骨质减少和骨质疏松症是最常见的代谢性骨疾病之一,代表着主要的公共卫生问题。患者骨折风险增加。糖尿病是导致骨量减少和骨质疏松症的最常见疾病之一。然而,糖尿病引起的骨量减少和骨质疏松的潜在机制尚不清楚.骨重建,包括骨的形成和吸收,是一个动态的过程。大电导Ca2+-激活的K+通道(BK通道)调节骨髓间充质干细胞的功能,成骨细胞,和破骨细胞。我们先前的研究揭示了BK通道在生理条件下通过各种途径与成骨细胞功能之间的关系。在这项研究中,我们报道了糖尿病诱导的骨量减少小鼠中BK通道的表达下降。BK缺乏增强线粒体Ca2+和激活经典PINK1(PTEN诱导的推定激酶1)-PRKN/Parkin(parkinRBRE3泛素蛋白连接酶)依赖性线粒体自噬,而BK通道的上调抑制了成骨细胞的线粒体自噬。此外,SLC25A5/ANT2(溶质载体家族25(线粒体载体,腺嘌呤核苷酸转运蛋白),成员5),参与PINK1-PRKN依赖性线粒体自噬的关键线粒体内膜蛋白,也受BK通道调控。总的来说,这些数据确定了BK通道在调节成骨细胞线粒体自噬中的新作用,这可能是糖尿病引起的骨骼疾病的潜在目标。
Osteopenia and osteoporosis are among the most common metabolic bone diseases and represent major public health problems, with sufferers having an increased fracture risk. Diabetes is one of the most common diseases contributing to osteopenia and osteoporosis. However, the mechanisms underlying diabetes-induced osteopenia and osteoporosis remain unclear. Bone reconstruction, including bone formation and absorption, is a dynamic process. Large-conductance Ca2+-activated K+ channels (BK channels) regulate the function of bone marrow-derived mesenchymal stem cells, osteoblasts, and osteoclasts. Our previous studies revealed the relationship between BK channels and the function of osteoblasts via various pathways under physiological conditions. In this study, we reported a decrease in the expression of BK channels in mice with diabetes-induced osteopenia. BK deficiency enhanced mitochondrial Ca2+ and activated classical PINK1 (PTEN induced putative kinase 1)-PRKN/Parkin (parkin RBR E3 ubiquitin protein ligase)-dependent mitophagy, whereas the upregulation of BK channels inhibited mitophagy in osteoblasts. Moreover, SLC25A5/ANT2 (solute carrier family 25 (mitochondrial carrier, adenine nucleotide translocator), member 5), a critical inner mitochondrial membrane protein participating in PINK1-PRKN-dependent mitophagy, was also regulated by BK channels. Overall, these data identified a novel role of BK channels in regulating mitophagy in osteoblasts, which might be a potential target for diabetes-induced bone diseases.Abbreviations: AGE, advanced glycation end products; Baf A1, bafilomycin A1; BK channels, big-conductance Ca2+-activated K+ channels; BMSCs, bone marrow-derived mesenchymal stem cells; BSA, bovine serum albumin; FBG, fasting blood glucose; IMM, inner mitochondrial membrane; ITPR1, inositol 1,4,5-trisphosphate receptor 1; MAM, mitochondria-associated ER membrane; OMM, outer mitochondrial membrane; PINK1, PTEN induced putative kinase 1; PPID/CyP-D, peptidylprolyl isomerase D (cyclophilin D); PRKN/PARK2, parkin RBR E3 ubiquitin protein ligase; ROS, reactive oxygen species; SLC25A5/ANT2, solute carrier family 25 (mitochondrial carrier, adenine nucleotide translocator), member 5; STZ, streptozotocin.