Scleraxis Modulates Bone Morphogenetic Protein 4 (BMP4)-Smad1 Protein-Smooth Muscle α-Actin (SMA) Signal Transduction in Diabetic Nephropathy

Abe, Hideharu; Tominaga, Tatsuya; Matsubara, Takeshi; Abe, Naoko; Kishi, Seiji; Nagai, Kojiro; Murakami, Taichi; Araoka, Toshikazu; Doi, Toshio

doi:10.1074/jbc.m111.275610

Cited by 27 publications

(21 citation statements)

References 60 publications

(36 reference statements)

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“…In support of this conclusion, it was recently reported that E2F1 plays a tumor suppressor role in colorectal cancer by activating CTNNBIP1 and inhibiting β-catenin activity [37]. MC activation, which is characterized by the induction of α-SMA expression, contributes to diabetic renal diseases [59]. Our results also demonstrate that transcriptionally active β-catenin induces α-SMA expression, which is indicative of MC activation and is accompanied by increased fibronectin expression in MMCs that are transfected with CTNNBIP1 siRNA and/or an miR-215 mimic.…”

Section: Discussionmentioning

confidence: 72%

“…Gene annotations demonstrated that CTNNBIP1 prevented the interaction between β-catenin and TCF/LEF family members, thus acting as a negative regulator of the Wnt/β-catenin signaling pathway [35], [55]-[58]. The central effector of the canonical Wnt cascade is β-catenin, which binds to TCF or LEF to initiate Wnt target gene transcription, including the myofibroblast conversion marker α-SMA and the fibrotic matrix protein fibronectin [47], [59], [60]. Additionally, using both gain- and loss-of-function experiments, we determined that only miR-215 regulated endogenous CTNNBIP1 expression ex vivo.…”

Section: Discussionmentioning

confidence: 99%

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Functional Implications of MicroRNA-215 in TGF-β1-Induced Phenotypic Transition of Mesangial Cells by Targeting CTNNBIP1

Pang

Guo

et al. 2013

PLoS ONE

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Mesangial cell (MC) phenotypic transition is crucial for the progression of diabetic nephropathy. A major stimulus mediating high glucose-induced MC phenotypic transition is TGF-β1. Our current study focuses on microRNA-215 (miR-215) and investigates its role in TGF-β1-mediated MC phenotypic transition. Using real-time quantitative PCR (qRT-PCR) and northern blotting, we determined that the miR-192/215 family is dramatically upregulated under diabetic conditions both in vitro and in vivo. Gain- and loss-of-function approaches demonstrated that miR-215 inhibition significantly inhibited TGF-β1-induced mouse mesangial cell (MMC) phenotypic transition, whereas miR-215 upregulation promoted MMC phenotypic transition. Interestingly, these changes were not detected in cells that were treated with TGF-β1 and miR-192 mimics or inhibitors. These results suggest that miR-215 participates in TGF-β1-induced MMC phenotypic transition. Luciferase reporter assays were used to identify whether catenin-beta interacting protein 1 (CTNNBIP1) is a direct target of miR-215, which was predicted by bioinformatic analysis. Mechanistic studies revealed that CTNNBIP1 suppresses Wnt/β-catenin signaling and that miR-215 promotes β-catenin activation and upregulates α-SMA and fibronectin expression in TGF-β1-treated MMCs by targeting CTNNBIP1. In addition, in vivo miR-215 silencing with a specific antagomir significantly increased CTNNBIP1 protein expression, resulting in reduced β-catenin activity and decreased α-SMA and fibronectin expression in db/db mouse kidney glomeruli. Taken together, our findings indicate that miR-215 plays an essential role in MC phenotypic transition by regulating the CTNNBIP1/β-catenin pathway, which is related to the pathogenesis of diabetic nephropathy.

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Section: Discussionmentioning

confidence: 72%

Section: Discussionmentioning

confidence: 99%

Functional Implications of MicroRNA-215 in TGF-β1-Induced Phenotypic Transition of Mesangial Cells by Targeting CTNNBIP1

Pang

Guo

et al. 2013

PLoS ONE

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“…Recently, it has been demonstrated that Scx can also directly transactivate the Twist1 and Snai1 promoters, 2 transcriptional regulators of epithelial mesenchymal transition, further suggesting that Scx can drive myofibroblast differentiation in cardiac fibroblasts (27). However, the effects of Scx-induced aSMA expression are tissue specific as it has previously been shown that Scx represses aSMA expression in the mesangial cells of the kidney (28). In our flexor tendon repair model, we found that a subset of Scx Lin differentiated into myofibroblasts (Fig.…”

Section: Discussionmentioning

confidence: 99%

Scleraxis lineage cells contribute to organized bridging tissue during tendon healing and identify a subpopulation of resident tendon cells

