The imbalance between osteogenesis and adipogenesis in the bone marrow is the main characteristic of osteoporosis (OP). Thus, exploring regulation of the differentiation of bone marrow stromal cells (BMSCs) into osteoblasts and adipocytes is important to identify novel targets for the treatment of OP. In the present study, the master regulator of endoplasmic reticulum (ER) stress, heat shock protein family A (Hsp70) member 5 (HSPA5) was shown to significantly accumulate in osteoblasts and adipocytes, but not in osteoclasts in bone sections from aged and postmenopausal OP mice. In vitro study revealed that HSPA5 negatively modulated osteogenic differentiation and positively promoted adipogenic differentiation, and that targeting HSPA5 with its inhibitor HA15 enhanced osteogenic differentiation and inhibited adipogenic differentiation. Also, HA15 treatment induces ER stress and autophagy, and decreases apoptosis in cells. We constructed a postmenopausal OP model in mice with ovariectomy surgery, and treated the mice with HA15. The results showed that HA15 treatment induced appropriate ER stress, activated autophagy and decreased apoptosis in osteoblasts, thereby alleviating bone loss in vivo. Our results indicated that HSPA5 participated in OP pathogenesis by regulating the differentiation of BMSCs. HSPA5 may serve as a new target for the treatment of OP, and targeting HSPA5 with HA15 prevents the progression of OP and provides a candidate therapeutic molecule for postmenopausal OP.

骨髓中成骨和脂肪生成之间的不平衡是骨质疏松症 (OP) 的主要特征。因此，探索骨髓基质细胞 (BMSC) 向成骨细胞和脂肪细胞分化的调控对于确定治疗 OP 的新靶点很重要。在本研究中，内质网 (ER) 应激的主要调节因子热休克蛋白家族 A (Hsp70) 成员 5 (HSPA5) 在成骨细胞和脂肪细胞中显着积累，但在老年和绝经后骨切片的破骨细胞中没有显着积累。 OP 老鼠。体外研究表明，HSPA5 负向调节成骨分化并正促进成脂分化，而靶向 HSPA5 及其抑制剂 HA15 可增强成骨分化并抑制成脂分化。此外，HA15 处理诱导内质网应激和自噬，并减少细胞凋亡。我们在卵巢切除手术小鼠中构建了绝经后 OP 模型，并用 HA15 治疗小鼠。结果表明，HA15治疗可诱导适当的内质网应激，激活自噬，减少成骨细胞凋亡，从而减轻体内骨质流失。. 我们的结果表明 HSPA5 通过调节 BMSCs 的分化参与了 OP 的发病机制。HSPA5 可作为治疗 OP 的新靶点，用 HA15 靶向 HSPA5 可阻止 OP 的进展并为绝经后 OP 提供候选治疗分子。