IL-6 Signaling Pathway in Keloids: A Target for Pharmacologic Intervention?

Keloids are cosmetically devastating lesions with considerable morbidity. Ghazizadeh et al. document enhanced expression of IL-6 and its receptors in keloid fibroblasts, with a concomitant increase in collagen biosynthesis. Anti-IL-6 antibodies or blocking the IL-6 receptors elicits reduced collagen synthesis, suggesting a role for IL-6 in the regulation of collagen gene expression. These observations imply the feasibility of a pharmacologic platform, based on the targeting of the IL-6 signaling pathway, in keloids

Elevated dietary magnesium during pregnancy and postnatal life prevents ectopic mineralization in Enpp1asj mice, a model for generalized arterial calcification of infancy.

Generalized arterial calcification of infancy (GACI) is an autosomal recessive disorder caused by mutations in the ENPP1 gene. It is characterized by mineralization of the arterial blood vessels, often diagnosed prenatally, and associated with death in early childhood. There is no effective treatment for this devastating disorder. We previously characterized the Enpp1asjmutant mouse as a model of GACI, and we have now explored the effect of elevated dietary magnesium (five-fold) in pregnant mothers and continuing for the first 14 weeks of postnatal life. The mothers were kept on either control diet or experimental diet supplemented with magnesium. Upon weaning at 4 weeks of age the pups were placed either on control diet or high magnesium diet. The degree of mineralization was assessed at 14 weeks of age by histopathology and a chemical calcium assay in muzzle skin, kidney and aorta. Mice placed on high magnesium diet showed little, if any, evidence of mineralization when their corresponding mothers were also placed on diet enriched with magnesium during pregnancy and nursing. The reduced ectopic mineralization in these mice was accompanied by increased calcium and magnesium content in the urine, suggesting that magnesium competes calcium-phosphate binding thereby preventing the mineral deposition. These results have implications for dietary management of pregnancies in which the fetus is suspected of having GACI. Moreover, augmenting a diet with high magnesium may be beneficial for other ectopic mineralization diseases, including nephrocalcinosis

Differential Expression of Type IV Procollagen and Laminin Genes by Fetal vs Adult Skin Fibroblasts in Culture: Determination of Subunit mRNA Steady-State Levels

Basement membrane zone gene expression by fibroblast cultures, established from individuals varying in age from 14 fetal weeks to 61 years, was examined by molecular hybridizations with human sequence specific cDNAs corresponding to type IV procollagen and laminin subunit polypeptides. Northern transfer analysis with poly(A)+ RNA revealed the presence of specific mRNA transcripts for α1 (IV) and α2(IV) chains of type IV procollagen as well as B1 and B2 chains of laminin. Laminin A chain mRNAs were not detected using the same RNA preparations. Quantitative estimates of the steady-state levels of type IV procollagen and laminin mRNAs indicated that they were of relatively low abundance, as compared with mRNA to type I procollagen. The expression of α1(IV) and α2(IV) collagen genes was high in fetal fibroblasts but was reduced to low, yet detectable, levels in cultures established from 3-d to 61-year-old individuals. In contrast, the laminin B1 and B2 chain mRNA levels showed little age-associated variation within the cultures examined. These results provide evidence for differential regulation of the expression of different basement membrane zone macro-molecules during chronologic aging

Biochemistry of the Elastic Fibers in Normal Connective Tissues and its Alterations in Diseases

The elastic fibers present in various connective tissues of the body are responsible for physiologic elasticity of the organs. These fibers consist of 2 distinct components, elastin and the elastic fiber microfibrils. Controlled synthesis and balanced interaction of these 2 components are essential for normal fibrillogenesis. The intracellular biosynthesis of elastin by connective tissue cells, such as smooth muscle cells, involves assembly of the polypeptide chains on the membrane-bound ribosomes, hydroxylation of some prolyl residues to hydroxyproline, and secretion of the polypeptides packaged in Golgi vacuoles. In the extracellular space the elastin molecules assemble into fiber structures which are stabilized by the synthesis of complex covalent cross-links, desmosines. Recently, aberrations in the structure or metabolism of elastin have been detected in a variety of heritable and acquired diseases affecting skin and other connective tissues. These conditions include pseudoxanthoma elasticum, cutis laxa, and elastosis perforans serpiginosa, as well as arteriosclerosis and other degenerative changes of the vascular connective tissues

Administration of bone marrow derived mesenchymal stem cells into the liver: potential to rescue pseudoxanthoma elasticum in a mouse model (Abcc6-/-).

Pseudoxanthoma elasticum (PXE) is a heritable ectopic mineralization disorder caused by loss-of-function mutations in the ABCC6 gene which is primarily expressed in the liver. There is currently no effective treatment for PXE. In this study, we characterized bone marrow derived mesenchymal stem cells (MSCs) and evaluated their ability to contribute to liver regeneration, with the aim to rescue PXE phenotype. The MSCs, isolated from GFP-transgenic mice by magnetic cell sorting, were shown to have high potential for hepatic differentiation, with expression of Abcc6, in culture. These cells were transplanted into the livers of 4-week-old immunodeficient Abcc6⁻/⁻ mice by intrasplenic injection one day after partial hepatectomy, when peak expression of the stromal cell derived factor-1 (SDF-1) in the liver was observed. Fluorescent bioimaging analyses indicated that transplanted MSCs homed into liver between day 1 and 7, and significant numbers of GFP-positive cells were confirmed in the liver by immunofluorescence. Moreover, enhanced engraftment efficiency was observed with MSCs with high expression levels of the chemokine receptor Cxcr4, a receptor for SDF-1. These data suggest that purified MSCs have the capability of differentiating into hepatic lineages relevant to PXE pathogenesis and may contribute to partial correction of the PXE phenotype