Cover image

Cover Long-range transcriptional regulation in Van Buchem (VB) disease and impact of SOST overexpression on bone metabolism and development. VB is a severe bone dysplasia characterized by increased bone mass and illustrated by the central hipbone and the bone density gradient on the left margin (low to high; top to bottom). VB is highly similar and maps to the same locus as sclerosteosis, a hyperosteosis caused by SOST mutations. Unlike sclerosteosis, VB patients do not carry any coding mutations, they are however linked to a homozygous 52kb noncoding deletion 35kb downstream of sclerostin. In this issue, through a combination of transgenic mice, comparative sequence analysis (represented by the sequence stream on the left), and various enhancer assays, Loots and colleagues suggest that VB and sclerosteosis are allelic, and that VB disease is caused by the removal of key bone-specific regulatory elements distantly positioned from the SOST promoter and contained within the noncoding VB deletion. The long-range transcriptional regulation is depicted by the concentric circles that ripple toward the mouse embryo (E14.5) that was used as an in vivo reporter assay to identify the best SOST-specific enhancer candidate. In addition, SOST transgenic mice are osteopenic and have severe limb abnormalities [microCT scans of normal and defective fore- (horizontal) and hind-limbs (vertical)].

The drawing of the hip bone was created using a traditional medical illustrator's technique originally developed by Max Brodel, founder of the Art as Applied to Medicine Department at Johns Hopkins University. The tone of the drawing is built up on textured paper by applying carbon dust in layers using a dry paintbrush. Dark and light shades are achieved by applying more carbon dust in specific areas, and erasing in others, allowing a large dynamic range of continuous tone. Sharp pencils and scalpel blades are used to produce details and highlights. (Cover illustration by Bang Wong, ClearScience, www.clearscience.info. [For details, see Loots et al., pp. 928–935.])