TGF beta −1, −2 and −3 in the modulation of fibrosis in the cornea and other organs

The TGF beta-1, -2 and -3 isoforms are transcribed from different genes but bind to the same receptors and signal through the same canonical and non-canonical signal transduction pathways. There are numerous regulatory mechanisms controlling the action of each isoform that include the organ-specific cells producing latent TGF beta growth factors, multiple effectors that activate the isoforms, ECM-associated SLRPs and basement membrane components that modulate the activity and localization of the isoforms, other interactive cytokine-growth factor receptor systems, such as PDGF and CTGF, TGF beta receptor expression on target cells, including myofibroblast precursors, receptor binding competition, positive and negative signal transduction effectors, and transcription and translational regulatory mechanisms. While there has long been the view that TGF beta-1and TGF beta-2 are pro-fibrotic, while TGF beta-3 is anti-fibrotic, this review suggests that view is too simplistic, at least in adult tissues, since TGF beta-3 shares far more similarities in its modulation of fibrotic gene expression with TGF beta-1 and TGF beta-2, than it does differences, and often the differences are subtle. Rather, TGF beta-3 should be seen as a fibro-modulatory partner to the other two isoforms that modulates a nuanced and better controlled response to injury. The complex interplay between the three isoforms and numerous interactive proteins, in the context of the cellular milieu, controls regenerative non-fibrotic vs. fibrotic healing in a response to injury in a particular organ, as well as the resolution of fibrosis, when that occurs. •TGF beta-1, -2 and -3 isoforms are transcribed from different genes.•TGF beta isoforms bind to the same receptors and signal through the same signal transduction pathways.•Numerous regulatory mechanisms control the action of each TGF beta isoform.•The long standing view that TGF beta-3 is anti-fibrotic, is too simplistic.•Rather, TGF beta-3 produces subtle fibro-modulatory differences.