Loss of fibulin-4 results in abnormal collagen fibril assembly in bone, caused by impaired lysyl oxidase processing and collagen cross-linking

Sasaki T, Stoop R, Sakai T, Heß A, Deutzmann R, Schlötzer-Schrehardt U, Chu ML, Von Der Mark K (2016)

Publication Type: Journal article

Publication year: 2016

Journal

Matrix Biology Elsevier

Book Volume: 50

Pages Range: 53-66

DOI: 10.1016/j.matbio.2015.12.002

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.

Authors with CRIS profile

Takako Sasaki Lehrstuhl für Experimentelle Medizin mit dem Schwerpunkt Molekulare Pathogeneseforschung Andreas Heß Lehrstuhl für Pharmakologie und Toxikologie Ursula Schlötzer-Schrehardt Medizinische Fakultät

Involved external institutions

Netherlands Organization for Applied Scientific Research / Nederlandse Organisatie voor toegepast-natuurwetenschappelijk onderzoek (TNO) NL Netherlands (NL) The University of Liverpool GB United Kingdom (GB) Universität Regensburg DE Germany (DE) Thomas Jefferson University US United States (USA) (US)

How to cite

APA:

Sasaki, T., Stoop, R., Sakai, T., Heß, A., Deutzmann, R., Schlötzer-Schrehardt, U.,... Von Der Mark, K. (2016). Loss of fibulin-4 results in abnormal collagen fibril assembly in bone, caused by impaired lysyl oxidase processing and collagen cross-linking. Matrix Biology, 50, 53-66. https://doi.org/10.1016/j.matbio.2015.12.002

MLA:

Sasaki, Takako, et al. "Loss of fibulin-4 results in abnormal collagen fibril assembly in bone, caused by impaired lysyl oxidase processing and collagen cross-linking." Matrix Biology 50 (2016): 53-66.

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