Inhibition of phosphatidylinositol 3‐kinase α (<scp>PI</scp>3Kα) prevents heterotopic ossification

Valer, José Antonio; Sánchez-de-Diego, Cristina; Gámez, Beatriz; Mishina, Yuji; Rosa, José Luís; Ventura, Francesc

doi:10.15252/emmm.201910567

Cited by 27 publications

(25 citation statements)

References 48 publications

(91 reference statements)

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“…The western blot results showed that the nesfatin-1-induced osteogenic differentiation of TDSCs was significantly suppressed by rapamycin. In vivo , as expected, rapamycin suppressed heterotopic bone formation when compared with the HO group, which has been previously reported ( Hino et al, 2018 ; Valer et al, 2019 ). Nesfatin-1 increased heterotopic bone formation and activation of mTOR signaling in the tendon, both decreased by rapamycin.…”

Section: Discussionsupporting

confidence: 88%

Nesfatin-1 Promotes the Osteogenic Differentiation of Tendon-Derived Stem Cells and the Pathogenesis of Heterotopic Ossification in Rat Tendons via the mTOR Pathway

Zhang

Chen

et al. 2020

Front. Cell Dev. Biol.

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Heterotopic ossification (HO) is a pathological condition involved in tendinopathy. Adipokines are known to play a key role in HO of tendinopathy. Nesfatin-1, an 82-amino acid adipokine is closely reportedly associated with diabetes mellitus (DM), which, in turn, is closely related to tendinopathy. In the present study, we aimed to investigate the effects of nesfatin-1 on the osteogenic differentiation of tendon-derived stem cells (TDSCs) and the pathogenesis of tendinopathy in rats. In vitro, TDSCs were incubated in osteogenic induction medium for 14 days with different nesfatin-1 concentration. In vivo, Sprague Dawley rats underwent Achilles tenotomy to evaluate the effect of nesfatin-1 on tendinopathy. Our results showed that the expression of nesfatin-1 expression in tendinopathy patients was significantly higher than that in healthy subjects. Nesfatin-1 affected the cytoskeleton and reduced the migration ability of TDSCs in vitro. Furthermore, nesfatin-1 inhibited the expression of Scx, Mkx, and Tnmd and promoted the expression of osteogenic genes, such as COL1a1, ALP, and RUNX2; these results suggested that nesfatin-1 inhibits cell migration, adversely impacts tendon phenotype, promotes osteogenic differentiation of TDSCs and the pathogenesis of HO in rat tendons. Moreover, we observed that nesfatin-1 suppressed autophagy and activated the mammalian target of rapamycin (mTOR) pathway both in vitro and in vivo. The suppression of the mTOR pathway alleviated nesfatin-1-induced HO development in rat tendons. Thus, nesfatin-1 promotes the osteogenic differentiation of TDSC and the pathogenesis of HO in rat tendons via the mTOR pathway; these findings highlight a new potential therapeutic target for tendinopathy.

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Section: Discussionsupporting

confidence: 88%

Nesfatin-1 Promotes the Osteogenic Differentiation of Tendon-Derived Stem Cells and the Pathogenesis of Heterotopic Ossification in Rat Tendons via the mTOR Pathway

Zhang

Chen

et al. 2020

Front. Cell Dev. Biol.

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“…Additionally, the PI3K/AKT/GSK3 pathway has been linked to SMAD1 levels in murine osteoblasts, affecting bone homeostasis and regulation [76]. Recently, PI3K signalling was also linked to HO and FOP since inhibitors of PI3Kα prevented heterotopic ossification in vivo [77]. The Rho/ROCK pathway, a regulator of mechanosensing, cell motility, and cytoskeleton organisation, has also been related to ACVR1.…”

