TGF-β2 is involved in the preservation of the chondrocyte phenotype under hypoxic conditions

Das, R.; Timur, Ufuk Tan; Edip, S.T.; Haak, Esther; Wruck, Christoph Jan; Weinans, Harrie; Jahr, Holger

doi:10.1016/j.aanat.2014.11.003

Cited by 24 publications

(38 citation statements)

References 81 publications

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“…Combined with the proof that hypoxia is established in the implanted constructs in vivo and that sFlk1 does not directly affect chondrogenesis in vitro in 20% oxygen conditions, these findings strongly suggest that VEGF blockade primes MSC to form cartilage indirectly by inhibiting angiogenesis and generating a hypoxic environment. Analysis of TGFβ expression and inhibition of TGFβ signaling further suggest that the hypoxic conditions activated chondrogenesis by inducing TGFβ upregulation, as recently observed in a chondrocyte culture model [42], thereby dispensing with the need to provide stimulation with exogenous morphogens. Further studies are required to define the temporal kinetics of TGFβ production at the protein level and whether possibly increased quantities would be found embedded within the deposited extracellular matrix or released in the culture medium.…”

Section: Discussionmentioning

confidence: 77%

Spontaneous In Vivo Chondrogenesis of Bone Marrow-Derived Mesenchymal Progenitor Cells by Blocking Vascular Endothelial Growth Factor Signaling

Marsano

Cunha

Ghanaati

et al. 2016

Stem Cells Translational Medicine

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This study assessed whether simple inhibition of angiogenesis by vascular endothelial growth factor (VEGF) blockade is sufficient to direct in vivo chondrogenic differentiation of implanted human mesenchymal stromal/stem cells (MSCs). MSCs transduced to express sFlk‐1 and directly implanted subcutaneously in nude mice without in vitro preculture spontaneously differentiated into the chondrocytic lineage with a stable phenotype for the observation time‐period of 12 weeks. These findings suggest that VEGF blockade is a robust strategy to enhance cartilage repair by endogenous or grafted mesenchymal progenitors.

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Section: Discussionmentioning

confidence: 77%

Spontaneous In Vivo Chondrogenesis of Bone Marrow-Derived Mesenchymal Progenitor Cells by Blocking Vascular Endothelial Growth Factor Signaling

Marsano

Cunha

Ghanaati

et al. 2016

Stem Cells Translational Medicine

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“…HAS2 is induced by hypoxia in chondrocytes, but the mechanism underlying this induction is not clear. In accordance with the results in chondrocytes, we found that hypoxia significantly increased the expression of HAS2 in OSCC cells in an HIF‐1α and NF‐κB dependent manner.…”

Section: Discussionmentioning

confidence: 99%

Long noncoding RNA HAS2‐AS1 mediates hypoxia‐induced invasiveness of oral squamous cell carcinoma

Zhu¹,

Wang

Chen

et al. 2017

Molecular Carcinogenesis

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A hypoxic microenvironment plays important roles in the progression of solid tumors, including oral squamous cell carcinoma (OSCC). Long noncoding RNAs (lncRNAs) have gained much attention in the past few years. However, it is not clear whether lncRNAs can regulate hypoxia adaptation of OSCC or which lncRNAs participate in this process. Using a lncRNA microarray, we analyzed the aberrant lncRNA expression profiles in OSCC tissues compared with paired normal oral mucosa and in hypoxic OSCC cells compared with normoxic OSCC cells. The top 10 lncRNAs that had more than threefold increase with P‐value <0.01 in both microarray data were validated by qRT‐PCR. Among the top 10 lncRNAs, hyaluronan synthase 2 antisense 1 (HAS2‐AS1) was the only one that has a hypoxia‐responsive element (HRE) on its promoter region and has been validated to increase in OSCC tissues and in cells cultured under hypoxia. Tumor HAS2‐AS1 levels were closely associated with lymph node metastasis and hypoxic tumor status in patients with OSCC. Moreover, the hypoxia‐induced HAS2‐AS1 expression is dependent on HIF‐1α which directly binds to and activates the transcription of HAS2‐AS1. In addition, HAS2‐AS1 mediates hypoxia‐induced epithelial mesenchymal transition of OSCC cells via stabilizing HAS2. In conclusion, our results suggest that hypoxia would induce an overexpression of HAS2‐AS1 in an HIF‐1α dependent manner. The increase of HAS2‐AS1 plays important roles mediating the hypoxia‐regulated EMT and invasiveness of OSCC.