2019

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During tendon healing, it is postulated that tendon cells drive tissue regeneration, whereas extrinsic cells drive pathologic scar formation. Tendon cells are frequently described as a homogenous, fibroblast population that is positive for the marker Scleraxis (Scx). It is controversial whether tendon cells localize within the forming scar tissue during adult tendon healing. We have previously demonstrated that S100 calcium‐binding protein A4 (S100a4) is a driver of tendon scar formation and marks a subset of tendon cells. The relationship between Scx and S100a4 has not been explored. In this study, we assessed the localization of Scx lineage cells (ScxLin) following adult murine flexor tendon repair and established the relationship between Scx and S100a4 throughout both homeostasis and healing. We showed that adult ScxLin localize within the scar tissue and organize into a cellular bridge during tendon healing. Additionally, we demonstrate that markers Scx and S100a4 label distinct populations in tendon during homeostasis and healing, with Scx found in the organized bridging tissue and S100a4 localized throughout the entire scar region. These studies define a heterogeneous tendon cell environment and demonstrate discrete contributions of subpopulations during healing. These data enhance our understanding and ability to target the cellular environment of the tendon.—Best, K. T., Loiselle, A. E. Scleraxis lineage cells contribute to organized bridging tissue during tendon healing and identify a subpopulation of resident tendon cells. FASEB J. 33, 8578–8587 (2019). http://www.fasebj.org

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“…Previous studies have demonstrated the expression of scleraxis [33][34][35], Nanog [36], and Sox 2 [37] in the cytoplasm. Although these transcription factors function in the cell nucleus, stimulatory signal is likely required to induce their translocation to the cell nucleus.…”

Section: Role Of Lrcs During Tendon Repairmentioning

confidence: 95%

In Vivo Identity of Tendon Stem Cells and the Roles of Stem Cells in Tendon Healing

Tan

Lui

Lee

2013

Stem Cells and Development

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We investigated the spatial distribution of stem cells in tendons and the roles of stem cells in early tendon repair. The relationship between tendon-derived stem cells (TDSCs) isolated in vitro and tendon stem cells in vivo was also explored. Iododeoxyuridine (IdU) label-retaining method was used for labeling stem cells in rat patellar tendons with and without injury. Co-localization of label-retaining cells (LRCs) with different markers was done by immunofluorescent staining. TDSCs were isolated from patellar tendon mid-substance after IdU pulsing, and the expression of different markers in fresh and expanded cells was done by immunofluorescent staining. More LRCs were found at the peritenon and tendon-bone junction compared with the mid-substance. Some LRCs at the peritenon were located at the perivascular niche. The LRC number and the expression of proliferative, tendon-related, pluripotency, and pericyte-related markers in LRCs in the window wound increased. Most of the freshly isolated TDSCs expressed IdU, and some TDSCs expressed pericyte-related markers, which were lost during expansion. Both freshly isolated and subcultured TDSCs expressed pluripotency markers, which were absent in LRCs in intact tendons. In conclusion, we identified LRCs at the peritenon, mid-substance, and tendon-bone junction. There were both vascular and non-vascular sources of LRCs at the peritenon, while the source of LRCs at the mid-substance was non-vascular. LRCs participated in tendon repair via migration, proliferation, activation for tenogenesis, and increased pluripotency. Some LRCs in the window wound were pericyte like. Most of the mid-substance TDSCs were LRCs. The pluripotency markers and pericyte-related marker in LRCs might be important for function after injury. Recently, stem/progenitor cells have been isolated from tendon tissues of varies species, including human, horse, rabbit, rat, and mouse [3][4][5][6]. These stem/progenitor cells isolated from tendon tissues exhibited self-renewal and multilineage differentiation potential [3][4][5][6]. Since the origin and identity of these cells were not clear, we called them tendon-derived stem cells (TDSCs) to indicate only the tissue from which the cells were isolated [5].Many studies suggested that the wall of capillaries, small vessels, and large vessels harbored stem/progenitor cells [7][8][9][10][11]. Some studies further suggested that mesenchymal stem cells (MSCs) were derived from pericytes [9,12].Pericytes/perivascular cells from a variety of tissues were reported to exhibit characteristics that were strikingly similar to those of MSCs [7][8][9][10][11]. For tendons, there was also evidence that the vasculature of tendon tissue might harbor stem cells [13]. However, tendon mid-substance is hypovascular compared with other tissues and receives its blood supply mainly from the endotenon and paratenon [14]. TDSCs isolated from the tendon mid-substance, while positive for alpha smooth muscle actin [5], were not positive for other pericyte-related markers [3,15]. Tend...

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Scleraxis Modulates Bone Morphogenetic Protein 4 (BMP4)-Smad1 Protein-Smooth Muscle α-Actin (SMA) Signal Transduction in Diabetic Nephropathy

Cited by 27 publications

References 60 publications

Functional Implications of MicroRNA-215 in TGF-β1-Induced Phenotypic Transition of Mesangial Cells by Targeting CTNNBIP1

Functional Implications of MicroRNA-215 in TGF-β1-Induced Phenotypic Transition of Mesangial Cells by Targeting CTNNBIP1

Scleraxis lineage cells contribute to organized bridging tissue during tendon healing and identify a subpopulation of resident tendon cells

In Vivo Identity of Tendon Stem Cells and the Roles of Stem Cells in Tendon Healing

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