Preclinical studies have found impaired osteogenic differentiation to be associated with type 2 diabetes (T2DM), which is related to skeletal accumulation of advanced glycation end products (AGEs). Our previous study also showed impaired osteogenic differentiation in peripheral blood-derived mononuclear cells (PBMC) isolated from patients with long-standing T2DM, which is conceivably due to the overexpression of receptor of advance glycation end products (RAGE) and the enhancement of cellular apoptosis. However, the existence of RAGE overexpression in earlier stages of diabetes remains unclear, as do the factors influencing that RAGE overexpression. This cross-sectional study enrolled 40 patients with T2DM treated with metformin monotherapy and 30 age-matched non-diabetic controls (NDM) to investigate the overexpression of RAGE in PBMC derived from patients with earlier stage diabetes, as well as to explore its determining factors. Almost all (90%) PBMC-isolated from NDM (NDM-pD) expressed osteoblast-specific genes including ALPL, BGLAP, COL1A1, and RUNX2/PPAR while only 40% of PBMC-derived from diabetic patients (DM-pD) expressed those genes. By using age- and pentosidine-matched NDM-pD as a reference, AGER and BAX/BCL2 expression in PBMC isolated from diabetic patients showing impaired osteoblast-specific gene expression (DM-iD) were 6.6 and 5 folds higher than the reference while AGER and BAX/BCL2 expression in DM-pD were comparable to the reference. AGER expression showed a significant positive correlation with age (r=0.470, p=0.003). The multivariate analysis demonstrated that both age and AGER expression correlated with the potential for osteogenic differentiation in the PBMC isolated from patients with diabetes. In conclusion, this study showed osteogenic differentiation impairment in approximately half of PBMC derived from type 2 diabetic patients receiving metformin monotherapy. Both AGER and BAX/BCL2 overexpression were demonstrated only in PBMC-isolated from diabetic patients with poor osteogenic differentiation. Therefore, this study not only illustrated the existence of RAGE overexpression in PBMC derived from patients with early stages of T2DM but also strengthened the linkage between that RAGE overexpression and the retardation of osteogenic differentiation. Age was also shown to be a positive influencing factor for RAGE overexpression. Furthermore, both age and RAGE overexpression were demonstrated as independent risk factors for determining osteogenic differentiation potential of the PBMC-isolated from T2DM.

中文翻译：

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受年龄影响的晚期糖基化终产物过度表达受体与 2 型糖尿病患者的成骨分化障碍相关。

临床前研究发现成骨分化受损与 2 型糖尿病 (T2DM) 相关，这与晚期糖基化终产物 (AGEs) 的骨骼积累有关。我们之前的研究还表明，从长期 T2DM 患者中分离的外周血来源的单个核细胞 (PBMC) 的成骨分化受损，这可能是由于高级糖基化终产物受体 (RAGE) 的过表达和细胞凋亡的增强. 然而，在糖尿病早期阶段是否存在 RAGE 过表达仍不清楚，影响 RAGE 过表达的因素也是如此。这项横断面研究招募了 40 名接受二甲双胍单药治疗的 T2DM 患者和 30 名年龄匹配的非糖尿病对照 (NDM)，以调查早期糖尿病患者的 PBMC 中 RAGE 的过表达，并探讨其决定因素. 几乎所有 (90%) 从 NDM 分离的 PBMC (NDM-pD) 都表达成骨细胞特异性基因，包括 ALPL、BGLAP、COL1A1 和 RUNX2/PPAR，而只有 40% 来自糖尿病患者 (DM-pD) 的 PBMC 表达了这些基因。通过使用年龄和戊糖苷匹配的 NDM-pD 作为参考，从显示受损的成骨细胞特异性基因表达 (DM-iD) 的糖尿病患者分离的 PBMC 中的 AGER 和 BAX/BCL2 表达分别比参考高 6.6 和 5 倍，而 AGER和 DM-pD 中的 BAX/BCL2 表达与参考相当。AGER 表达与年龄呈显着正相关（r=0.470，p=0.003）。多变量分析表明，年龄和 AGER 表达都与从糖尿病患者分离的 PBMC 中成骨分化的潜力相关。总之，这项研究显示，大约一半来自接受二甲双胍单药治疗的 2 型糖尿病患者的 PBMC 中存在成骨分化障碍。AGER 和 BAX/BCL2 过表达仅在从具有较差成骨分化的糖尿病患者中分离出来的 PBMC 中得到证实。因此，本研究不仅说明了来自早期 T2DM 患者的 PBMC 中存在 RAGE 过表达，而且加强了 RAGE 过表达与成骨分化阻滞之间的联系。年龄也被证明是 RAGE 过度表达的积极影响因素。此外，年龄和 RAGE 过表达都被证明是确定从 T2DM 分离的 PBMC 的成骨分化潜能的独立危险因素。