Aspirin inhibits inflammation and scar formation in the injury tendon healing through regulating JNK/STAT‐3 signalling pathway

Wang, Yunjiao; He, Gang; Tang, Hong; Shi, Youxing; Kang, Xin; Lyu, Jingtong; Zhu, Min; Zhou, Mei; Yang, Mingyu; Mu, Miduo; Chen, Wan; Zhou, Binghua; Zhang, Jiqiang; Tang, Kanglai

doi:10.1111/cpr.12650

Cited by 113 publications

(91 citation statements)

References 43 publications

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“…In the current study, the biomechanical properties of injury tendon were increased by aspirin treatment, suggesting that aspirin treatment decreased the risk of injury tendon rupture. Our previous study has proved that aspirin improved the biomechanical properties of injury tendon through regulating inflammation and extracellular matrix formation . The present study showed that aspirin reversed the fate of TSCs adipogenic differentiation and inhibited lipids accumulation and infiltration in injury tendon; hence, the biomechanical properties were improved.…”

Section: Discussionsupporting

confidence: 60%

Aspirin inhibits adipogenesis of tendon stem cells and lipids accumulation in rat injury tendon through regulating PTEN/PI3K/AKT signalling

Wang

et al. 2019

J Cellular Molecular Medi

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Tendon injury repairs are big challenges in sports medicine, and fatty infiltration after tendon injury is very common and hampers tendon injury healing process. Tendon stem cells (TSCs), as precursors of tendon cells, have shown promising effect on injury tendon repair for their tenogenesis and tendon extracellular matrix formation. Adipocytes and lipids accumulation is a landmark event in pathological process of tendon injury, and this may induce tendon rupture in clinical practice. Based on this, it is important to inhibit TSCs adipogenesis and lipids infiltration to restore structure and function of injury tendon. Aspirin, as the representative of non‐steroidal anti‐inflammatory drugs (NSAIDs), has been widely used in tendon injury for its anti‐inflammatory and analgesic actions, but effect of aspirin on TSCs adipogenesis and fatty infiltration is still unclear. Under adipogenesis conditions, TSCs were treated with concentration gradient of aspirin. Oil red O staining was performed to observe changes of lipids accumulation. Next, we used RNA sequencing to compare profile changes of gene expression between induction group and aspirin‐treated group. Then, we verified the effect of filtrated signalling on TSCs adipogenesis. At last, we established rat tendon injury model and compared changes of biomechanical properties after aspirin treatment. The results showed that aspirin decreased lipids accumulation in injury tendon and inhibited TSCs adipogenesis. RNA sequencing filtrated PTEN/PI3K/AKT signalling as our target. After adding the signalling activators of VO‐Ohpic and IGF‐1, inhibited adipogenesis of TSCs was reversed. Still, aspirin promoted maximum loading, ultimate stress and breaking elongation of injury tendon. In conclusion, by down‐regulating PTEN/PI3K/AKT signalling, aspirin inhibited adipogenesis of TSCs and fatty infiltration in injury tendon, promoted biomechanical properties and decreased rupture risk of injury tendon. All these provided new therapeutic potential and medicine evidence of aspirin in treating tendon injury and tendinopathy.

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Section: Discussionsupporting

confidence: 60%

Aspirin inhibits adipogenesis of tendon stem cells and lipids accumulation in rat injury tendon through regulating PTEN/PI3K/AKT signalling

Wang

et al. 2019

J Cellular Molecular Medi

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“…Yuan et al () demonstrated that aspirin could promote osteogenic differentiation of human dental pulp stem cells. Interestingly, S. Chen et al () have reported that IL‐6 inhibited tenogenic differentiation via the JAK/STAT‐3 signaling pathway in TSCs, and our previous study has shown that aspirin significantly inhibited expression of IL‐6 (Wang, He, et al, ). Our present study showed that the tendon‐related markers of TNMD, TNC, and SCX were upregulated by aspirin treatment in vitro and in vivo.…”

Section: Discussionmentioning

confidence: 95%

“…We followed the same methods as in previous studies (Dirks & Warden, ; Wang, He et al, ; Warden, ). A total of 24 male Sprague–Dawley rats were randomly divided into three groups: control group, microdamaged model group, aspirin treatment group.…”

Section: Methodsmentioning

confidence: 99%

“…Its anti-inflammation and pain relief effect have been widely accepted, but evidence of its effect on TSC differentiation is lacking, especially its effect on injury tendon repair. In our previous study (Wang, He, et al, 2019), we have found that aspirin promoted injury tendon healing through anti-inflammation and inhibition of scar formation. Besides anti-inflammation and scar formation, we hypothesize that aspirin also promoted injury tendon healing through inducing tenogenic differentiation of TSCs.…”

Section: Introductionmentioning

confidence: 91%

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Aspirin promotes tenogenic differentiation of tendon stem cells and facilitates tendinopathy healing through regulating the GDF7/Smad1/5 signaling pathway

