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Editors Selection IGR 11-2

Basic Research: SMAD7 effect on HTM cells

Comment by Terete Borras on:

23718 Gene expression profiling of TGFbeta2- and/or BMP7-treated trabecular meshwork cells: Identification of Smad7 as a critical inhibitor of TGF-beta2 signaling, Fuchshofer R; Stephan DA; Russell P et al., Experimental Eye Research, 2009; 88: 1020-1032

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Following their observation that the combination BMP7+TGFß2 reversed TGFß2 effects in HTM cells (IOVS 48, 715, 2007), Fuchshofer et al. (529) conducted an extensive microarray study to search for possible mediators. They used Affymetrix U133A chips and compared HTM cells 7 d post-confluent treated with the single or combined factors. TGFß2 vs Control rendered 16 altered genes. One of them was Smad7, an inhibitor of TGFß2.

Smad7 was not altered in the comparison BMP7+TGFß2 vs TGFß2, but a more sensitive real-time PCR showed a small increase of this gene during the combination treatment. This difference prompted the investigators to look into the effect of silencing Smad7 on the expression of Connective Tissue Growth Factor (CTGF), a marker for TGFß2-induced fibrosis. These are very interesting experiments, if nothing else but for the complexity they bring to the interpretation of the results: TGFß2 induced Smad7 and CTGF ~3-fold. BMP7+TGFß2 induced Smad7 just a little more (~3.8-fold), and reduced CTGF to 1.4-fold. When silencing Smad7, TGFß2 still induced CTGF to the same level. However, silencing Smad7 during the BMP7+TGFß2 treatment reversed the reduced CTGF expression to ~3.5-fold. In other words, high levels of Smad7 did not inhibit CTGF expression in TGFß2-treated cells, but slightly higher levels of Smad7 were able to dramatically inhibit CTGF in the combination treatment. Conversely, silencing Smad7 did not lead to a CTGF increase in TGFß2-treated cells, but did lead to a great CTGF increase in cells treated with both factors.

A hard to understand negative feed back loop is proposed. But rather, it appears that Smad7 has a 'biphasic' regulation, where this inhibitor is first induced at high levels in an inactive state and then gets activated after reaching the threshold. Since the experiments here are impeccably performed, chances are that this could be a characteristic of the TM. But to show that Smad7 is a critical inhibitor of the TGFß2 pathway in the TM rather than another secondary effect of BMP7, the authors might need to deliver increasing controlled concentrations of the Smad7 gene to TGFß2-treated cells and monitor CTGF levels. Would then CTGF decrease when the cell reaches the Smad7 threshold level? This laboratory has a good TGFß2 ongoing program and most likely we will be hearing more of this type of experiments in the future.

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