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Young, David A.; Lakey, Rachel; Pennington, Caroline J.; Jones, Debbie; Kevorkian, Lara; Edwards, Dylan R.; Cawston, Timothy E.; Clark, Ian M.

doi:10.1186/ar1702

Cited by 156 publications

(58 citation statements)

References 60 publications

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“…Therefore, the suppression of type II collagen expression by HDAC inhibitors suggests that HDAC activity is required for the maintenance of cartilage homeostasis. In contrast to our current results, it has been suggested that HDAC is a target for the suppression of cartilage degradation (33,34). This is based on reports that HDAC inhibitors suppress the ability of IL-1␣ and oncostatin M to enhance the expression of the matrix metalloproteinase gene in SW1353 chondrosarcoma cells and primary human chondrocytes (34) and that HDAC inhibitors modulate the expression of genes involved in the pathogenesis of adjuvant-induced rheumatoid arthritis (35).…”

Section: Hdac Regulates the Growth And Differentiation Of Variouscontrasting

confidence: 97%

“…In contrast to our current results, it has been suggested that HDAC is a target for the suppression of cartilage degradation (33,34). This is based on reports that HDAC inhibitors suppress the ability of IL-1␣ and oncostatin M to enhance the expression of the matrix metalloproteinase gene in SW1353 chondrosarcoma cells and primary human chondrocytes (34) and that HDAC inhibitors modulate the expression of genes involved in the pathogenesis of adjuvant-induced rheumatoid arthritis (35). Therefore, our finding that HDAC inhibitors block chondrocyte synthesis of type II collagen, a key molecule in cartilage extracellular matrix, raises questions about the use of HDAC inhibitors to suppress cartilage degradation.…”

Section: Hdac Regulates the Growth And Differentiation Of Variouscontrasting

confidence: 97%

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Regulation of Type II Collagen Expression by Histone Deacetylase in Articular Chondrocytes

Huh

Ryu

Chun

2007

Journal of Biological Chemistry

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Histone deacetylase (HDAC) regulates various cellular processes by modulating gene expression. Here, we investigated the role of HDAC in the expression of type II collagen, a marker of differentiated chondrocytes. We found that HDAC activity in primary articular chondrocytes decreases during dedifferentiation induced by serial monolayer culture and that the activity recovered during redifferentiation induced by three-dimensional culture in a cell pellet. Inhibition of HDAC with trichostatin A or PXD101 was sufficient to block type II collagen expression in primary culture chondrocytes. HDAC inhibition also blocked the redifferentiation of dedifferentiated chondrocytes by suppressing the synthesis and accumulation of type II collagen. HDAC inhibition promoted the expression of Wnt-5a, which is known to inhibit type II collagen expression, and knockdown of Wnt-5a blocked the ability of HDAC inhibitors to suppress type II collagen expression. In addition, the induction of Wnt-5a expression by HDAC inhibitors was associated with acetylation of the Wnt-5a promoter. Taken together, our results suggest that HDAC promotes type II collagen expression by suppressing the transcription of Wnt-5a.Differentiation of uncommitted mesenchymal cells into chondrocytes is initiated by the proliferation and recruitment of chondrogenic mesenchymal cells into condensations. These precartilage condensations develop into cartilage nodules containing differentiated chondrocytes. Chondrogenesis can be mimicked by micromass culture of mesenchymal cells in vitro. Differentiated chondrocytes are characterized by the ability to synthesize cartilage-specific extracellular matrix molecules including type II collagen and sulfated proteoglycans, which are necessary for normal cartilage development (1, 2). The activity of cartilage-specific matrix molecule synthesis by the differentiated chondrocytes is unstable and rapidly lost in response to certain environmental changes. For instance, proinflammatory cytokines such as interleukin (IL) 2 -1␤ cause the loss of differentiated chondrocyte phenotypes (dedifferentiation) by halting the synthesis of cartilage-specific matrix molecules (3, 4). Chondrocyte dedifferentiation is also induced by serial monolayer culture and is accompanied by a gradual shift in the expression of type II collagen and aggrecan to type I and III collagen and versican, respectively (5, 6). Dedifferentiated chondrocytes redifferentiate in three-dimensional culture in an alginate gel or cell pellet (6, 7). Although maintenance of a differentiated chondrocyte phenotype is important for cartilage homeostasis, the detailed mechanisms of the differentiation and dedifferentiation of chondrocytes remain largely unknown. Because chondrocyte differentiation/dedifferentiation is regulated by various soluble factors including growth factors and cytokines, we hypothesized that histone deacetylase (HDAC) may regulate the differentiation status of chondrocytes. HDAC modulates the growth and differentiation of various cell types by governing...

