Molecular mechanism of hypoxia-induced chondrogenesis and its application in in vivo cartilage tissue engineering

Duval, Elise; Baugé, Catherine; Andriamanalijaona, Rina; Benateau, Hervé; Leclercq, S.; Dutoit, Soizic; Poulain, Laurent; Galéra, Philippe; Boumédiene, Karim

doi:10.1016/j.biomaterials.2012.04.061

Cited by 113 publications

(121 citation statements)

References 37 publications

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“…HIF-1␣ as a key component in the genetic program that regulates chondrogenesis by regulating SOX9 expression in hypoxic prechondrogenic cells during early skeletogenesis [25]. In the cartilage engineering, HIF-1␣ also shows its chondrogenesis capacity; overexpressed HIF-1␣ is effective and sufficient to induce chondrocyte phenotype in human bone marrow cells even without use of exogenous growth factors [26]. HIF-1␣ also acts as a central regulator of collagen production that allows chondrocytes to maintain their function as professional secretory cells in the hypoxic growth plate [27,28].…”

Section: Hif-1␣ In Cartilage and Oamentioning

confidence: 99%

Role of HIF-1α and HIF-2α in osteoarthritis

2015

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Section: Hif-1␣ In Cartilage and Oamentioning

confidence: 99%

Role of HIF-1α and HIF-2α in osteoarthritis

2015

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“…In contrast with HIF-1α [45], the role of HIF-2α during chondrogenesis is debatable [46]. It has been shown that HIF-2α can induce the expression of hypertrophic markers such as type X collagen and MMP13 in hypertrophic and osteoarthritic chondrocytes [47,48].…”

Section: Discussionmentioning

confidence: 99%

Inverse Regulation of Early and Late Chondrogenic Differentiation by Oxygen Tension Provides Cues for Stem Cell-Based Cartilage Tissue Engineering

Portron

Hivernaud

Merceron

et al. 2015

Cell Physiol Biochem

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Background/Aims: Multipotent stem/stromal cells (MSC) are considered promising for cartilage tissue engineering. However, chondrogenic differentiation of MSC can ultimately lead to the formation of hypertrophic chondrocytes responsible for the calcification of cartilage. To prevent the production of this calcified matrix at the articular site, the late hypertrophic differentiation of MSCs must be carefully controlled. Given that articular cartilage is avascular, we hypothesized that in addition to its stimulatory role in the early differentiation of chondrogenic cells, hypoxia may prevent their late hypertrophic conversion. Methods: Early and late chondrogenic differentiation were evaluated using human adipose MSC and murine ATDC5 cells cultured under either normoxic (21%O₂) or hypoxic (5%O₂) conditions. To investigate the effect of hypoxia on late chondrogenic differentiation, the transcriptional activity of hypoxia-inducible factor-1alpha (HIF-1α) and HIF-2α were evaluated using the NoShift DNA-binding assay and through modulation of their activity (chemical inhibitor, RNA interference). Results: Our data demonstrate that low oxygen tension not only stimulates the early chondrogenic commitment of two complementary models of chondrogenic cells, but also inhibits their hypertrophic differentiation. Conclusion: These results suggest that hypoxia can be used as an instrumental tool to prevent the formation of a calcified matrix in MSC-based cartilage tissue engineering.

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“…HIF-1α shows a capacity for inducing chondrogenesis in the setting of cartilage engineering. HIF-1α effectively induced the chondrocyte phenotype of human bone marrow cells without exogenous growth factors [4]. In the hypoxia growth plate, HIF-1α maintains chondrocytes function as professional secretory cells by regulating collagen production [5].…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-146a Induced by Hypoxia Promotes Chondrocyte Autophagy through Bcl-2

Zhang¹,

Wang

Chu

et al. 2015

Cell Physiol Biochem

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Background/Aims: There have been many studies on the etiology of osteoarthritis (OA) with regard to the function of inflammatory cytokines, the process of cartilage degradation, the function of miR-146a, hypoxia stimulation and autophagy in OA chondrocytes, but there have been no reports on the relationship between miR-146a and autophagy in cartilage, especially under hypoxia. This study aimed to confirm the relationship of miR-146a and autophagy in cartilage under hypoxia. Methods: Chondrocytes were treated by hypoxia gradients, and the main factors including HIF-1α, HIF-2α, miR-146a and Bcl-2 and autophagy markers ULK-1, ATG-5 were detected by quantitative PCR (Q-PCR) and western blotting. The autophagy marker LC-3 was detected by immunofluorescence. The reciprocal effects between miR-146a and Bcl-2 were confirmed by several combinations of shRNAs and adenovirus-gene systems followed by Q-PCR and western blot detection. Results: Hypoxia maintained the chondrocytes phenotype and promoted autophagy and miR-146a expression via HIF-1α, but not HIF-2α, while miR-146a did not reversely affect HIF-1α. The autophagy induced by hypoxia through HIF-1α, miR-146a and Bcl-2. Simply, hypoxia induced HIF-1α, and HIF-1α increased miR-146a, but miR-146a suppressed Bcl-2, an autophagy inhibitor. While Bcl-2 affected neither HIF-1α nor miR-146a. The absence of both HIF-1α and miR-146a or Bcl-2 over-expression inhibited hypoxia-induced autophagy. Conclusion: HIF-1α, miR-146a and Bcl-2 play crucial roles during hypoxia-induced autophagy, Hypoxia, HIF-1α and miR-146a promote chondrocytes autophagy via depressing Bcl-2. We conclude that miR-146a may serve as a novel therapeutic target for protecting cartilage from degeneration in OA.

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Molecular mechanism of hypoxia-induced chondrogenesis and its application in in vivo cartilage tissue engineering

Cited by 113 publications

References 37 publications

Role of HIF-1α and HIF-2α in osteoarthritis

Role of HIF-1α and HIF-2α in osteoarthritis

Inverse Regulation of Early and Late Chondrogenic Differentiation by Oxygen Tension Provides Cues for Stem Cell-Based Cartilage Tissue Engineering

MicroRNA-146a Induced by Hypoxia Promotes Chondrocyte Autophagy through Bcl-2

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