发现支持二甲双胍改善 OA 患者疼痛、ADL、Sport/Rec 和 QOL 的可能有益作用。我们的发现支持 Bcl-2 的 CC 基因型和 CXCL-16 的 GG+GA 基因型与 OA 之间的关联。
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