Research ArticleFibrosis

The αvβ1 integrin plays a critical in vivo role in tissue fibrosis

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Science Translational Medicine  20 May 2015:
Vol. 7, Issue 288, pp. 288ra79
DOI: 10.1126/scitranslmed.aaa5094

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Integrating integrin inhibition

Integrins are a family of cell surface receptors that form cell-cell and cell–extracellular matrix contacts and, as such, are key targets in treating fibrotic disease. However, promiscuous pairing has limited our understanding of the contribution of individual integrin heterodimers. Now, Reed et al. have developed a specific small-molecule inhibitor of the integrin αvβ1, which is highly expressed on activated fibroblasts. This inhibitor decreased the severity of disease in mouse models of lung and liver fibrosis, in part through downstream effects on transforming growth factor–β. These data suggest that αvβ1 may be a viable target for fibrosis therapy.

Abstract

Integrins are transmembrane heterodimeric receptors that contribute to diverse biological functions and play critical roles in many human diseases. Studies using integrin subunit knockout mice and inhibitory antibodies have identified important roles for nearly every integrin heterodimer and led to the development of a number of potentially useful therapeutics. One notable exception is the αvβ1 integrin. αv and β1 subunits are individually present in numerous dimer pairs, making it challenging to infer specific roles for αvβ1 by genetic inactivation of individual subunits, and αvβ1 complex–specific blocking antibodies do not yet exist. We therefore developed a potent and highly specific small-molecule inhibitor of αvβ1 to probe the function of this understudied integrin. We found that αvβ1, which is highly expressed on activated fibroblasts, directly binds to the latency-associated peptide of transforming growth factor–β1 (TGFβ1) and mediates TGFβ1 activation. Therapeutic delivery of this αvβ1 inhibitor attenuated bleomycin-induced pulmonary fibrosis and carbon tetrachloride–induced liver fibrosis, suggesting that drugs based on this lead compound could be broadly useful for treatment of diseases characterized by excessive tissue fibrosis.

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