A new MMP‐mediated prodomain cleavage mechanism to activate bone morphogenetic proteins from the extracellular matrix

Since their discovery as pluripotent cytokines extractable from bone matrix, it has been speculated how bone morphogenetic proteins (BMPs) become released and activated from the extracellular matrix (ECM). In contrast to TGF‐βs, most investigated BMPs are secreted as bioactive prodomain (PD)–growth...

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Bibliographic Details
Published in:The FASEB journal 2021-03, Vol.35 (3), p.e21353-n/a
Main Authors: Furlan, Ariane G., Spanou, Chara E. S., Godwin, Alan R. F., Wohl, Alexander P., Zimmermann, Laura‐Marie A., Imhof, Thomas, Koch, Manuel, Baldock, Clair, Sengle, Gerhard
Format: Article
Language:English
Subjects:
Amino Acid Motifs
Animals
bone morphogenetic protein (BMP)
Bone Morphogenetic Protein 7 - chemistry
Bone Morphogenetic Protein 7 - metabolism
Bone Morphogenetic Proteins - chemistry
Bone Morphogenetic Proteins - metabolism
extracellular matrix (ECM)
Extracellular Matrix - metabolism
fibrillin
HEK293 Cells
Humans
matrix metalloproteinase (MMP)
Matrix Metalloproteinase 13 - physiology
Matrix Metalloproteinases - physiology
Mice
Molecular Docking Simulation
Protein Domains
single particle transmission electron microscopy
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Summary:Since their discovery as pluripotent cytokines extractable from bone matrix, it has been speculated how bone morphogenetic proteins (BMPs) become released and activated from the extracellular matrix (ECM). In contrast to TGF‐βs, most investigated BMPs are secreted as bioactive prodomain (PD)–growth factor (GF) complexes (CPLXs). Recently, we demonstrated that PD‐dependent targeting of BMP‐7 CPLXs to the extracellular fibrillin microfibril (FMF) components fibrillin‐1 and ‐2 represents a BMP sequestration mechanism by rendering the GF latent. Understanding how BMPs become activated from ECM scaffolds such as FMF is crucial to elucidate pathomechanisms characterized by aberrant BMP activation and ECM destruction. Here, we describe a new MMP‐dependent BMP‐7 activation mechanism from ECM‐targeted pools via specific PD degradation. Using Edman sequencing and mutagenesis, we identified a new and conserved MMP‐13 cleavage site within the BMP‐7 PD. A degradation screen with different BMP family PDs and representative MMP family members suggested utilization of the identified site in a general MMP‐driven BMP activation mechanism. Furthermore, sandwich ELISA and solid phase cleavage studies in combination with bioactivity assays, single particle TEM, and in silico molecular docking experiments provided evidence that PD cleavage by MMP‐13 leads to BMP‐7 CPLX disintegration and bioactive GF release.
ISSN:0892-6638
1530-6860
DOI:10.1096/fj.202001264R