BMP1 is Not Required for Lung Fibrosis in Mice

2021 ◽  
Author(s):  
Hsiao-Yen Ma ◽  
Elsa-Noah N’Diaye ◽  
Patrick Caplazi ◽  
Zhiyu Huang ◽  
Alexander Arlantico ◽  
...  
Keyword(s):  
Therapeutic Target ◽  
Lung Fibrosis ◽  
Collagen Fiber ◽  
Fiber Formation ◽  
Conditional Knockout ◽  
Type I ◽  
Type I Procollagen ◽  
Morphogenetic Protein ◽  
Carboxyl Terminal ◽  
Mouse Lungs

Abstract Bone morphogenetic protein 1 (BMP1) belongs to the astacin/BMP1/tolloid-like family of zinc metalloproteinases, which play a fundamental role in the development and formation of extracellular matrix (ECM). BMP1 mediates the cleavage of carboxyl terminal (C-term) propeptides from procollagens, a crucial step in fibrillar collagen fiber formation. Blocking BMP1 by small molecule or antibody inhibitors has been linked to anti-fibrotic activity in the preclinical models of skin, kidney and liver fibrosis. Therefore, we reason that BMP1 may be important for the pathogenesis of lung fibrosis and BMP1 could be a potential therapeutic target for progressive fibrotic disease such as idiopathic pulmonary fibrosis (IPF). Here, we observed the increased expression of BMP1 in both human IPF lungs and mouse fibrotic lungs induced by bleomycin. Furthermore, we developed an inducible Bmp1 conditional knockout (cKO) mouse strain. We found that Bmp1 deletion does not protect mice from lung fibrosis triggered by bleomycin. Moreover, we found no significant impact of BMP1 deficiency upon C-term propeptide of type I procollagen (CICP) production in the fibrotic mouse lungs. Based on these results, we propose that BMP1 is not required for lung fibrosis in mice and BMP1 may not be considered a candidate therapeutic target for IPF.

Smad3 deficiency attenuates bleomycin-induced pulmonary fibrosis in mice

2002 ◽  
Vol 282 (3) ◽  
pp. L585-L593 ◽  
Author(s):  
Jingsong Zhao ◽  
Wei Shi ◽  
Yan-Ling Wang ◽  
Hui Chen ◽  
Pablo Bringas ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Lung Fibrosis ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Type I ◽  
Wild Type ◽  
Type I Procollagen ◽  
Novel Target ◽  
Mouse Lungs

Transforming growth factor-β (TGF-β) signaling plays an important regulatory role during lung fibrogenesis. Smad3 was identified in the pathway for transducing TGF-β signals from the cell membrane to the nucleus. Using mice without Smad3 gene expression, we investigated whether Smad3 could regulate bleomycin-induced pulmonary fibrosis in vivo. Mice deficient in Smad3 demonstrated suppressed type I procollagen mRNA expression and reduced hydroxyproline content in the lungs compared with wild-type mice treated with bleomycin. Furthermore, loss of Smad3 greatly attenuated morphological fibrotic responses to bleomycin in the mouse lungs, suggesting that Smad3 is implicated in the pathogenesis of pulmonary fibrosis. These results show that Smad3 contributes to bleomycin-induced lung injury and that Smad3 may serve as a novel target for potential therapeutic treatment of lung fibrosis.

scholarly journals PCOLCE2Encodes a Functional Procollagen C-Proteinase Enhancer (PCPE2) That Is a Collagen-binding Protein Differing in Distribution of Expression and Post-translational Modification from the Previously Described PCPE1

2002 ◽  
Vol 277 (51) ◽  
pp. 49820-49830 ◽  
Author(s):  
Barry M. Steiglitz ◽  
Douglas R. Keene ◽  
Daniel S. Greenspan
Keyword(s):  
Expressed Sequence Tag ◽  
Open Angle Glaucoma ◽  
Type I ◽  
Post Translational Modification ◽  
Collagen Binding ◽  
Type I Procollagen ◽  
Morphogenetic Protein ◽  
Fibrillar Collagens ◽  
Cell Layers ◽  
Novel Protein

The procollagen COOH-terminal proteinase enhancer (PCPE) is a glycoprotein that binds the COOH-terminal propeptide of type I procollagen and potentiates its cleavage by procollagen C-proteinases, such as bone morphogenetic protein-1 (BMP-1). Recently, sequencing of a human expressed sequence tag, which maps near the primary open angle glaucoma region on chromosome 3q21, showed it to encode a novel protein with only 43% identity with PCPE but with a similar domain structure. Here we show this novel protein to be a functional procollagen COOH-terminal proteinase enhancer with activity comparable with that of PCPE and thus propose the designations PCPE2 and PCPE1, respectively. PCPE2 is shown to have a much more limited distribution of expression than does PCPE1, with strong expression primarily in nonossified cartilage in developing tissues and at high levels in the adult heart. PCPE2 is shown to be a glycoprotein that differs markedly in the nature of its glycosylation from that of PCPE1. PCPE2 is also shown to have markedly stronger affinity for heparin than PCPE1, which may account for higher affinities for cell layers. Unexpectedly, both PCPE1 and PCPE2 were found to be collagen-binding proteins, capable of binding at multiple sites on the triple helical portions of fibrillar collagens and also capable of competing for such binding with procollagen C-proteinases. The latter observations may provide insights into the ways PCPEs affect the kinetics of the C-proteinase reaction and into the physical interactions that occur between procollagen C-proteinases and their substrates.

Production of a Novel, Self-Assembled, Collagenous Matrix Mimicking the Hierarchical Structure of Native Aligned Connective Tissue

1995 ◽  
Vol 414 ◽  
Author(s):  
G. D. Pins ◽  
D. L. Christiansen ◽  
R. Patel ◽  
F. H. Silver
Keyword(s):  
Self Assembly ◽  
Collagen Fiber ◽  
Type I Collagen ◽  
Tensile Tests ◽  
Fiber Formation ◽  
Morphological Properties ◽  
Uniaxial Tensile ◽  
Type I ◽  
Native Collagen

AbstractThe primary goal of the biomaterials scientist and tissue engineer is to create a biocompatible implant which mimics the mechanical and morphological properties of the tissue being replaced. In vitro experimentation has documented the propensity of soluble type I collagen to self-assemble and form microscopic collagen fibrils with periodic banding analogous to native collagen fiber. Our laboratory has further investigated in vitro self-assembly by incorporating several of the “natural” processes into a multi-step fiber formation procedure which generates macroscopic collagen fiber from its molecular constituents. Results of uniaxial tensile tests and ultrastructural analyses indicate that these coextruded and stretched collagen fibers have mechanical properties and fibrillar substructure comparable to that observed in native collagen fiber.

scholarly journals Cleavage of Type I Procollagen by Human Mast Cell Chymase Initiates Collagen Fibril Formation and Generates a Unique Carboxyl-terminal Propeptide

1997 ◽  
Vol 272 (11) ◽  
pp. 7127-7131 ◽  
Author(s):  
Mark W. Kofford ◽  
Lawrence B. Schwartz ◽  
Norman M. Schechter ◽  
Dorne R. Yager ◽  
Robert F. Diegelmann ◽  
...  
Keyword(s):  
Mast Cell ◽  
Collagen Fibril ◽  
Fibril Formation ◽  
Human Mast Cell ◽  
Type I ◽  
Type I Procollagen ◽  
Carboxyl Terminal ◽  
Mast Cell Chymase
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