Macrophages (Mφs) are master regulators of the immune response and may serve as therapeutic targets in aging societies. This study aimed to determine the function of M1Mφ-exosomes (Exos) in the development of osteoporosis (OP) and the involvement of microRNA (miR)-98 and dual specificity phosphatase 1 (DUSP1). A murine model of OP was established using ovariectomies (OVX). Bone loss was observed in OVX-treated mice, as manifested by reduced bone mineral density and decreased number of bone trabecula. The bone loss was further aggravated by treatment with M1Mφ-Exos. Exos also suppressed osteogenic differentiation of MC3T3-E1 cells. miRNA microarray analysis revealed that the miR-98 level was notably upregulated in cells after Exo treatment, and DUSP1 was confirmed as a target of miR-98. Meanwhile, downregulation of miR-98 or upregulation of DUSP1 restored the osteogenic differentiation ability of MC3T3-E1 cells. In addition, upregulation of DUSP1 reduced bone loss in murine bone tissues and suppressed JNK phosphorylation. In summary, M1Mφ-derived exosomal miR-98 exacerbates bone loss and OP by downregulating DUSP1 and activating the JNK signaling pathway. miR-98 may therefore serve as a therapeutic target in OP management.

中文翻译：

---

M1 巨噬细胞衍生的外泌体通过 microRNA-98/DUSP1/JNK 轴加重绝经后骨质疏松症的骨质流失

巨噬细胞 (Mφs) 是免疫反应的主要调节剂，可作为老龄化社会的治疗靶点。本研究旨在确定 M1Mφ-外泌体 (Exos) 在骨质疏松症 (OP) 发展中的功能以及 microRNA (miR)-98 和双特异性磷酸酶 1 (DUSP1) 的参与。使用卵巢切除术 (OVX) 建立了 OP 的小鼠模型。在 OVX 治疗的小鼠中观察到骨丢失，表现为骨矿物质密度降低和骨小梁数量减少。用 M1Mφ-Exos 治疗进一步加重了骨质流失。Exos 还抑制了 MC3T3-E1 细胞的成骨分化。miRNA微阵列分析显示，经过Exo处理后，细胞中的miR-98水平显着上调，DUSP1被证实是miR-98的靶标。同时，miR-98的下调或DUSP1的上调恢复了MC3T3-E1细胞的成骨分化能力。此外，DUSP1 的上调减少了小鼠骨组织中的骨质流失并抑制了 JNK 磷酸化。总之，M1Mφ 衍生的外泌体 miR-98 通过下调 DUSP1 和激活 JNK 信号通路加剧骨质流失和 OP。因此，miR-98 可以作为 OP 管理的治疗靶点。