Controlling BMP growth factor bioavailability: The extracellular matrix as multi skilled platform

Zimmermann, Laura-Marie A; Correns, Annkatrin; Furlan, Ariane G; Spanou, Chara E S; Sengle, Gerhard

doi:10.1016/j.cellsig.2021.110071

Cited by 21 publications

(16 citation statements)

References 142 publications

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“…The present study showed that MMC can promote the deposition of a critical ECM scaffolding protein, fibrillin-1, in a human lung fibroblast cell line as well as in several Marfan syndrome patient-derived skin fibroblasts. Since fibrillin-1 microfibrils are required for the formation and maintenance of elastic fibres and for the deposition of LTBPs and fibulins as well as TGFβ and BMP growth factors, these findings could be broadly relevant for tissue-engineering approaches to generate elastic tissues, such as blood vessels, tendons or skin (Ramirez and Rifkin, 2009;Zimmermann et al, 2021). In addition, findings supported the notion that biochemical processes, such as ECM formation, may be accelerated by MMC in cell culture settings, which may better represent the highly concentrated, i.e.…”

Section: Discussionmentioning

confidence: 99%

Macromolecular crowding enhances fibrillin-1 deposition in the extracellular matrix

Satz-Jacobowitz¹,

Taye²,

Karoulias³

et al. 2022

eCM

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Biochemical and biophysical factors need consideration when modelling in vivo cellular behaviour using in vitro cell culture systems. One underappreciated factor is the high concentration of macromolecules present in vivo, which is typically not simulated under standard cell culture conditions. This disparity is especially relevant when studying biochemical processes that govern extracellular matrix (ECM) deposition, which may be altered due to dilution of secreted macromolecules by the relatively large volumes of culture medium required for cell maintenance in vitro. Macromolecular crowding (MMC) utilises the addition of inert macromolecules to cell culture medium to mimic such high concentration environments found in vivo. The present study induced MMC using the sucrose polymer Ficoll and examined whether fibrillin-1 deposition by human lung fibroblasts could be augmented. Fibrillin-1 forms extracellular microfibrils, which are versatile scaffolds required for elastic fibre formation, deposition of other ECM proteins and growth factor regulation. Pathogenic variants in the fibrillin-1 gene (FBN1) cause Marfan syndrome, where ECM deposition of fibrillin-1 can be compromised. Using immunocytochemistry, significantly enhanced fibrillin-1 deposition was observed when lung fibroblasts were cultured under MMC conditions. MMC also augmented fibrillin-1 deposition in Marfan syndrome patient-derived skin fibroblasts in a cell line- and likely FBN1 variant-specific manner. The ability of MMC to increase fibrillin-1 deposition suggested potential applications for tissue-engineering approaches, e.g. to generate tendon or vascular tissues, where fibrillin-1 microfibrils and elastic fibres are key determinants of their biomechanical properties. Moreover, it suggested the potency of MMC to better mimic in vivo ECM environments in cell culture studies.

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Section: Discussionmentioning

confidence: 99%

Macromolecular crowding enhances fibrillin-1 deposition in the extracellular matrix

Satz-Jacobowitz¹,

Taye²,

Karoulias³

et al. 2022

eCM

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“…BMPs were originally discovered because they can induce bone and cartilage formation ectopically [18][19][20] , and later studies revealed that BMPs are widely distributed in multiple tissues and cells of the human body 21,22 and can be involved in processes such as embryogenesis, embryonic development, histiocyte differentiation and proliferation 23 . Reports in recent years have shown that BMPs and their signaling pathways are closely related to human tumors [24][25][26] .…”

Section: Discussionmentioning

confidence: 99%

BMP-2 Promotes Breast Cancer Metastasis by Inducing EMT via PI3K/Akt Signaling Pathway

