Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing 210029, Jiangsu Province, China.
Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing 210029, Jiangsu Province, China.
Aging (Albany NY). 2020 Feb 3;12(3):2084-2100. doi: 10.18632/aging.102723.
The dysfunction of bone marrow stromal cells (BMSCs) may be a core factor in Type 2 diabetes mellitus (T2DM) associated osteoporosis. However, the underlying mechanism is not well understood. Here, we delineated the critical role of insulin impeding osteogenesis of BMSCs in T2DM. Compared with BMSCs from healthy people (H-BMSCs), BMSCs from T2DM patient (DM-BMSCs) showed decreased osteogenic differentiation and autophagy level, and increased senescent phenotype. H-BMSCs incubated in hyperglycemic and hyperinsulinemic conditions similarly showed these phenotypes of DM-BMSCs. Notably, enhanced TGF-β1 expression was detected not only in DM-BMSCs and high-glucose and insulin-treated H-BMSCs, but also in bone callus of streptozocin-induced diabetic rats. Moreover, inhibiting TGF-β1 signaling not only enhanced osteogenic differentiation and autophagy level of DM-BMSCs, but also delayed senescence of DM-BMSCs, as well as promoted mandible defect healing of diabetic rats. Finally, we further verified that it was TGF-β receptor II (TβRII), not TβRI, markedly increased in both DM-BMSCs and insulin-treated H-BMSCs. Our data revealed that insulin impeded osteogenesis of BMSCs by inhibiting autophagy and promoting premature senescence, which it should be responsible for T2DM-induced bone loss, at least in part. These findings suggest that inhibiting TGF-β1 pathway may be a potential therapeutic target for T2DM associated bone disorders.
骨髓基质细胞 (BMSCs) 的功能障碍可能是 2 型糖尿病 (T2DM) 相关骨质疏松症的核心因素。然而，其潜在机制尚不清楚。在这里，我们阐述了胰岛素阻碍 BMSCs 成骨作用在 T2DM 中的关键作用。与来自健康人的 BMSCs (H-BMSCs) 相比，来自 T2DM 患者的 BMSCs (DM-BMSCs) 表现出成骨分化和自噬水平降低，以及衰老表型增加。在高血糖和高胰岛素条件下孵育的 H-BMSCs 也表现出 DM-BMSCs 的这些表型。值得注意的是，不仅在 DM-BMSCs 和高糖和胰岛素处理的 H-BMSCs 中检测到增强的 TGF-β1 表达，而且在链脲佐菌素诱导的糖尿病大鼠的骨痂中也检测到了增强的 TGF-β1 表达。此外，抑制 TGF-β1 信号通路不仅增强了 DM-BMSCs 的成骨分化和自噬水平，而且延缓了 DM-BMSCs 的衰老，同时促进了糖尿病大鼠下颌骨缺损的愈合。最后，我们进一步证实，不仅是 DM-BMSCs，而且是胰岛素处理的 H-BMSCs 中，TGF-β 受体 II (TβRII) 而不是 TβRI 明显增加。我们的数据表明，胰岛素通过抑制自噬和促进过早衰老来阻碍 BMSCs 的成骨作用，这至少部分是导致 T2DM 引起的骨丢失的原因。这些发现表明，抑制 TGF-β1 途径可能是治疗 T2DM 相关骨疾病的潜在靶点。
