Targeting macrophage polarization as a promising therapeutic strategy for the treatment of osteoarthritis

Wang, Weiyun; Chu, Yaru; Zhang, Pengyuan; Liang, Zhuo; Fan, Zhenlin; Guo, Xueqiang; Zhou, Guangdong; Ren, Wenjie

doi:10.1016/j.intimp.2023.109790

Cited by 36 publications

(14 citation statements)

References 147 publications

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“…These results indicated that M1-polarized macrophages in synovitis had a profound impact on OA progression. In investigating the mechanism of interaction between macrophages and chondrocytes, some studies have shown that macrophages activated pro-inflammatory M1 polarization through metabolic reprogramming during OA, while polarized macrophages further promoted synovitis and cartilage extracellular matrix degradation by secreting a large number of proinflammatory factors and EVs, but the key initiating factors of synovial macrophage polarization and the mechanism of macrophages regulating chondrocyte metabolism remain unclear [ 34 , 35 ]. In the present study, we found that mechanical overloading promoted increased M1 polarization in synovial macrophages, indicating that macrophages responded to mechanical stimulation in the environment.…”

Section: Discussionmentioning

confidence: 99%

Macrophage-derived ectosomal miR-350-3p promotes osteoarthritis progression through downregulating chondrocyte H3K36 methyltransferase NSD1

Lin,

Yin,

Huang

et al. 2024

Cell Death Discov.

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Mechanical overloading can promote cartilage senescence and osteoarthritis (OA) development, but its impact on synovial macrophages and the interaction between macrophages and chondrocytes remain unknown. Here, we found that macrophages exhibited M1 polarization under mechanical overloading and secreted ectosomes that induced cartilage degradation and senescence. By performing miRNA sequencing on ectosomes, we identified highly expressed miR-350-3p as a key factor mediating the homeostatic imbalance of chondrocytes caused by M1-polarized macrophages, this result being confirmed by altering the miR-350-3p level in chondrocytes with mimics and inhibitor. In experimental OA mice, miR-350-3p was increased in synovium and cartilage, while intra-articular injection of antagomir-350-3p inhibited the increase of miR-350-3p and alleviated cartilage degeneration and senescence. Further studies showed that macrophage-derived ectosomal miR-350-3p promoted OA progression by inhibiting nuclear receptor binding SET domain protein 1(NSD1) in chondrocytes and regulating histone H3 lysine 36(H3K36) methylation. This study demonstrated that the targeting of macrophage-derived ectosomal miRNAs was a potential therapeutic method for mechanical overload-induced OA.

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Section: Discussionmentioning

confidence: 99%

Macrophage-derived ectosomal miR-350-3p promotes osteoarthritis progression through downregulating chondrocyte H3K36 methyltransferase NSD1

Lin,

Yin,

Huang

et al. 2024

Cell Death Discov.

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“…OA progression has been shown to be closely related to the imbalances between the M1/M2 phenotype of synovial macrophages. Therefore the inhibition of M1 polarization to the advantage of the M2 phenotype represents a possible strategy for slowing the progression of OA [ 67 ].…”

Section: The Oa Inflammatory Response: Mechanism and Mediatorsmentioning

confidence: 99%

Knee Osteoarthritis: Epidemiology, Pathogenesis, and Mesenchymal Stem Cells: What Else Is New? An Update

Giorgino

Albano

Fusco

et al. 2023

IJMS

103

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Osteoarthritis (OA) is a chronic disease and the most common orthopedic disorder. A vast majority of the social OA burden is related to hips and knees. The prevalence of knee OA varied across studies and such differences are reflected by the heterogeneity of data reported by studies conducted worldwide. A complete understanding of the pathogenetic mechanisms underlying this pathology is essential. The OA inflammatory process starts in the synovial membrane with the activation of the immune system, involving both humoral and cellular mediators. A crucial role in this process is played by the so-called “damage-associated molecular patterns” (DAMPs). Mesenchymal stem cells (MSCs) may be a promising option among all possible therapeutic options. However, many issues are still debated, such as the best cell source, their nature, and the right amount. Further studies are needed to clarify the remaining doubts. This review provides an overview of the most recent and relevant data on the molecular mechanism of cartilage damage in knee OA, including current therapeutic approaches in regenerative medicine.

