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Title: On MEF2C regulation of the chondrocyte phenotype
Author: Lazzarano, Stefano
ISNI:       0000 0004 6059 1324
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2015
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Articular cartilage is a highly specialised tissue composed of a mechanically competent matrix and a single cell population - the chondrocytes. The maintaining of a specialised phenotype requires the integration of intracellular signalling, that in response to appropriate extracellular stimuli, results in expression of cell-specific genes. Previous work in our laboratory has identified hypoxia as one such key stimulus, which through HIF-2α, enhances expression of cartilage master regulator SOX9 and its matrix-encoding target genes (COL2A1, AGC and COL9A1). MEF2C transcription factor is known to be involved in muscle and cardiovascular development; however, recently it has been shown to play a key role in chondrocyte hypertrophy co-ordinately with SOX9. In a previous microarray analysis, we found that MEF2C was upregulated during hypoxia-induced re-dedifferentiation of human articular chondrocytes (HACs); interestingly where its suggested genetic target - COL10A1 - was barely detectable. In this research we therefore investigated a possible new and unknown function of MEF2C transcription factor as a potential genetic regulator of the permanent articular chondrocyte phenotype. In this study, MEF2C protein was detected with a nuclear localisation in chondrocytes in situ in intact healthy human articular cartilage. Experiments in isolated HACs revealed that, at both gene and protein levels, hypoxia enhances MEF2C expression in a HIF-2α and SOX9 dependent fashion. Subsequently, depletion experiments of MEF2C indicated that it is required for SOX9 gene expression both in normoxia and hypoxia. Our results, therefore suggest a mutual positive regulation between MEF2C and SOX9 transcription factors in articular cartilage. Thus, based on our studies a new and critical function for transcription factor MEF2C in HACs has been identified, where it helps promote expression of the differentiated chondrocyte phenotype through mutual regulation with SOX9. These findings give important new insights into our understanding of the transcription factor networks that regulate expression of the articular chondrocyte phenotype.
Supervisor: Chris, Murphy Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral