MicroRNA‐1 regulates chondrocyte phenotype by repressing histone deacetylase 4 during growth plate development

Li, Pengcui; Wei, Xiaochun; Guan, Yingjie; Chen, Qian; Zhao, Tingcun; Sun, Changqi; Wei, Lei

doi:10.1096/fj.13-249318

Cited by 40 publications

(41 citation statements)

References 35 publications

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“…Thus, caspase seems to be the only connection between elevated p38 activity and increased HDAC4 degradation in chondrocytes. In addition to the experimental evidence supporting the HDAC4/Runx2 interaction provided in this manuscript and by Vega et al, 2004, we also showed HDAC4 inhibits Runx2 promoter in a dose-dependent manner (Li et al, 2014). Arnold et al also showed that HDAC4 regulates the chondrocyte hypertrophy through MEF2 (Arnold et al, 2007).…”

Section: Resultssupporting

confidence: 63%

Mitogen-activated protein kinase p38 induces HDAC4 degradation in hypertrophic chondrocytes

Zhou

Chen

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Histone deacetylase 4 (HDAC4) is a critical negative regulator for chondrocyte hypertrophy by binding to and inhibiting Runx2, a critical transcription factor for chondrocyte hypertrophy. It is unclear how HDAC4 expression and stability are regulated during growth plate development. We report here that inhibition of mitogen-activated protein kinase (MAPK) p38 by dominant negative p38 or p38 inhibitor prevents HDAC4 degradation. Mutation of a potential caspase-2 and 3 cleavage site Asp289 stabilizes HDAC4 in chondrocytes. In contrast, constitutively active MAPK kinase 6 (constitutive activator of p38) transgenic mice exhibit decreased HDAC4 content in vivo. We also observed p38 stimulates caspase-3 activity in chondrocytes. Inhibition of p38 or caspases reduced HDAC4 degradation. HDAC4 inhibited Runx2 promoter activity in a dose-dependent manner and caspase inhibitors further enhanced this inhibition by preventing HDAC4 degradation. Overall, these results demonstrate that p38 promotes HDAC4 degradation by increasing caspase-mediated cleavage, which releases Runx2 from a repressive influence of HDAC4 and promotes the chondrocyte hypertrophy and bone formation.

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Section: Resultssupporting

confidence: 63%

Mitogen-activated protein kinase p38 induces HDAC4 degradation in hypertrophic chondrocytes

Zhou

Chen

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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“…Runx2 is a well known transcriptional factor that strongly induces Col X, Ihh and MMP-13 production[37-40]. Our previous studies[21] showed that CaMKIV modulates chondrocyte differentiation through regulating Runx2 promoter activities via HDAC4 subcellular localization during growth plate development.…”

Section: Discussionmentioning

confidence: 99%

Compression regulates gene expression of chondrocytes through HDAC4 nuclear relocation via PP2A-dependent HDAC4 dephosphorylation

Chen

Wei

Wang

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Biomechanics play a critical role in the modulation of chondrocyte function. The mechanisms by which mechanical loading is transduced into intracellular signals that regulate chondrocyte gene expression remain largely unknown. Histone deacetylase 4 (HDAC4) is specifically expressed in chondrocytes. Mice lacking HDAC4 display chondrocyte hypertrophy, ectopic and premature ossification, and die early during the perinatal period. HDAC4 has a remarkable ability to translocate between the cell's cytoplasm and nucleus. It has been established that subcellular relocation of HDAC4 plays a critical role in chondrocyte differentiation and proliferation. However, it remains unclear whether subcellular relocation of HDAC4 in chondrocytes can be induced by mechanical loading. In this study, we first report that compressive loading induces HDAC4 relocation from the cytoplasm to the nucleus of chondrocytes via stimulation of Ser/Thr-phosphoprotein phosphatases 2A (PP2A) activity, which results in dephosphorylation of HDAC4. Dephosphorylated HDAC4 relocates to the nucleus to achieve transcriptional repression of Runx2 and regulates chondrocyte gene expression in response to compression. Our results elucidate the mechanism by which mechanical compression regulates chondrocyte gene expression through HDAC4 relocation from the cell's cytoplasm to the nucleus via PP2A-depended HDAC4 dephosphorylation.

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“…MiR1 is highly expressed in the hypertrophic zone of growth plate cartilage, some 8fold higher than in the proliferation zone [77] . MiR1 strongly promotes chondrocyte proliferation and differentiation, including induction of the expression of chondrocyte markers Indian hedgehog and Col X, and acts by targetting HDAC4.…”

Section: Chondrocyte Differentiationmentioning

confidence: 99%

Roles of the canonical myomiRs miR-1, -133 and -206 in cell development and disease

Mitchelson¹

2015

WJBC

140

132

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MicroRNAs are small non-coding RNAs that participate in different biological processes, providing subtle combinational regulation of cellular pathways, often by regulating components of signalling pathways. Aberrant expression of miRNAs is an important factor in the development and progression of disease. The canonical myomiRs (miR-1, -133 and -206) are central to the development and health of mammalian skeletal and cardiac muscles, but new findings show they have regulatory roles in the development of other mammalian non-muscle tissues, including nerve, brain structures, adipose and some specialised immunological cells. Moreover, the deregulation of myomiR expression is associated with a variety of different cancers, where typically they have tumor suppressor functions, although examples of an oncogenic role illustrate their diverse function in different cell environments. This review examines the involvement of the related myomiRs at the crossroads between cell development/ tissue regeneration/tissue inflammation responses, and cancer development. Core tip: The roles of the canonical muscle-associated microRNAs are reviewed, including microRNA families miR-1 and miR-133, and single miR-206, which are collectively known as the "myomiRs". The myomiRs act at the crossroads of the molecular regulation of muscle cells, linking between pathways for cell differentiation, development and maintenance, but also potentiate aberrant cell growth in numerous non-muscle cancers. Typically myomiRs are downregulated in cancers, but some myomiRs are upregulated in a few cancers, yet each dysregulation event advances tumor progression. The review examines normal and disease-linked molecular changes associated with the myomiRs, and collates the extensive literature into accessible tables. REVIEW

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MicroRNA‐1 regulates chondrocyte phenotype by repressing histone deacetylase 4 during growth plate development

Cited by 40 publications

References 35 publications

Mitogen-activated protein kinase p38 induces HDAC4 degradation in hypertrophic chondrocytes

Mitogen-activated protein kinase p38 induces HDAC4 degradation in hypertrophic chondrocytes

Compression regulates gene expression of chondrocytes through HDAC4 nuclear relocation via PP2A-dependent HDAC4 dephosphorylation

Roles of the canonical myomiRs miR-1, -133 and -206 in cell development and disease

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