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Skeletogenesis, remodeling, and maintenance in adult tissues are regulated by sequential activation of genes coding for specific transcription factors. The conserved Homeobox genes (<i>HOX</i>, in humans) are involved in several skeletal pathologies. Osteoarthritis (OA) is characterized by homeostatic alterations of cartilage and bone synthesis, resulting in cartilage destruction and increased bone formation. We postulate that alterations in <i>HOX</i> expression in Mesenchymal Stem cells (MSCs) are likely one of the causes explaining the homeostatic alterations in OA and that this altered expression could be the result of epigenetic regulation. The expression of <i>HOX</i> genes in osteoarthritic-derived MSCs was screened using PCR arrays. Epigenetic regulation of <i>HOX</i> was analyzed measuring the degree of DNA methylation in their promoters. We demonstrate the downregulated expression of <i>HOXA9</i> and <i>HOXC8</i> in OA-MSCs. However, their expression does not correlate with promoter methylation status, suggesting that other epigenetic mechanisms could be implicated in the regulation of <i>HOX</i> expression. Studies on the role of these genes under active differentiation conditions need to be addressed for a better knowledge of the mechanisms regulating the expression of <i>HOX</i>, to allow a better understanding of OA pathology and to define possible biomarkers for therapeutic treatment.