Targeting macrophagic SHP2 for ameliorating osteoarthritis via TLR signaling

Sun, Ziying; Liu, Qianqian; Lv, Zhongyang; Li, Jiawei; Xu, Xingquan; Wang, Maochun; Sun, Kuoyang; Shi, Tianshu; Liu, Zizheng; Tan, Guihua; Yan, Wenqiang; Wu, Rui; Yang, Yannick Xiaofan; Ikegawa, Shiro; Jiang, Qing; Sun, Yang; Shi, Dongquan

doi:10.1016/j.apsb.2022.02.010

Cited by 33 publications

(20 citation statements)

References 33 publications

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“…As in the previous study, the quantity of F4/80positive cells was upregulated in OA humans in contrast to the normal synovium (Fig. 1a and b) [39]. In addition, the percentage of PIM-1-positive cells was also elevated in the synovium of OA humans (Fig.…”

Section: Pim-1 Expression Was Upregulated In Macrophages Insupporting

confidence: 83%

Targeting macrophagic PIM-1 alleviates osteoarthritis by inhibiting NLRP3 inflammasome activation via suppressing mitochondrial ROS/ Cl- efflux signaling pathway

Zhang,

Xie,

Qian

et al. 2023

Preprint

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Background Osteoarthritis (OA), in which macrophage-driven synovitis is considered closely related to cartilage destruction and could occur at any stage, is an inflammatory arthritis. However, there are no effective targets to cure the progression of OA. The NLRP3 inflammasome in synovial macrophages participates in the pathological inflammatory process and treatment strategies targeting it are considered to be an effective approach for OA. PIM-1 kinase, as a downstream effector of many cytokine signaling pathways, plays a pro-inflammatory role in inflammatory disease. Methods In this study, we evaluated the expression of the PIM-1 and the infiltration of synovial macrophages in the OA human synovium OA. The effects and mechanism of PIM-1 were investigated in mice and human macrophages stimulated by lipopolysaccharide (LPS) and different agonists such as nigericin, ATP, MSU, and Alum. The protective effects on chondrocytes were assessed by a modified co-culture system induced by macrophage CM. The therapeutic effect in vivo was confirmed by the medial meniscus (DMM)-induced OA in mice. Results The expression of PIM-1 was increased in the human OA synovium which was accompanied by the infiltration of synovial macrophages. In vitro experiments, suppression of PIM-1 by SMI-4a, a specific inhibitor, rapidly inhibited the NLRP3 inflammasome activation in mice and human macrophages. In addition, PIM-1 suppression had broad inhibitory functions against NLRC4, and AIM2 inflammasome activation and GSDME-mediated pyroptosis. Furthermore, PIM-1 inhibition specifically blocked the apoptosis-associated speck-like protein containing a CARD (ASC) oligomerization in the assembly stage. Mechanistically, PIM-1 inhibition alleviated the mitochondrial reactive oxygen species (ROS)/ chloride intracellular channel proteins (CLICs)-dependent Cl- efflux signaling pathway, which eventually resulted in the blockade of the ASC oligomerization and NLRP3 inflammasome activation. Furthermore, PIM-1 suppression showed chondroprotective effects in the modified co-culture system. Finally, SMI-4a significantly suppressed the expression of PIM-1 in the synovium and reduced the synovitis scores and the Osteoarthritis Research Society International (OARSI) score in the destabilization of the medial meniscus (DMM)-induced OA model. Conclusions Therefore, PIM-1 represented a new class of promising targets as a treatment of OA to target these mechanisms in macrophages and widened the road to therapeutic strategies for OA.

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Section: Pim-1 Expression Was Upregulated In Macrophages Insupporting

confidence: 83%

Targeting macrophagic PIM-1 alleviates osteoarthritis by inhibiting NLRP3 inflammasome activation via suppressing mitochondrial ROS/ Cl- efflux signaling pathway

Zhang,

Xie,

Qian

et al. 2023

Preprint

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“…Recent studies have revealed that activation of the PI3K/Akt signaling was positively related to synovial inflammation and OA progression, 49,50 and inhibition of the PI3K/Akt pathway could promote M1 macrophages repolarizing to the M2 phenotype and downregulate the expression of pro-inflammatory cytokines and VEGF in SFs. 51,52 These data indicated that TA-NM@Lip effectively induced the phenotypic alteration of M1 macrophages and activated SFs by enhancing the capacity of TA in suppressing the PI3K/Akt pathway.…”

Section: Ta-nm@lip Effectively Reprograms the Phenotype Of Both M1 Ma...mentioning

confidence: 82%

Apoptotic Neutrophil Membrane-Camouflaged Liposomes for Dually Targeting Synovial Macrophages and Fibroblasts to Attenuate Osteoarthritis