Zhang

Shi

Wang

et al. 2022

Preprint

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Purpose:Bone morphogenetic proteins (BMPs) are important members of the TGF-β superfamily and can be abnormally expressed in various tumors. The purpose of this paper is to investigate the expression of bone morphogenetic proteins-2(BMP-2) in breast cancer and its effects on breast tumor cells and the regulation mechanism.Method:The effects of BMP-2 on the proliferation, cloning, apoptosis, migration and invasion of breast cancer cells were investigated by MTT assay, plate cloning experiment, flow cytometry (FCM), scratch test and transwell assay. The relationship between BMP-2 and epithelial-mesenchymal transition (EMT)-related indicators in cell lines, and the relationship between BMP-2 and PI3K/Akt pathway-related proteins were analyzed using real-time PCR and Western blot. Breast cancer xenograft models were established to observe effects of BMP-2 on the growth and metastasis of xenograft tumors, and real-time PCR and immunohistochemistry were used to detect changes in EMT-related protein expression in xenograft tumors.Results:BMP-2 was highly expressed in MBA-MD-231 and T47D cell lines. The results of in vitro experiments showed that rhBMP-2 could promote the proliferation, colony formation, migration and invasion of breast cancer cells, and reduce the apoptosis ability. The expression of BMP-2 was significantly correlated with EMT. With increasing BMP-2 concentration, the expression of E-cadherin and Cx43 was significantly down-regulated in the epithelial phenotype, while the expression of N-cadherin, fibronectin (FN), and vimentin mRNA was significantly up-regulated in the mesenchymal phenotype. BMP-2 could promote p-PI3K, p-Akt and p-mTOR expression in the PI3K/Akt signaling pathway, which in turn regulated the EMT process. However, after the addition of LY294002, an inhibitor of this signaling pathway, no significant up-regulation of p-PI3K, p-Akt, and p-mTOR was observed, and there was no significant change in EMT-related indicators. Through the establishment of the BMP-2 high expression xenograft model in nude mice, it was found that the growth rate of xenograft in the BMP-2 group was significantly faster than that in the control group, and metastasis to lymph node and bone were likely to occur. Compared with the control group, E-cadherin expression was attenuated and vimentin expression was enhanced in the BMP-2 group, suggesting EMT.Conclusion:BMP-2 is highly expressed in breast cancer tissues and is a malignant regulator of breast cancer cells. Its mechanism of action may be the induction of the EMT via PI3K/Akt pathway. BMP-2 is expected to be a new target for controlling the growth and metastasis of breast cancer.

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“…Fibrillins assemble into "beads-on-a-string" microfibrils that are not only indispensable for conferring elasticity to the aortic wall, but also control the bioavailability of growth factors targeted to the extracellular matrix (ECM) architecture (2). Fibrillin microfibrils (FMF) not only represent the structural core of elastic fibers, but also decorate the surface of elastic fibers and form independent networks.…”

Section: Introductionmentioning

confidence: 99%

“…Supramolecular networks composed of fibrillins (fibrillin-1 and fibrillin-2) and associated ligands form intricate cellular microenvironments that balance tissue homoeostasis and direct remodeling (1). Fibrillins assemble into “beads-on-a-string” microfibrils that are not only indispensable for conferring elasticity to the aortic wall, but also control the bioavailability of growth factors targeted to the extracellular matrix (ECM) architecture (2). Fibrillin microfibrils (FMF) not only represent the structural core of elastic fibers, but also decorate the surface of elastic fibers and form independent networks.…”

Section: Introductionmentioning

confidence: 99%

Targeting of MMP-13 prevents aortic aneurysm formation in Marfan mice

Zimmermann

Furlan

Mehrkens

et al. 2022

Preprint

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Fibrillin-1 assembles into microfibrils that not only define the structural integrity and biomechanics of the aorta but also target and sequester growth factors within the extracellular microenvironment of aortic resident cells. To better understand how dominant negative effects on fibrillin microfibril stability manifest in growth factor driven aortic disease, we analyzed early events of aortic aneurysm formation within the first two weeks of postnatal life in the dominant negative Fbn1 GT8 Marfan mouse model. Echocardiography analysis of homozygous GT8 Fbn1 mice showed significant aortic root enlargement within the second week of postnatal life which correlated with the onset of fibrillin-1 fiber degradation, aberrantly increased BMP activity and upregulated transcript levels of the collagenase MMP-13. We also found the aortic collagen network structurally disturbed where the mutant GT8-fibrillin-1 was detected. Genetic ablation or pharmacological inhibition of MMP-13 in Fbn1 GT8 Marfan mice prevents aortic root dilatation implicating the relevance of this mechanism in aortic aneurysm formation in Marfan syndrome.

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Controlling BMP growth factor bioavailability: The extracellular matrix as multi skilled platform

Cited by 21 publications

References 142 publications

Macromolecular crowding enhances fibrillin-1 deposition in the extracellular matrix

Macromolecular crowding enhances fibrillin-1 deposition in the extracellular matrix

BMP-2 Promotes Breast Cancer Metastasis by Inducing EMT via PI3K/Akt Signaling Pathway

Targeting of MMP-13 prevents aortic aneurysm formation in Marfan mice

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