Transforming growth factor-beta1 promotes articular cartilage repair through canonical Smad and Hippo pathways in bone mesenchymal stem cells

Ying, Jun; Wang, Pinger; Zhang, Shanxing; Xu, Taotao; Zhang, Lei; Dong, Rui; Xu, Shibing; Tong, Peijian; Wu, Chengliang; Jin, Hongting

doi:10.1016/j.lfs.2017.11.028

Cited by 54 publications

(47 citation statements)

References 31 publications

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“…However, the role of the Hippo signaling pathway in chondrocyte differentiation and bone repair remains unclear. YAP1 may directly regulate the expression of SOX6 to promote the proliferation of chondrocytes ( 43 ), and inhibit the expression of collagen α-1(X) chain by interacting with runt-related transcription factor 2 (Runx2) to inhibit chondrocyte maturation ( 44 ). In the growth plate of the mouse embryo, YAP1 is expressed in the resting and proliferating layers, while p-YAP1 is expressed in the hypertrophic layer, and the expression of collagen α-1(X) chain and Runx2 in the hypertrophic layer is marked ( 43 ).…”

Section: Discussionmentioning

confidence: 99%

Hypoxia promotes maintenance of the chondrogenic phenotype in rat growth plate chondrocytes through the HIF-1α/YAP signaling pathway

Jing

et al. 2018

Int J Mol Med

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The Hippo-yes-associated protein (YAP) signaling pathway was previously identified to serve an important role in controlling chondrocyte differentiation and post-natal growth. Growth plate cartilage tissue is avascular, and hypoxia-inducible factor (HIF)-1α is essential for chondrocytes to maintain their chondrogenic phenotype in a hypoxic environment. In the present study, the role of hypoxia and HIF-1α in the regulation of YAP in chondrocytes was investigated. The data demonstrated that hypoxia promoted the maintenance of the chondrogenic phenotype, HIF-1α expression and YAP activation in chondrocytes in a time-dependent manner. Hypoxia promoted YAP activation in a Hippo-independent manner. Inhibiting the expression of HIF-1α decreased the activation of YAP and downregulated the expression of sex-determining region-box 9 protein (SOX9) under hypoxic conditions, while the upregulation of HIF-1α by cobalt chloride promoted the expression and nuclear translocation of YAP and upregulated the expression of SOX9 and collagen II chain under normoxic conditions. In addition, inhibition of YAP expression under hypoxia did not affect the expression of the HIF-1α signaling pathway, but inhibited the up-regulation of SOX9 expression caused by hypoxia. In addition, reoxygenation following hypoxia inhibited the activation of YAP caused by hypoxia in chondrocytes, whereas the upregulation of SOX9 and collagen II chain also appeared to be inhibited. In conclusion, the results of the present study demonstrated that hypoxia promoted YAP activation via HIF-1α. Therefore, the HIF-1α/YAP signaling axis may serve an important role in controlling growth plate chondrocyte differentiation and the maintenance of the chondrogenic phenotype in growth plate chondrocytes.

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Section: Discussionmentioning

confidence: 99%

Hypoxia promotes maintenance of the chondrogenic phenotype in rat growth plate chondrocytes through the HIF-1α/YAP signaling pathway

Jing

et al. 2018

Int J Mol Med

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“…Data represent mean ± SEM. *p < 0.05, **p < 0.01, n = 3 Ying et al 2018;Jahr et al 2019). The protein expression of TGF-β1 and phosphorylated-Smad2/3 was increased and their downstream expression of Runx2 was decreased.…”

Section: Effect Of Exosomes On the Repair Of Cartilage Defectmentioning

confidence: 95%

“…Therefore, we speculated that 3D-Exos might specifically activate the TGF-β1-dependent Smad2/3 signaling pathway to facilitate cartilage repair. To our knowledge, chondrogenesis is influenced by complicated cross-talk among signaling pathways, such as Wnt, Hedgehog, BMP, and AKT/ERK (Mao et al 2018;Ying et al 2018;Chen et al 2019). Further investigation is needed to picture comprehensive understanding of the pathway involved in 3D-Exos-induced chondrogenesis.…”

Section: Effect Of Exosomes On the Repair Of Cartilage Defectmentioning

confidence: 99%

Exosomes produced from 3D cultures of umbilical cord mesenchymal stem cells in a hollow-fiber bioreactor show improved osteochondral regeneration activity

Yan

2019

Cell Biol Toxicol

153

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Animal and clinical studies have shown that mesenchymal stem cells (MSCs) play an important role in cartilage repair. The therapeutic effect of mesenchymal stem cells based therapies has been increasingly demonstrated to exosome-mediated paracrine secretion. Here, we investigated the cellular processes and mechanism of exosomes produced by conventional 2D culture (2D-Exos) and exosomes produced from 3D culture (3D-Exos) of umbilical MSCs (U-MSCs) in a hollowfiber bioreactor for the treatment of cartilage repair. We found that the yield of 3D-Exos was 7.5-fold higher than that of 2D-Exos. The in vitro experiments indicated that both 2D-Exos and 3D-Exos can stimulate chondrocyte proliferation, migration, and matrix synthesis, and inhibit apoptosis, with 3D-Exos exerting a stronger effect than 2D-Exos. This effect was partly attributed to the activation of transforming growth factor beta 1 and Smad2/3 signaling. The injection of 2D-Exos and 3D-Exos showed enhanced gross appearance and attenuated cartilage defect; however, 3D-Exos showed a superior therapeutic effect than 2D-Exos. In summary, our study provides novel insights into the chondroprotective effects of exosomes produced from 3D culture of U-MSCs in a hollow-fiber bioreactor. Because of its promising biological function and high yield, 3D-Exos may become a promising therapeutic method for the treatment of cartilage defects.

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“…Various GFs that affect chondrogenic differentiation, homeostasis, and healing processes have been identified. Transforming growth factor‐β (TGFs‐β) family (Ying et al, ); bone morphogenetic proteins (BMPs) family (Chubinskaya & Rueger, ); insulin growth factor I (IGF‐I; Zhang et al, ), fibroblast growth factor (FGF) family;(Khan, Muhammad, Scammahorn, Dell'Accio, & Vincent, ) platelet‐derived growth factor (PDGF; Yokota et al, ) are among the most widely investigated GFs for articular tissue regeneration. Basic fibroblast growth factor (bFGF) can be found bound in the pericellular matrix, perlecan (Chia et al, ).…”

Section: Introductionmentioning

confidence: 99%

Dual growth factor delivery using PLGA nanoparticles in silk fibroin/PEGDMA hydrogels for articular cartilage tissue engineering

et al. 2019

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Transforming growth factor-beta1 promotes articular cartilage repair through canonical Smad and Hippo pathways in bone mesenchymal stem cells

Cited by 54 publications

References 31 publications

Hypoxia promotes maintenance of the chondrogenic phenotype in rat growth plate chondrocytes through the HIF-1α/YAP signaling pathway

Hypoxia promotes maintenance of the chondrogenic phenotype in rat growth plate chondrocytes through the HIF-1α/YAP signaling pathway

Exosomes produced from 3D cultures of umbilical cord mesenchymal stem cells in a hollow-fiber bioreactor show improved osteochondral regeneration activity

Dual growth factor delivery using PLGA nanoparticles in silk fibroin/PEGDMA hydrogels for articular cartilage tissue engineering

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