Deng,

Chen,

Zhao

et al. 2023

ACS Appl. Mater. Interfaces

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No current pharmacological approach is capable of simultaneously inhibiting the symptomatology and structural progression of osteoarthritis. M1 macrophages and activated synovial fibroblasts (SFs) mutually contribute to the propagation of joint pain and cartilage destruction in osteoarthritis. Here, we report the engineering of an apoptotic neutrophil membranecamouflaged liposome (termed "NM@Lip") for precise delivery of triamcinolone acetonide (TA) by dually targeting M1 macrophages and activated SFs in osteoarthritic joints. NM@Lip has a high cellular uptake in M1 macrophages and activated SFs. Furthermore, TA-loaded NM@Lip (TA-NM@Lip) effectively repolarizes M1 macrophages to the M2 phenotype and transforms pathological SFs to the deactivated phenotype by inhibiting the PI3K/Akt pathway. NM@Lip retains in the joint for up to 28 days and selectively distributes into M1 macrophages and activated SFs in synovium with low distribution in cartilage. TA-NM@Lip decreases the levels of pro-inflammatory cytokines, chemokines, and cartilage-degrading enzymes in osteoarthritic joints. In a rodent model of osteoarthritis-related pain, a single intra-articular TA-NM@Lip injection attenuates synovitis effectively and achieves complete pain relief with long-lasting effects. In a rodent model of osteoarthritis-related joint degeneration, repeated intra-articular TA-NM@Lip injections induce no obvious cartilage damage and effectively attenuate cartilage degeneration. Taken together, TA-NM@Lip represents a promising nanotherapeutic approach for osteoarthritis therapy.

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“…The enzyme activity of the PTP SH2 domain‐containing phosphatase 2 (SHP‐2) was significantly increased in human OA samples with serious articular cartilage injury and in IL‐1β‐stimulated mouse chondrocytes 21 . A recent study further found that SHP099, an allosteric inhibitor of SHP‐2, attenuated OA progression by inhibiting M1 macrophage polarization 22 . As for COVID‐19, Genome‐wide association studies found that alkaline phosphatase was associated with severe COVID‐19 23 while proteomics analysis in plasma further showed a higher expression of protein phosphatase in recovered COVID‐19 patients than that of healthy subjects 24 .…”

Section: Discussionmentioning

confidence: 99%

Bioinformatics and system biology analysis revealed the crosstalk between COVID‐19 and osteoarthritis

Lai,

Jiang,

Liao

et al. 2023

Immunity Inflam & Disease

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BackgroundThe global coronavirus disease 2019 (COVID‐19) outbreak has significantly impacted public health. Moreover, there has been an association between the incidence and severity of osteoarthritis (OA) and the onset of COVID‐19. However, the optimal diagnosis and treatment strategies for patients with both diseases remain uncertain. Bioinformatics is a novel approach that may help find the common pathology between COVID‐19 and OA.MethodsDifferentially expressed genes (DEGs) were screened by R package “limma.” Functional enrichment analyses were performed to find key biological functions. Protein–protein interaction (PPI) network was constructed by STRING database and then Cytoscape was used to select hub genes. External data sets and OA mouse model validated and identified the hub genes in both mRNA and protein levels. Related transcriptional factors (TF) and microRNAs (miRNAs) were predicted with miRTarBase and JASPR database. Candidate drugs were obtained from Drug Signatures database. The immune infiltration levels of COVID‐19 and OA were evaluated by CIBERSORT and scRNA‐seq.ResultsA total of 74 common DEGs were identified between COVID‐19 and OA. Receiver operating characteristic curves validated the effective diagnostic values (area under curve > 0.7) of four hub genes (matrix metalloproteinases 9, ATF3, CCL4, and RELA) in both the training and validation data sets of COVID‐19 and OA. Quantitative polymerase chain reaction and Western Blot showed significantly higher hub gene expression in OA mice than in healthy controls. A total of 84 miRNAs and 28 TFs were identified to regulate the process of hub gene expression. The top 10 potential drugs were screened including “Simvastatin,” “Hydrocortisone,” and “Troglitazone” which have been proven by Food and Drug Administration. Correlated with hub gene expression, Macrophage M0 was highly expressed while Natural killer cells and Mast cells were low in both COVID‐19 and OA.ConclusionFour hub genes, disease‐related miRNAs, TFs, drugs, and immune infiltration help to understand the pathogenesis and perform further studies, providing a potential therapy target for COVID‐19 and OA.

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Targeting macrophagic SHP2 for ameliorating osteoarthritis via TLR signaling

Cited by 33 publications

References 33 publications

Targeting macrophagic PIM-1 alleviates osteoarthritis by inhibiting NLRP3 inflammasome activation via suppressing mitochondrial ROS/ Cl- efflux signaling pathway

Targeting macrophagic PIM-1 alleviates osteoarthritis by inhibiting NLRP3 inflammasome activation via suppressing mitochondrial ROS/ Cl- efflux signaling pathway

Apoptotic Neutrophil Membrane-Camouflaged Liposomes for Dually Targeting Synovial Macrophages and Fibroblasts to Attenuate Osteoarthritis

Bioinformatics and system biology analysis revealed the crosstalk between COVID‐19 and osteoarthritis

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