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

Abstract

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.

Comprehensive analysis of M2 macrophage-derived exosomes facilitating osteogenic differentiation of human periodontal ligament stem cells

“…In fact, there is a lack of studies on the effect of macrophage polarization on the osteogenic differentiation of hPDLSCs. However, the role of macrophage polarization in bone homeostasis of OTM is well documented, with M2 macrophages contributing to the periodontal tissue remodeling process [27][28][29] and M1 macrophages favoring osteoclastogenesis, periodontal tissue inflammation and bone loss [30][31][32]. Notably, previous studies have demonstrated that, under normal conditions, PDLSCs promote macrophage polarization toward M2, which facilitates the regeneration of periodontal tissue [15,33]; In response to lipopolysaccharide or force induction, PDLSCs then increase the ratio of M1/M2 macrophages, which contributes to inflammatory bone remodeling and OTM processes [18,34].…”

Immunoporosis: Role of immune system in the pathophysiology of different types of osteoporosis

“…found that extracellular vesicles (EVs), which contain protein and micro-RNA cargo, are secreted by some cells and endocytosed by target cells whose function is affected by those EVs’ cargo ( 25 ). Although macrophage-derived EVs contain different types of miRNAs, the current mainstream view is that naïve (M0) and M2-derived EVs promote repair/regeneration and M1 EVs inhibit bone repair and promote bone loss ( 26 , 27 ). Interestingly, mesenchymal stem cell-derived EVs affect the activity and polarization of macrophages ( 28 , 29 ), suggesting the interaction between mesenchymal stem cells and immune cells.…”

MSC-EV therapy for bone/cartilage diseases

“…Ovariectomy is a widely used, reproducible post-menopausal osteoporotic model that can be applied to various species including mice ( Cui et al, 2022 ; Hu et al, 2020b ; Li et al, 2016 ; Yahao and Xinjia, 2021 ; Yang et al, 2019 ; Yu et al, 2021 ), rats ( Zhang et al, 2021d ), and rabbits ( Sadat-Ali et al, 2021 ). Other interesting models such as a fatigue loading model ( Xun et al, 2021 ), a disuse model by tail-suspension ( Yang et al, 2020 ), a proteoglycan-induced ankylosing spondylitis model ( Hu et al, 2022 ), and an LPS-induced osteolysis model ( Ren et al, 2022 ) have also been identified.…”