Title
Loss of fibulin-4 results in abnormal collagen fibril assembly in bone, caused by impaired lysyl oxidase processing and collagen cross-linking
Author
Sasaki, T.
Stoop, R.
Sakai, T.
Hess, A.
Deutzmann, R.
Schlötzer-Schrehardt, U.
Chu, M.L.
von der Mark, K.
Publication year
2016
Abstract
The extracellular matrix protein fibulin-4 has been shown to be indispensable for elastic fiber assembly, but there is also evidence from human mutations that it is involved in controlling skeletal development and bone stability. Fibulin-4 mutations were identified in patients suffering from vascular abnormality and/or cutis laxa, and some of these patients exhibited bone fragility, arachnodactyly and joint laxity. In order to elucidate the role of fibulin-4 in bone structure and skeletal development, we analyzed structural changes in skeletal tissues of Fbln4-/- mice. Immunostaining confirmed that fibulin-4 is highly expressed in cartilage, bone, ligaments and tendons. No morphological abnormalities were found in the skeleton of Fbln4-/- mice as compared to wild type littermates except forelimb contractures as well as unusually thick collagen fibrils. Furthermore, fibulin-4 deficiency caused enhanced susceptibility of bone collagen for acid extraction, consistent with significantly reduced lysylpyridinoline and hydroxylysylpyridinoline cross-links in bone. In accordance with that, the amount of lysyl oxidase in long bones and calvaria was strongly decreased and proteolytic activation of lysyl oxidase was reduced in fibulin-4 deficient osteoblasts, while addition of recombinant fibulin-4 rescued the activation. The finding suggested that fibulin-4 is important for the proteolytic activation of lysyl oxidase which has a pivotal role in cross-linking of collagen and elastin. © 2015 International Society of Matrix Biology.
Subject
Life
MHR - Metabolic Health Research
ELSS - Earth, Life and Social Sciences
Biomedical Innovation
Biology
Healthy Living
Collagen cross-linking
Elastic fiber
Fibulin-4
Lysyl oxidase
To reference this document use:
http://resolver.tudelft.nl/uuid:1378a0d0-6799-4a7d-a126-4cc54e95c73f
DOI
https://doi.org/10.1016/j.matbio.2015.12.002
TNO identifier
534876
ISSN
0945-053X
Source
Matrix Biology, 50, 53-66
Document type
article