Transforming Growth Factor-β3 (TGF-β3) Knock-in Ameliorates Inflammation Due to TGF-β1 Deficiency While Promoting Glucose Tolerance

Three homologues of TGF-beta exist in mammals as follows: TGF-beta 1, TGF-beta 2, and TGF-beta 3. All three proteins share high homology in their amino acid sequence, yet each TGF-beta isoform has unique heterologous motifs that are highly conserved during evolution. Although these TGF-beta proteins share similar properties in vitro, isoform-specific properties have been suggested through in vivo studies and by the unique phenotypes for each TGF-beta knock-out mouse. To test our hypothesis that each of these homologues has nonredundant functions, and to identify such isoform-specific roles, we genetically exchanged the coding sequence of the mature TGF-beta 1 ligand with a sequence from TGF-beta 3 using targeted recombination to create chimeric TGF-beta 1/3 knock-in mice (TGF-beta 1(L beta 3/L beta 3)). In the TGF-beta 1(L beta 3/L beta 3) mouse, localization and activation still occur through the TGF-beta 1 latent associated peptide, but cell signaling is triggered through the TGF-beta 3 ligand that binds to TGF-beta receptors. Unlike TGF-beta 1(-/-) mice, the TGF-beta 1(L beta 3/L beta 3) mice show neither embryonic lethality nor signs of multifocal inflammation, demonstrating that knock-in of the TGF-beta 3 ligand can prevent the vasculogenesis defects and autoimmunity associated with TGF-beta 1 deficiency. However, the TGF-beta 1(L beta 3/L beta 3) mice have a shortened life span and display tooth and bone defects, indicating that the TGF-beta homologues are not completely interchangeable. Remarkably, the TGF-beta 1(L beta 3/L beta 3) mice display an improved metabolic phenotype with reduced body weight gain and enhanced glucose tolerance by induction of beneficial changes to the white adipose tissue compartment. These findings reveal both redundant and unique nonoverlapping functional diversity in TGF-beta isoform signaling that has relevance to the design of therapeutics aimed at targeting the TGF-beta pathway in human disease.