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Section: Hdac Regulates the Growth And Differentiation Of Variouscontrasting

confidence: 97%

Section: Hdac Regulates the Growth And Differentiation Of Variouscontrasting

confidence: 97%

Regulation of Type II Collagen Expression by Histone Deacetylase in Articular Chondrocytes

Huh

Ryu

Chun

2007

Journal of Biological Chemistry

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“…26,46,47) Trichostatin A, a HDAC inhibitor, suppressed synovial inflammation and subsequent cartilage destruction in a collagen antibody-induced arthritis mouse model. 26) In this regard, we examined whether or not emodin can influence HDAC expression and activity in IL-1b and LPStreated synoviocytes under hypoxia.…”

Section: Discussionmentioning

confidence: 99%

Emodin Inhibits Proinflammatory Responses and Inactivates Histone Deacetylase 1 in Hypoxic Rheumatoid Synoviocytes

Song

Jeong

et al. 2011

Biological & Pharmaceutical Bulletin

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“…Although HDACs are critically involved in diverse biological processes, their function in chondrocyte biology and cartilage diseases have only recently been explored. Recent work indicates that inhibition of HDACs reduces the expression of matrix metalloproteinase in chondrocytes and fibroblasts (7) and, therefore, inhibits arthritis progression in animal models (8,9). Additionally, it has been demonstrated that HDAC4, a Class II enzyme, plays a critical role in the onset of chondrocyte hypertrophy during endochondral ossification (10).…”

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confidence: 99%

Regulation of Cartilage-specific Gene Expression in Human Chondrocytes by SirT1 and Nicotinamide Phosphoribosyltransferase

Dvir-Ginzberg

Gagarina

Lee

et al. 2008

Journal of Biological Chemistry

179

230

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SirT1 is an NAD-dependent histone deacetylase that regulates gene expression, differentiation, development, and organism life span. Here we investigate the function of SirT1 in human chondrocytes derived from osteoarthritic patients. Elevation of SirT1 protein levels or activity in these chondrocytes led to a dramatic increase in cartilage-specific gene expression, whereas a reduction in SirT1 levels or activity significantly lowered cartilage gene expression. SirT1 associated with the cartilage-specific transcription factor Sox9, enhancing transcription from the collagen 2(␣1) promoter in a Sox9-dependent fashion. Consistent with this association, SirT1 was targeted to the collagen 2(␣1) enhancer and promoter, which in turn recruited the coactivators GCN5, PGC1␣, and p300. This led to elevated marks of active chromatin within the promoter; that is, acetylated histone K9/K14 and histone H4K5 as well as trimethylated histone H3K4. Finally, alterations in the NAD salvage pathway enzyme nicotinamide phosphoribosyltransferase led to changes in NAD levels, SirT activity, and cartilage-specific gene expression in human chondrocytes. SirT1, nicotinamide phosphoribosyltransferase, and NAD may, therefore, provide a positive function in human cartilage by elevating expression of genes encoding cartilage extracellular matrix.Transcriptional control over cartilage-specific gene expression plays a critical role in maintenance of the chondrocyte phenotype (1). Much effort has, therefore, gone into the characterization of chondrocyte-specific transcription factors such as Sox9, -5, and -6 (28). However, it is likely that other factors such as chromatin-modifying enzymes play important roles in controlling cartilage-specific gene expression. Chromatinmodifying enzymes, which include the histone acetyltransferases (HATs) 2 and the histone deacetylases (HDACs) can act as potent transcriptional coactivators and corepressors, respectively, for a variety of genes (2). HATs modify the core histones through acetylation of lysine residues, thereby relaxing chromatin for transcription initiation and elongation (3). HDACs remove the acetyl groups, leading to chromatin condensation and transcriptional repression (4). Additionally, acetylation and deacetylation of transcription factors provide another level of regulation over gene expression (2). In some contexts HDACs are more sensitive to environmental or developmental cues than the HATs and can provide a regulatory role in transcription. In this regard, HDACs have been demonstrated to control both cell proliferation and differentiation through the deacetylation of transcription factors, cytoplasmic proteins, and histones (5, 6). Although HDACs are critically involved in diverse biological processes, their function in chondrocyte biology and cartilage diseases have only recently been explored. Recent work indicates that inhibition of HDACs reduces the expression of matrix metalloproteinase in chondrocytes and fibroblasts (7) and, therefore, inhibits arthritis progression in animal models...

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Untitled

Cited by 156 publications

References 60 publications

Regulation of Type II Collagen Expression by Histone Deacetylase in Articular Chondrocytes

Regulation of Type II Collagen Expression by Histone Deacetylase in Articular Chondrocytes

Emodin Inhibits Proinflammatory Responses and Inactivates Histone Deacetylase 1 in Hypoxic Rheumatoid Synoviocytes

Regulation of Cartilage-specific Gene Expression in Human Chondrocytes by SirT1 and Nicotinamide Phosphoribosyltransferase

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