Section: Fibrodysplasia Ossificans Progressivamentioning

confidence: 99%

ACVR1 Function in Health and Disease

Valer

Sánchez-de-Diego

Pimenta-Lopes

et al. 2019

Cells

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Activin A receptor type I (ACVR1) encodes for a bone morphogenetic protein type I receptor of the TGFβ receptor superfamily. It is involved in a wide variety of biological processes, including bone, heart, cartilage, nervous, and reproductive system development and regulation. Moreover, ACVR1 has been extensively studied for its causal role in fibrodysplasia ossificans progressiva (FOP), a rare genetic disorder characterised by progressive heterotopic ossification. ACVR1 is linked to different pathologies, including cardiac malformations and alterations in the reproductive system. More recently, ACVR1 has been experimentally validated as a cancer driver gene in diffuse intrinsic pontine glioma (DIPG), a malignant childhood brainstem glioma, and its function is being studied in other cancer types. Here, we review ACVR1 receptor function and signalling in physiological and pathological processes and its regulation according to cell type and mutational status. Learning from different functions and alterations linked to ACVR1 is a key step in the development of interdisciplinary research towards the identification of novel treatments for these pathologies.

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“…Moreover, BMP-7 regulated the differentiation ability of MSC in the formation of heterotopic ossification of soft tissue through the Wnt/β-catenin pathway (Fu et al, 2017). In fibrodysplasia ossificans progressive disease, mTOR (Agarwal et al, 2016) and NF-κB/MAPK (Barruet et al, 2018) were related with the formation of muscle heterotopic ossification under crosstalk with BMP signaling, and BMPs together with SMAD, AKT, and mTOR/S6K signaling could prevent heterotopic ossification progress when the activity of PI3Kα was inhibited (Valer et al, 2019). RhoA-BMPs (Mu et al, 2013) and CGRP-SP-BMP-2 (Tuzmen et al, 2018) signaling also regulated heterotopic ossification progress in dystrophic muscle and Achilles tendon of mice, respectively.…”

Section: Discussionmentioning

confidence: 99%

Higher BMP Expression in Tendon Stem/Progenitor Cells Contributes to the Increased Heterotopic Ossification in Achilles Tendon With Aging

Dai

Liu

et al. 2020

Front. Cell Dev. Biol.

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Although the mineralization in tendon tissue has been reported in a series of aging and disease models, the underlying mechanisms remain unknown. This study aimed to describe the appearance of heterotopic ossification in rat Achilles tendon and further verify whether this tissue metaplasia is related to the enhanced osteogenic differentiation of tendon stem/progenitor cells (TSPCs) owing to the higher expression of bone morphogenetic proteins (BMP-2/4/7) with aging. The male SD rats, aged 4, 8, and 20 months (M), were used. The analyses of ossification and BMP expression in tendon were tested by radiological view (X-ray and CT), histological staining [hematoxylin and eosin (HE), Alcian blue, and Alizarin red], immunohistochemistry, and Western blot. The osteogenic differentiation potential and BMP expression of TSPCs were examined by Alizarin red S staining and real-time PCR. TSPCs were treated with BMP-2 or noggin, and the osteogenic differentiation potential was also examined. X-ray and CT showed the appearance of heterotopic ossification in tendon, and the volume and density of ossification was increased with aging. Histological staining showed the appearance of calcified region surrounded by chondrocyte-like cells and the increased osteogenesis-related gene and BMP expression in ossified tendon with aging. Moreover, the osteogenic differentiation potential and BMP expression in TSPCs isolated from ossified tendon were increased with aging. Additionally, BMP-2 increased the calcium nodule formation and osteogenesis-related gene expression in TSPCs. The addition of noggin inhibited BMP-induced enhancement of osteogenic differentiation. Thus, these findings suggested that the enhanced osteogenic differentiation of TSPCs contributes to the increased heterotopic ossification in aged tendon, which might be induced by the higher expression of BMPs with aging.

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Inhibition of phosphatidylinositol 3‐kinase α (PI3Kα) prevents heterotopic ossification

Cited by 27 publications

References 48 publications

Nesfatin-1 Promotes the Osteogenic Differentiation of Tendon-Derived Stem Cells and the Pathogenesis of Heterotopic Ossification in Rat Tendons via the mTOR Pathway

Nesfatin-1 Promotes the Osteogenic Differentiation of Tendon-Derived Stem Cells and the Pathogenesis of Heterotopic Ossification in Rat Tendons via the mTOR Pathway

ACVR1 Function in Health and Disease

Higher BMP Expression in Tendon Stem/Progenitor Cells Contributes to the Increased Heterotopic Ossification in Achilles Tendon With Aging

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