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“…Synovium is composed predominantly of two cell types: macrophage-like and fibroblast-like cells (Fb) [1]. To date, many studies have reported the presence of heterogeneous macrophages such as M1 and M2 macrophages in synovium and noted that they contribute to osteoarthritis pathology [2][3][4]. Interestingly, in the early stages of the disease, synovitis becomes apparent even before significant radiographic evidence of cartilage damage.…”

Section: Introductionmentioning

confidence: 99%

“…Key driver gene analysis of 476 upregulated genes in CD39−CD55+ fibroblasts 4. FN transcript variant 5, * 5 ITIH4 transcript variant 2, *6 ITIH4 transcript variant 1, * 7 NRP2 transcript variant 2, * 8 NRP2 transcript variant 5, * 9 PDPN transcript variant 1, * 10 PDPN transcript variant 2, * 11 PRG4 transcript variant B, * 12 PRG4 transcript variant C, * 13 PRG4 transcript variant D, * 14 SELP transcript variant X5, * 15 SEMA3A transcript variant X1, * 16 SEMA3A transcript variant X3, * 17 VCAM1 transcript variant 1, * 18 VCAM1 transcript variant 2.…”

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confidence: 99%

CD39+CD55− Fb Subset Exhibits Myofibroblast-Like Phenotype and Is Associated with Pain in Osteoarthritis of the Knee

Tsuchiya,

Ohashi,

Kodera

et al. 2023

Biomedicines

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Recent studies utilizing single-cell analysis have unveiled the presence of various fibroblast (Fb) subsets within the synovium under inflammatory conditions in osteoarthritis (OA), distinguishing them from those in rheumatoid arthritis (RA). Moreover, it has been reported that pain in knee OA patients is linked to specific fibroblast subsets. Single-cell expression profiling methods offer an incredibly detailed view of the molecular states of individual cells. However, one limitation of these methods is that they require the destruction of cells during the analysis process, rendering it impossible to directly assess cell function. In our study, we employ flow cytometric analysis, utilizing cell surface markers CD39 and CD55, in an attempt to isolate fibroblast subsets and investigate their relationship with OA pathology. Synovial tissues were obtained from 25 knee OA (KOA) patients. Of these, six samples were analyzed by RNA-seq (n = 3) and LC/MS analysis (n = 3). All 25 samples were analyzed to estimate the proportion of Fb (CD45−CD31−CD90+) subset by flow cytometry. The proportion of Fb subsets (CD39+CD55− and CD39−CD55+) and their association with osteoarthritis pathology were evaluated. CD39+CD55− Fb highly expressed myogenic markers such as CNN1, IGFBP7, MYH11, and TPM1 compared to CD39−CD55+ Fb. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of upregulated differentially expressed genes (DEGs) in CD39+CD55− Fb identified the Apelin pathway and cGMP-PKC-signaling pathway as possibly contributing to pain. LC/MS analysis indicated that proteins encoded by myogenic marker genes, including CNN1, IGFBP7, and MYH11, were also significantly higher than in CD39−CD55+ Fb. CD39−CD55+ Fb highly expressed PRG4 genes and proteins. Upregulated DEGs were enriched for pathways associated with proinflammatory states (‘RA’, ‘TNF signaling pathway’, ‘IL-17 signaling pathway’). The proportion of CD39+CD55− Fb in synovium significantly correlated with both resting and active pain levels in knee OA (KOA) patients (resting pain, ρ = 0.513, p = 0.009; active pain, ρ = 0.483, p = 0.015). There was no correlation between joint space width (JSW) and the proportion of CD39+CD55− Fb. In contrast, there was no correlation between the proportion of CD39−CD55+ Fb and resting pain, active pain, or JSW. In conclusion, CD39+CD55− cells exhibit a myofibroblast phenotype, and its proportion is associated with KOA pain. Our study sheds light on the potential significance of CD39+CD55− synovial fibroblasts in osteoarthritis, their myofibroblast-like phenotype, and their association with joint pain. These findings provide a foundation for further research into the mechanisms underlying fibrosis, the impact of altered gene expression on osteoarthritic joints, and potential therapeutic strategies.

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Targeting macrophage polarization as a promising therapeutic strategy for the treatment of osteoarthritis

Cited by 36 publications

References 147 publications

Macrophage-derived ectosomal miR-350-3p promotes osteoarthritis progression through downregulating chondrocyte H3K36 methyltransferase NSD1

Macrophage-derived ectosomal miR-350-3p promotes osteoarthritis progression through downregulating chondrocyte H3K36 methyltransferase NSD1

Knee Osteoarthritis: Epidemiology, Pathogenesis, and Mesenchymal Stem Cells: What Else Is New? An Update

CD39+CD55− Fb Subset Exhibits Myofibroblast-Like Phenotype and Is Associated with Pain in Osteoarthritis of the Knee

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