Objective

Obesity is a known risk factor for knee osteoarthritis (OA). Diabetes has been associated with progression of OA and metformin is the first-line treatment in type 2 diabetes. The effect of the body mass index (BMI) and metformin on the expression of certain matrix genes in human chondrocytes is unclear. The purpose of this study was to investigate the effect of BMI and metformin on the expression of matrix genes in primary human chondrocytes.

Design

Adult female patients undergoing knee arthroplasty for end-stage OA were enrolled. Primary chondrocytes were cultivated and stimulated with metformin. Matrix gene expression was analyzed using polymerase chain reaction. Clinical data were used in multivariable regression models to assess the influence of BMI and metformin stimulation on gene expression.

Results

A total of 14 patients were analyzed. BMI was a predictor of increased expression in ADAMTS5 (β = −0.11, P = 0.03). Metformin slightly reduced expression in ADAMTS5 (β = 0.34, P = 0.04), HIF-1a (β = 0.39, P = 0.04), IL4 (β = 0.30, P = 0.02), MMP1 (β = 0.47, P < 0.01), and SOX9 (β = 0.37, P = 0.03). The hip-knee-ankle angle and proton pump inhibitors (PPIs) intake were associated with reduced SOX9 expression (β = 0.23, P < 0.01; β = 2.39, P < 0.01). Higher C-reactive protein (CRP) levels were associated with increased MMP1 expression (β = −0.16, P = 0.02).

Conclusion

We found that BMI exerts a destructive effect via induction of ADAMTS5. Metformin reduced the expression of catabolic genes ADAMTS5 and MMP1 and might play a role in disease prevention. Limb malalignment and PPI intake was associated with a reduced expression of SOX9, and higher CRP levels correlated with increased MMP1 expression, indicating a destructive process.

中文翻译：

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体重指数和二甲双胍对关节炎原代人软骨细胞基质基因表达的影响

客观的

肥胖是膝关节骨性关节炎 (OA) 的已知危险因素。糖尿病与 OA 的进展有关，二甲双胍是 2 型糖尿病的一线治疗药物。体重指数（BMI）和二甲双胍对人软骨细胞中某些基质基因表达的影响尚不清楚。本研究的目的是研究 BMI 和二甲双胍对人原代软骨细胞基质基因表达的影响。

设计

招募了因终末期 OA 接受膝关节置换术的成年女性患者。用二甲双胍培养和刺激原代软骨细胞。使用聚合酶链式反应分析基质基因表达。临床数据用于多变量回归模型，以评估 BMI 和二甲双胍刺激对基因表达的影响。

结果

共分析了 14 名患者。BMI 是 ADAMTS5 表达增加的预测因子（β = -0.11，P = 0.03）。二甲双胍在 ADAMTS5 (β = 0.34, P = 0.04)、HIF-1a (β = 0.39, P = 0.04)、IL4 (β = 0.30, P = 0.02)、MMP1 (β = 0.47, P < 0.01)中的表达略有降低, 和 SOX9 (β = 0.37, P = 0.03)。髋-膝-踝角和质子泵抑制剂 (PPI) 摄入与 SOX9 表达降低相关 (β = 0.23, P < 0.01; β = 2.39, P < 0.01)。较高的 C 反应蛋白 (CRP) 水平与增加的 MMP1 表达相关 (β = -0.16, P = 0.02)。

结论

我们发现 BMI 通过诱导 ADAMTS5 发挥破坏性作用。二甲双胍降低了分解代谢基因 ADAMTS5 和 MMP1 的表达，可能在疾病预防中发挥作用。肢体排列不齐和 PPI 摄入与 SOX9 的表达减少有关，而较高的 CRP 水平与增加的 MMP1 表达相关，表明这是一个破坏性的过程。