Abstract
Osteoarthritis (OA) is a serious joint inflammation that leads to cartilage degeneration and joint dysfunction. Mesenchymal stem cells (MSCs) are used as a cell-based therapy that showed promising results in promoting cartilage repair. However, recent studies and clinical trials explored unsatisfied outcomes because of slow chondrogenic differentiation and increased calcification without clear reasons. Here, we report that the overexpression of indoleamine 2,3 dioxygenase 1 (IDO1) in the synovial fluid of OA patients impairs chondrogenic differentiation of MSCs in the joint of the OA mice model. The effect of MSCs mixed with IDO1 inhibitor on the cartilage regeneration was tested compared to MSCs mixed with IDO1 in the OA animal model. Further, the mechanism exploring the effect of IDO1 on chondrogenic differentiation was investigated. Subsequently, miRNA transcriptome sequencing was performed for MSCs cocultured with IDO1, and then TargetScan was used to verify the target of miR-122-5p in the SF-MSCs. Interestingly, we found that MSCs mixed with IDO1 inhibitor showed a significant performance to promote cartilage regeneration in the OA animal model, while MSCs mixed with IDO1 failed to stimulate cartilage regeneration. Importantly, the overexpression of IDO1 showed significant inhibition to Sox9 and Collagen type II (COL2A1) through activating the expression of β-catenin, since inhibiting of IDO1 significantly promoted chondrogenic signaling of MSCs (Sox9, COL2A1, Aggrecan). Further, miRNA transcriptome sequencing of SF-MSCs that treated with IDO1 showed significant downregulation of miR-122-5p which perfectly targets Wnt1. The expression of Wnt1 was noticed high when IDO1 was overexpressed. In summary, our results suggest that IDO1 overexpression in the synovial fluid of OA patients impairs chondrogenic differentiation of MSCs and cartilage regeneration through downregulation of miR-122-5p that activates the Wnt1/β-catenin pathway.
Highlights
Osteoarthritis (OA) is an articular cartilage degenerative disease that causes serious dysfunction of the joint [1]
It inhibits cartilage regeneration and mesenchymal stem cells (MSCs)-based therapy through downregulation of miR-122-5p, which activates the signaling of wnt1/b-catenin that significantly inhibited the expression of Sox9 and COL2A1
In order to observe the effect of IDO1 blocking during MSCs transplantation on cartilage regeneration, the OA animal model was established as presented in Supplementary Figure 1
Summary
Osteoarthritis (OA) is an articular cartilage degenerative disease that causes serious dysfunction of the joint [1]. The novel strategy to reduce the progression of OA depends on eliminating articular cartilage loss and enhancing cartilage regeneration [4]. Clinical attempts work to slow down cartilage degeneration and enhance cartilage repair with various strategies such as modification of cytokines, chemokines, and enzymes [5]. The use of mesenchymal stem cells (MSCs) transplantation for cartilage repair and OA treatment was reported by several studies and clinical trials [5, 7, 8]. Recent studies reported unsatisfactory outcomes including calcification [9] and other challenges that slow down the regeneration of cartilage and completely inhibit cartilage repair without clear reasons. We noticed that high levels of indoleamine 2,3 dioxygenase 1 (IDO1) were reported in the synovial fluid of OA patients [10,11,12]
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