Transgenic analysis of scleroderma: understanding key pathogenic events in vivo.
Modern molecular genetic methods have allowed better understanding of established mouse models of scleroderma and also facilitated the development of new and better defined mouse strains for investigating the pathogenesis of the disease. The best characterized scleroderma animal model is the type 1 tight skin mouse (Tsk1). Backcrossing these animals with other mutant strains has been informative. These experiments implicate the IL-4 ligand-receptor axis in the development of skin fibrosis. Parallel expression analysis of genes using microarrays has provided insight into novel mediators of fibrosis including the C-C chemokine MCP-3. Other experiments suggest that embryonically defined fibroblast-specific regulatory elements may be targets for activation in this model. The same lineage-specific elements have been used to selectively activate TGF beta signaling pathways in fibrosis to generate a novel model for scleroderma and also have been used to develop systems for ligand-dependent fibroblast-specific genetic recombination that will allow further analysis key candidate genes implicated in scleroderma pathogenesis. Better mouse models will improve understanding of this intractable rheumatic disease and can be expected to ultimately lead to improved treatments and outcome.
Denton
Christopher P
CP
Centre for Rheumatology, Royal Free Hospital, Pond Street, London NW3 2QG, UK. c.denton@rfc.ucl.ac.uk
Abraham
David J
DJ
D000818:Animals; D054410:Chemokine CCL7; D003433:Crosses, Genetic; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005355:Fibrosis; D005544:Forecasting; D015870:Gene Expression; D017930:Genes, Reporter; D006801:Humans; D051379:Mice; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D008954:Models, Biological; D018945:Monocyte Chemoattractant Proteins / Q000235:genetics / Q000378:metabolism*; D019948:Receptors, Interleukin-4 / Q000235:genetics / Q000378:metabolism*; D011995:Recombination, Genetic; D012595:Scleroderma, Systemic / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism
C515450:CCL7 protein, human; C515451:Ccl7 protein, mouse; D054410:Chemokine CCL7; D016207:Cytokines; D018945:Monocyte Chemoattractant Proteins; D019948:Receptors, Interleukin-4; D016212:Transforming Growth Factor beta