Characterization of osteogenic differentiation and gene expression profile of multiple miliary osteoma cutis

Multiple miliary osteoma cutis (MMOC) is a rare skin disorder characterized by heterotopic ossification in dermis and subcutis. The etiology and disease mechanism is unknown, but earlier data indicates that it seems to be different from other diseases containing heterotopic intramembranous ossification. The purpose of this study was to further investigate the pathogenesis of MMOC by comparing patients osteoma affected skin area to their unaffected healthy skin area, as well as to skin from controls. This comparison was made by using osteogenic differentiation studies in cell cultures and by gene expression experiments. Both patient and control dermal fibroblast-like cells were able to differentiate into osteoblast-like matrix mineralizing cells. The differentiation seems to diminish with bone morphogenetic protein (BMP) 4 and 2/7 exposures and seems to correlate with proportion of stem cell associated cell surface marker CD105 positive cells. Microarray analysis revealed altered gene expression patterns between skin samples of patients and controls, as well as between samples taken from different skin areas. BMP receptor II and G-protein -stimulatory subunit genes were among downregulated and -catenin among upregulated genes in patient compared to control samples. Genes for homeobox proteins were among downregulated and gene for secreted frizzled related protein 2 among upregulated genes when compared patients osteoma area to their unaffected area. Differences in unaffected skin area in patients and controls suggest that the nature of MMOC may be more systemic than previously thought. Detected differences in separate skin areas may, in turn, provide new information for understanding the localized characteristics of MMOC. BMPs inhibitory effect to osteogenic differentiation of human dermal fibroblast-like cells may provide a new perspective to the clinical use of BMPs.

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