Journal
FASEB JOURNAL
Volume 35, Issue 3, Pages -Publisher
WILEY
DOI: 10.1096/fj.202001264R
Keywords
bone morphogenetic protein (BMP); extracellular matrix (ECM); fibrillin; matrix metalloproteinase (MMP); single particle transmission electron microscopy
Categories
Funding
- Deutsche Forschungsgemeinschaft (DFG) [73111208 SFB829/B12, 397484323 TRR259/B09, FOR2722/C2, FOR2722/B2]
- MCTI | CNPq | Instituto Nacional de Ciencia e Tecnologia da Criosfera (INCT da Criosfera) [231369/2013-1]
- RCUK | Biotechnology and Biological Sciences Research Council (BBSRC) [BB/S015779/1]
- Wellcome Trust (Wellcome) [203128/Z/16/Z]
- Wellcome Trust [203128/Z/16/Z] Funding Source: Wellcome Trust
- BBSRC [BB/N015398/1, BB/S015779/1] Funding Source: UKRI
Ask authors/readers for more resources
The study reveals a new MMP-dependent activation mechanism for BMP-7 from targeted ECM pools via specific prodomain degradation. Cleavage of prodomain by MMP-13 leads to disintegration of BMP-7 complex and release of bioactive growth factor, providing insights into pathomechanisms characterized by aberrant BMP activation and ECM destruction.
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-beta s, 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available