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“…The TGF-β superfamily plays significant roles in enhancing chondrocyte growth, chondrocyte proliferation and osteochondrogenic differentiation [ 25 ]. TGF-β2 can stimulate chondrocyte proliferation and cartilage regeneration [ 32 , 33 ]; TGF-β3 may act as a chemotactic molecule (i.e., biological cue) that can recruit bone marrow stem cells, induce the recruited stem cells toward chondrogenesis, and enhance the compressive properties of neocartilage [ 34 ]. Based on the current data, we thus suggest that direct manipulation of in situ microenvironments (i.e., GlcNAc injection) provides a better mix of endogenous growth factors and cytokines, especially in the early stage, for cartilage repair.…”

Section: Discussionmentioning

confidence: 99%

The repair of full-thickness articular cartilage defect using intra-articular administration of N-acetyl-d-glucosamine in the rabbit knee: randomized controlled trial

Chang

Lin

et al. 2015

BioMed Eng OnLine

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BackgroundAlthough various alterative models of therapy are used for cartilage repair, no definite conclusion has been reached. Glucosamine (GlcN) is widely used as a nutritional supplement. However, the clinical- evidence-based outcome of GlcN administration remains controversial. N-acetyl-d-glucosamine (GlcNAc), a derivative of GlcN, shows chondroprotective activity and mediates the activation of articular chondrocytes. Therefore, we investigated the effect of intra-articular administration of GlcNAc in rabbits’ knee joints with experimental full-thickness articular cartilage (FTAC) defects.MethodsTwelve male adult New Zealand white rabbits, providing 24 knees, were used in this study. FTAC defects were created in the high-weight-bearing area of the medial femoral condyles of bilateral knees. All rabbits were randomly allocated to analysis at postsurgical week 4 or postsurgical week 12. In the week 4 group, rabbits’ knees (six per group) were intra-articularly injected with normal saline or with GlcNAc twice per week for 3 weeks, beginning 1 week postoperatively. In the week 12 group, the rabbits’ knees (six in each group) were intra-articularly injected with normal saline or with GlcNAc twice per week for 4 weeks, beginning 1 week postoperatively. Rabbits were sacrificed at 4 or 12 weeks after surgery for macroscopic, histological and radiological examinations of the knee joints.ResultsAll rabbits had no systemic or local adverse effects. The saline and GlcNAc groups showed visible differences in healing of the FTAC defect at the end of testing. At week 4, the GlcNAc group had a higher level of collagen type II (COL II) and showed up-regulated production of transforming growth factor (TGF)-β2 and TGF-β3, suggesting the involvement of endogenous growth factors. At week 12, the GlcNAc group displayed formation of hyaline-like cartilage regeneration with mature chondrocytes (SOX9+), robust glycosaminoglycan (GAG) content, and positive COL II content in both the adjacent cartilage and reparative sites. However, the saline group demonstrated mainly fibrocartilage scar tissue, indicating COL I expression. Furthermore, the GlcNAc group had significantly higher bone volume per tissue volume and higher trabecular thickness than the saline group.ConclusionsIntra-articular GlcNAc may promote the repair of experimental FTAC defects in the rabbit knee joint model.

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TGF-β2 is involved in the preservation of the chondrocyte phenotype under hypoxic conditions

Cited by 24 publications

References 81 publications

Spontaneous In Vivo Chondrogenesis of Bone Marrow-Derived Mesenchymal Progenitor Cells by Blocking Vascular Endothelial Growth Factor Signaling

Spontaneous In Vivo Chondrogenesis of Bone Marrow-Derived Mesenchymal Progenitor Cells by Blocking Vascular Endothelial Growth Factor Signaling

Long noncoding RNA HAS2‐AS1 mediates hypoxia‐induced invasiveness of oral squamous cell carcinoma

The repair of full-thickness articular cartilage defect using intra-articular administration of N-acetyl-d-glucosamine in the rabbit knee: randomized controlled trial

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