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  current news   Press   selected story    
     
  4th May 2012  
  Attenuated BMP1 Function Compromises Osteogenesis, Leading to Bone Fragility in Humans and Zebrafish
 
 




Authors
PV Asharani1,*, Katharina Keupp2,3,4,*, Oliver Semler5, Wenshen Wang1, Yun Li2,3,4, Holger Thiele6, Gökhan Yigit2,3,4, Esther Pohl2,3,4, Jutta Becker3, Peter Frommolt4,6, Carmen Sonntag7,8, Janine Altmüller6, Katharina Zimmermann3, Daniel S. Greenspan9, Christian Netzer3, Eckhard Schönau5, Radu Wirth3, Matthias Hammerschmidt2,4,7, Peter Nürnberg2,4,6, Bernd Wollnik2,3,4, §, Thomas J. Carney1, §

1 - Institute of Molecular and Cell Biology, Proteos, Singapore 138673
2 -
Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
3 -
Institute of Human Genetics, University Hospital Cologne, University of Cologne, Cologne, Germany
4 -
Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
5 -
Children's Hospital, University of Cologne, Cologne, Germany
6 -
Cologne Center for Genomics, University of Cologne, Cologne, Germany
7 -
Institute of Developmental Biology, University of Cologne, Cologne, Germany
8 -
Present address: Australian Regenerative Medicine Institute (ARMI), Monash University, Victoria, 3800, Australia
9 -
Department of Cell and Regenerative Biology, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin, USA..
* -
contributed equally to this work
§ -
shared last authors

Published in The American Journal of Human Genetics 90, 1–13, April 6, 2012

Abstract

Bone morphogenic protein 1 (BMP1)is an astacin metalloprotease with important cellular functions and diverse substrates, including extracellular matrix (ECM) proteins and antagonists of some TGFβ superfamily members. Combining whole-exome sequencing and filtering for homozygous stretches of identified variants, we found a homozygous causative BMP1 mutation, c.34G>C, in a consanguineous family with increased bone mineralization density and multiple recurrent fractures. The mutation is located within the BMP1 signal peptide and leads to impaired secretion and an alteration in posttranslational modification. We also characterize a zebrafish bone mutant harboring lesions in bmp1a, demonstrating conservation of BMP1 function in osteogenesis across species. Genetic, biochemical and histological analysis of this mutant, combined with comparison to a second, similar locus, reveals a critical requirement for Bmp1a in the generation of mature collagen in bone, downstream of osteoblast maturation. We thus define the molecular and cellular bases of BMP1-dependent osteogenesis and show the importance of this protein for bone formation and stability.

Figure Legend: frf displays defects in fibrillar collagen order and Col1a1a processing (a) Major proteolytic targets of Bmp1 include a C-terminal domain within pro-Collagen I removing the C-propeptide (orange ovals), and cleavage of the BMP2/4 inhibitor, Chordin (red hexagon) to release free BMP2/4 (green oval). (b-g) Picrosirius red stained saggital (b-e) and transverse (f-g) sections of WT (b, d, f) and frf-/- larvae at 11dpf (b-c), 20dpf (d-e) and 4 months (f-g). Sections viewed under polarized light reveal the reduced Collagen fibre associated birefringency in the Centra region (b-e) and fin rays (f-g)  infrf-/-  mutants (c, e, g) compared to WT (b, d, f). (H-I) Transmission electron micrographs of longitudinal sections of WT (H) andfrf-/-(I) larval medial fins at 6dpf showing loss of structured collagen fibres in the mutant. (J-K) Western blots of protein extracted from WT (lane 1) andfrf-/-mutant (lane 2) larvae probed with an antibody directed against zebrafish Collagen1a1a (upper panels in both (J and K) or an antibody against bactin as a loading control (lower panels). The four possible Collagen1a1 forms are indicated on the right, including Pro-collagen1a1 retaining both C- and N- terminal propetides (Pro α1(I)), mature collagen α1(I) retaining neither propeptides (α1(I)), a form retaining only the N-propeptide (pN α1(I)) and a form retaining only the C-propeptide (pCα1(I)). In 6dpf (J) and 4 month (K)frf-/-mutants, the two forms retaining the C-propeptide predominate.

For more information about Thomas CARNEY's laboratory, please click here.