Wang

Tang

et al. 2019

Journal Cellular Physiology

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Tendinopathy is a common musculoskeletal system disorder in sports medicine, but regeneration ability of injury tendon is limited. Tendon stem cells (TSCs) have shown the definitive treatment evidence for tendinopathy and tendon injuries due to their tenogenesis capacity. Aspirin, as the representative of nonsteroidal anti-inflammatory drugs for its anti-inflammatory and analgestic actions, has been commonly used in treating tendinopathy in clinical, but the effect of aspirin on tenogenesis of TSCs is unclear. We hypothesized that aspirin could promote injury tendon healing through inducing TSCs tenogenesis. The aim of the present study is to make clear the effect of aspirin on TSC tenogenesis and tendon healing in tendinopathy, and thus provide new treatment evidence and strategy of aspirin for clinical practice. First, TSCs were treated with aspirin under tenogenic medium for 3, 7, and 14 days. Sirius Red staining was performed to observe the TSC differentiation. Furthermore, RNA sequencing was utilized to screen out different genes between the induction group and aspirin treatment group. Then, we identified the filtrated molecules and compared their effect on tenogenesis and related signaling pathway. At last, we constructed the tendinopathy model and compared biomechanical changes after aspirin intake.From the results, we found that aspirin promoted tenogenesis of TSCs. RNA sequencing showed that growth differentiation factor 6 (GDF6), GDF7, and GDF11were upregulated in induction medium with the aspirin group compared with the induction medium group. GDF7 increased tenogenesis and activated Smad1/5 signaling. In addition, aspirin increased the expression of TNC, TNMD, and Scx and biomechanical properties of the injured tendon. In conclusion, aspirin promoted TSC tenogenesis and tendinopathy healing through GDF7/Smad1/5 signaling, and this provided new treatment evidence of aspirin for tendinopathy and tendon injuries. K E Y W O R D S NSAIDs, stem cell differentiation, tendon injury healing SUPPORTING INFORMATION Additional supporting information may be found online in the Supporting Information section. How to cite this article: Wang Y, He G, Tang H, et al. Aspirin promotes tenogenic differentiation of tendon stem cells and facilitates tendinopathy healing through regulating the GDF7/Smad1/5 signaling pathway. J Cell Physiol. 2020;235: 4778-4789. https://doi.

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“…Stat3/Stat5 binding sites referred to as STAT-binding elements are usually located in enhancer/promoter regions and first introns of target genes and characterized by clusters of conserved binding motifs with an interferon gammaactivated site-like core sequence (TTCT/CNA/GGAA) (Hutchins et al, 2013;Wingelhofer et al, 2018). It is noteworthy that the activation of JNK/Stat3 signaling has been demonstrated during scar formation as induced by aspirin and was associated with the upregulation of Mrc1 (Wang et al, 2019). Furthermore, an increased expression of Mrc1 in macrophages was accompanied by enhanced Jak2-Stat3 pathway activation (Huang et al, 2019), indicating that Stat3 is a potential positive regulator of Mrc1 expression.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Microglial TGFβ Signaling Increases Expression of Mrc1

Ehr

Attaai

Neidert

et al. 2020

Front. Cell. Neurosci.

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Microglia are constantly surveying their microenvironment and rapidly react to impairments by changing their morphology, migrating toward stimuli and adopting gene expression profiles characterizing their activated state. The increased expression of the M2-like marker Mannose receptor 1 (Mrc1), which is also referred to as CD206, in microglia has been reported after M2-like activation in vitro and in vivo. Mrc1 is a 175-kDa transmembrane pattern recognition receptor which binds a variety of carbohydrates and is involved in the pinocytosis and the phagocytosis of immune cells, including microglia, and thought to contribute to a neuroprotective microglial phenotype. Here we analyzed the effects of TGFβ signaling on Mrc1 expression in microglia in vivo and in vitro. Using C57BL/6 wild type and Cx3cr1 CreERT2 :R26-YFP:Tgfbr2 fl/fl mice-derived microglia, we show that the silencing of TGFβ signaling results in the upregulation of Mrc1, whereas recombinant TGFβ1 induced the delayed downregulation of Mrc1. Furthermore, chromatin immunoprecipitation experiments provided evidence that Mrc1 is not a direct Smad2/Smad4 target gene in microglia. Altogether our data indicate that the changes in Mrc1 expression after the activation or the silencing of microglial TGFβ signaling are likely to be mediated by modifications of the secondary intracellular signaling events influenced by TGFβ signaling.

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Aspirin inhibits inflammation and scar formation in the injury tendon healing through regulating JNK/STAT‐3 signalling pathway

Cited by 113 publications

References 43 publications

Aspirin inhibits adipogenesis of tendon stem cells and lipids accumulation in rat injury tendon through regulating PTEN/PI3K/AKT signalling

Aspirin inhibits adipogenesis of tendon stem cells and lipids accumulation in rat injury tendon through regulating PTEN/PI3K/AKT signalling

Aspirin promotes tenogenic differentiation of tendon stem cells and facilitates tendinopathy healing through regulating the GDF7/Smad1/5 signaling pathway

Inhibition of Microglial TGFβ Signaling Increases Expression of Mrc1

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