M1 macrophage‐derived exosomes aggravate bone loss in postmenopausal osteoporosis via a microRNA‐98/DUSP1/JNK axis

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.