Research ArticleWound Healing

BMP-1 disrupts cell adhesion and enhances TGF-β activation through cleavage of the matricellular protein thrombospondin-1

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Science Signaling  07 Jul 2020:
Vol. 13, Issue 639, eaba3880
DOI: 10.1126/scisignal.aba3880

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BMP-1 cleaves TSP-1 for TGF-β activation

The extracellular protease BMP-1 modifies components of the extracellular matrix and controls the activation of latent growth factors within the matrix. Anastasi et al. found that overexpressed BMP-1 cleaved the matricellular protein thrombospondin-1 (TSP-1), causing release of a TSP-1 fragment from the matrix. This reduced cell adhesion and stimulated the activation of latent TGF-β in two human cell lines. Cleaved TSP-1 was present in human corneal scars, and cleavage of TSP-1 by BMP-1 stimulated transdifferentiation of primary human keratocytes into myofibroblasts and promoted TGF-β–dependent myofibroblast activation in mouse corneas ex vivo. These findings highlight the context-specific effects of matrix remodeling on cell adhesion and growth factor signaling.

Abstract

Bone morphogenetic protein 1 (BMP-1) is an important metalloproteinase that synchronizes growth factor activation with extracellular matrix assembly during morphogenesis and tissue repair. The mechanisms by which BMP-1 exerts these effects are highly context dependent. Because BMP-1 overexpression induces marked phenotypic changes in two human cell lines (HT1080 and 293-EBNA cells), we investigated how BMP-1 simultaneously affects cell-matrix interactions and growth factor activity in these cells. Increasing BMP-1 led to a loss of cell adhesion that depended on the matricellular glycoprotein thrombospondin-1 (TSP-1). BMP-1 cleaved TSP-1 between the VWFC/procollagen-like domain and the type 1 repeats that mediate several key TSP-1 functions. This cleavage induced the release of TSP-1 C-terminal domains from the extracellular matrix and abolished its previously described multisite cooperative interactions with heparan sulfate proteoglycans and CD36 on HT1080 cells. In addition, BMP-1–dependent proteolysis potentiated the TSP-1–mediated activation of latent transforming growth factor–β (TGF-β), leading to increased signaling through the canonical SMAD pathway. In primary human corneal stromal cells (keratocytes), endogenous BMP-1 cleaved TSP-1, and the addition of exogenous BMP-1 enhanced cleavage, but this had no substantial effect on cell adhesion. Instead, processed TSP-1 promoted the differentiation of keratocytes into myofibroblasts and stimulated production of the myofibroblast marker α-SMA, consistent with the presence of processed TSP-1 in human corneal scars. Our results indicate that BMP-1 can both trigger the disruption of cell adhesion and stimulate TGF-β signaling in TSP-1–rich microenvironments, which has important potential consequences for wound healing and tumor progression.

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