State Key Laboratory of Pharmaceutical Biotechnology, Department of Sports Medicine and Adult Reconstructive Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, P.R. China.
Joint Research Center for Bone and Joint Disease, Model Animal Research Center (MARC), Nanjing University, Nanjing, P.R. China.
FASEB J. 2020 Jun;34(6):8402-8415. doi: 10.1096/fj.201902528RRR. Epub 2020 May 4.
Bone loss is a severe complication of primary biliary cirrhosis (PBC). Trehalose was intermittently administered in bile duct-ligated (BDL) male rats, a PBC-related osteoporosis model, for 4 weeks to reduce osteoporosis. Femoral bones were assessed ex vivo by micro computed tomography (CT) and histomorphometry. The potential mechanisms related to the reduction of osteoporosis were explored by evaluating the effect of trehalose on osteoblast autophagy, osteogenesis, osteoclastogenesis, and ERK phosphorylation. The results demonstrated that trehalose reduced osteoporosis of BDL rats and decreased osteoblast-mediated osteoclast differentiation by enhancing osteoblast autophagy to regulate osteoprotegerin (OPG) secretion. Hydroxychloroquine (HCQ) increased the expression of OPG and OPG/receptor activator genes for nuclear factor-κB ligand (RANKL) ratio, and reduced osteoblast-mediated osteoclastogenesis by inhibiting autophagy flux and inducing autophagosome formation. Furthermore, trehalose increased the phosphorylation of ERK1/2 in MC3T3-E1 cells, and the ERK inhibitor PD98059 reversed the upregulation of OPG gene and reduction of trehalose-induced osteoclastogeneis. The treatment with HCQ markedly increased the ERK phosphorylation. The correlation between autophagosome formation and ERK phosphorylation was confirmed in autophagy proteins (ATG) 4B or ATG5-deficient cells. Thus, trehalose could decrease osteoblast-mediated osteoclastogenesis and reduce PBC-related bone loss by regulating ERK phosphorylation via autophagosome formation.
骨丢失是原发性胆汁性肝硬化（PBC）的严重并发症。海藻糖间歇性地给予胆管结扎（BDL）雄性大鼠，一种与 PBC 相关的骨质疏松症模型，以减少骨质疏松症。通过微计算机断层扫描（CT）和组织形态计量学对股骨进行离体评估。通过评估海藻糖对成骨细胞自噬、成骨、破骨细胞生成和 ERK 磷酸化的影响，探讨与骨质疏松症减少相关的潜在机制。结果表明，海藻糖通过增强成骨细胞自噬来调节骨保护素（OPG）的分泌，从而减少 BDL 大鼠的骨质疏松症，并减少成骨细胞介导的破骨细胞分化。羟氯喹（HCQ）通过抑制自噬流和诱导自噬体形成增加 OPG 和 OPG/核因子-κB 配体（RANKL）受体激活剂基因的表达，减少成骨细胞介导的破骨细胞生成。此外，海藻糖增加了 MC3T3-E1 细胞中 ERK1/2 的磷酸化，ERK 抑制剂 PD98059 逆转了 OPG 基因的上调和海藻糖诱导的破骨细胞生成减少。HCQ 的治疗明显增加了 ERK 磷酸化。在自噬蛋白（ATG）4B 或 ATG5 缺陷细胞中证实了自噬体形成与 ERK 磷酸化之间的相关性。因此，海藻糖通过自噬体形成调节 ERK 磷酸化，可减少成骨细胞介导的破骨细胞生成，减少 PBC 相关的骨丢失。
