Effect of cannabidiol on human gingival fibroblast extracellular matrix metabolism: MMP production and activity, and production of fibronectin and transforming growth factor β

The extracellular matrix (ECM) as well as soluble mediators like cytokines can influence the behavior of cells in very distinct as well as cooperative ways. One group of ECM molecules which shows an especially broad cooperativety with cytokines and growth factors are the proteoglycans. Proteoglycans can interact with their core proteins as well as their glycosaminoglycan chains with cytokines. These interactions can modify the binding of cytokines to their cell surface receptors or they can lead to the storage of the soluble factors in the matrix. Proteoglycans themselves may even have cytokine activity. In this review we describe different proteoglycans and their interactions and relationships with cytokines and we discuss in more detail the extracellular regulation of the activity of transforming growth factor-β (TGF-β) by proteoglycans and other ECM molecules. In the third part the interaction of heparan sulfate chains with fibroblast growth factor-2 (FGF-2, basic FGF) as a prototype example for the interaction of heparin-binding cytokines with heparan sulfate proteoglycans is presented to illustrate the different levels of mutual dependence of the cytokine network and the ECM.

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Transforming growth factor–β in tissue fibrosis

Journal of Experimental Medicine ◽

10.1084/jem.20190103 ◽

2020 ◽

Vol 217 (3) ◽

Cited By ~ 6

Author(s):

Nikolaos G. Frangogiannis

Keyword(s):

Extracellular Matrix ◽

Growth Factor ◽

Epithelial Cells ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Cell Types ◽

Cellular Targets ◽

Extracellular Matrix Molecules ◽

Interacting Networks

TGF-β is extensively implicated in the pathogenesis of fibrosis. In fibrotic lesions, spatially restricted generation of bioactive TGF-β from latent stores requires the cooperation of proteases, integrins, and specialized extracellular matrix molecules. Although fibroblasts are major targets of TGF-β, some fibrogenic actions may reflect activation of other cell types, including macrophages, epithelial cells, and vascular cells. TGF-β–driven fibrosis is mediated through Smad-dependent or non-Smad pathways and is modulated by coreceptors and by interacting networks. This review discusses the role of TGF-β in fibrosis, highlighting mechanisms of TGF-β activation and signaling, the cellular targets of TGF-β actions, and the challenges of therapeutic translation.

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

Science Signaling ◽

10.1126/scisignal.aba3880 ◽

2020 ◽

Vol 13 (639) ◽

pp. eaba3880 ◽

Cited By ~ 3

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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Identification of the growth factor–binding sequence in the extracellular matrix protein MAGP-1

Journal of Biological Chemistry ◽

10.1074/jbc.ra119.010540 ◽

2020 ◽

Vol 295 (9) ◽

pp. 2687-2697 ◽

Cited By ~ 2

Author(s):

Thomas J. Broekelmann ◽

Nicholas K. Bodmer ◽

Robert P. Mecham

Keyword(s):

Extracellular Matrix ◽

Growth Factor ◽

Matrix Protein ◽

Transforming Growth Factor ◽

Cultured Cells ◽

Transforming Growth Factor Β ◽

Bmp Signaling ◽

Extracellular Matrix Protein ◽

Surface Plasmon Resonance Analysis ◽

Factor Binding

Microfibril-associated glycoprotein-1 (MAGP-1) is a component of vertebrate extracellular matrix (ECM) microfibrils that, together with the fibrillins, contributes to microfibril function. Many of the phenotypes associated with MAGP-1 gene inactivation are consistent with dysregulation of the transforming growth factor β (TGFβ)/bone morphogenetic protein (BMP) signaling system. We have previously shown that full-length MAGP-1 binds active TGFβ-1 and some BMPs. The work presented here further defines the growth factor–binding domain of MAGP-1. Using recombinant domains and synthetic peptides, along with surface plasmon resonance analysis to measure the kinetics of the MAGP-1–TGFβ-1 interaction, we localized the TGFβ- and BMP-binding site in MAGP-1 to a 19-amino acid–long, highly acidic sequence near the N terminus. This domain was specific for binding active, but not latent, TGFβ-1. Growth factor activity experiments revealed that TGFβ-1 retains signaling activity when complexed with MAGP-1. Furthermore, when bound to fibrillin, MAGP-1 retained the ability to interact with TGFβ-1, and active TGFβ-1 did not bind fibrillin in the absence of MAGP-1. The absence of MAGP was sufficient to raise the amount of total TGFβ stored in the ECM of cultured cells, suggesting that the MAGPs compete with the TGFβ large latent complex for binding to microfibrils. Together, these results indicate that MAGP-1 plays an active role in TGFβ signaling in the ECM.

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