Thrombospondin-1 promotes fibroblast-mediated collagen gel contraction caused by activation of latent transforming growth factor β-1

2003 ◽  
Vol 31 (2) ◽  
pp. 99-109 ◽  
Author(s):  
Kensuke Sakai ◽  
Yukio Sumi ◽  
Hisako Muramatsu ◽  
Ken-ichiro Hata ◽  
Takashi Muramatsu ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Collagen Gel ◽  
Transforming Growth Factor Β ◽  
Collagen Gel Contraction ◽  
Thrombospondin 1

scholarly journals α1β1 Integrin-Mediated Collagen Matrix Remodeling by Rat Mesangial Cells Is Differentially Regulated by Transforming Growth Factor-β and Platelet-Derived Growth Factor-BB

1999 ◽  
Vol 10 (4) ◽  
pp. 779-789
Author(s):  
SHOJI KAGAMI ◽  
SHUJI KONDO ◽  
KLEMENS LÖSTER ◽  
WERNER REUTTER ◽  
TAKASHI KUHARA ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Mesangial Cells ◽  
Collagen Gel ◽  
Collagen Matrix ◽  
Transforming Growth Factor Β ◽  
Platelet Derived Growth Factor ◽  
Matrix Remodeling ◽  
Mesangial Matrix ◽  
Collagen Gel Contraction

Abstract. Pathologic remodeling of mesangial matrix after glomerular injury is the central biologic feature of glomerular scarring (sclerosis). Transforming growth factor-β (TGF-β) and platelet-derived growth factor (PDGF)-BB have been implicated in the development of glomerular scarring in rat and human glomerulonephritis. To clarify molecular and cellular mechanisms involved in abnormal mesangial remodeling, this study focused on the role of α1β1 integrin, a collagen/laminin receptor, in rat mesangial cells, using collagen gel contraction as an experimental model of in vivo collagen matrix remodeling and scar formation. In addition, the influence of TGF-β and PDGF-BB on mesangial cell (MC)-mediated collagen gel contraction in association with the α1β1 integrin expression was evaluated. Integrin function blocking studies using anti-α1, β1 subunit antibodies indicated that MC-α1β1 integrin is essentially required not only for collagen-dependent adhesion/migration, but also for gel contraction. Protein synthesis and mRNA analysis experiments demonstrated that TGF-β, but not PDGF-BB, increases the expression of α1β1 integrin in mesangial cells cultured on plastic surface and in collagen gels. The upregulation of α1β1 integrin expression by TGF-β correlated with increases in gel contraction and collagen-dependent adhesion but not migration of mesangial cells. On the other hand, PDGF-BB enhanced MC-mediated gel contraction and migration without affecting cell adhesion to collagen I. Growth factor-induced collagen-dependent adhesion, migration, and gel contraction were significantly attenuated by incubation with anti-α1, β1 subunit antibodies. Thus, these data indicate that α1β1 integrin-mediated collagen matrix remodeling can be modulated by TGF-β and PDGF-BB via different mechanisms. α1β1 integrin-mediated mesangial matrix remodeling induced by TGF-β or PDGF-BB may be a pathogenic mechanism leading to glomerular scarring.

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

2020 ◽  
Vol 13 (639) ◽  
pp. eaba3880 ◽  
Author(s):  
Cyril Anastasi ◽  
Patricia Rousselle ◽  
Maya Talantikite ◽  
Agnès Tessier ◽  
Caroline Cluzel ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Cell Adhesion ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Substantial Effect ◽  
Matricellular Protein ◽  
Matrix Assembly ◽  
Morphogenetic Protein ◽  
Thrombospondin 1

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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