title: Disruption of the latent transforming growth factor-beta binding protein-1 gene causes alteration in facial structure and influences TGF-beta bioavailability.
abstract: Latent transforming growth factor-beta binding proteins are a family of extracellular matrix proteins comprising four isoforms (LTBP-1, -2, -3, -4) with different structures, tissue expression patterns and affinity for TGF-beta. So far, respective knockout models have highlighted some essential functions for LTBP-2, LTBP-3 and LTBP-4, while the physiological significance of LTBP-1 is only superficially known. Here we report for the first time the generation and characterization of a mouse model lacking both the long and short LTBP-1 isoform. Surprisingly, respective mice are viable and fertile. However, detailed X-ray analysis of the skull revealed a modified facial profile. In addition, the gene disruption induces a reduced biological activity of TGF-beta that became evident in an experimental model of hepatic fibrogenesis in which the LTBP-1 knockout animals were less prone to hepatic fibrogenesis. Furthermore, comparative cDNA microarray gene expression profiling of cultured hepatic stellate cells confirmed that respective nulls were less receptive to cellular activation and transdifferentiation into myofibroblasts. Therefore, we conclude that LTBP-1 has essential functions in the control of TGF-beta activation.
authors.affiliation: Institute of Clinical Chemistry and Pathobiochemistry, RWTH University Hospital Aachen, Pauwelsstr. 30, D-52074 Aachen, Germany.
authors.forename: Falko
authors.initials: F
authors.lastname: Drews
authors.forename: Sebastian
authors.initials: S
authors.lastname: Knöbel
authors.forename: Markus
authors.initials: M
authors.lastname: Moser
authors.forename: Kai G
authors.initials: KG
authors.lastname: Muhlack
authors.forename: Simone
authors.initials: S
authors.lastname: Mohren
authors.forename: Christian
authors.initials: C
authors.lastname: Stoll
authors.forename: Andreas
authors.initials: A
authors.lastname: Bosio
authors.forename: Axel M
authors.initials: AM
authors.lastname: Gressner
authors.forename: Ralf
authors.initials: R
authors.lastname: Weiskirchen
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D015536:Down-Regulation; D005145:Face / Q000033:anatomy & histology*; D053779:Latent TGF-beta Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics
chemical_list: D053779:Latent TGF-beta Binding Proteins; C509033:Ltbp1 protein, mouse; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta