TGFβ2 and TGFβ3 isoforms drive fibrotic disease pathogenesis.

Area of Science:

• Fibrosis research
• Molecular mechanisms of TGFβ signaling
• Immunology and inflammation

Background:

• Transforming growth factor-β (TGFβ) is a key driver of fibrogenesis.
• The roles and activation of TGFβ2 and TGFβ3 in postnatal fibrosis are not well understood.
• Distinct functions of TGFβ isoforms in development and disease.

Purpose of the Study:

• To investigate the pathological roles and activation mechanisms of TGFβ2 and TGFβ3 in fibrosis.
• To determine if selective inhibition of TGFβ2/3 is a viable therapeutic strategy.
• To compare the effects of isoform-specific TGFβ inhibition with pan-TGFβ blockade.

Main Methods:

• Analysis of TGFβ isoform expression in human fibrotic tissues.
• Investigation of latent TGFβ2 and TGFβ3 activation mechanisms.
• Utilizing inducible conditional knockout mice and isoform-selective antibodies in vivo.
• Cocrystallography of TGFβ2-antibody complexes to elucidate binding and inhibition mechanisms.

Main Results:

• TGFβ2 and TGFβ3 are activated by integrin-independent mechanisms with lower thresholds than TGFβ1.
• TGFB2 and TGFB3 expression is elevated in human fibrotic lung and liver tissues.
• Selective inhibition of TGFβ2 and TGFβ3 in mouse models reduced fibrosis without causing inflammation.
• Cocrystal structure revealed an allosteric inhibitory mechanism for TGFβ2/3 antibodies.

Conclusions:

• TGFβ2 and TGFβ3 play independent pathological roles in fibrosis.
• Selective inhibition of TGFβ2 and/or TGFβ3 offers a potential therapeutic strategy for fibrosis.
• Targeting TGFβ2/3 may mitigate fibrosis without the adverse inflammatory effects of pan-TGFβ inhibition.