ArticleHuman molecular genetics2015
Loss of fibulin-4 disrupts collagen synthesis and maturation: implications for pathology resulting from EFEMP2 mutations.
Article in Human molecular genetics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 54 citations in OpenAlex.
- Fibulin-4 is required for the mechanical stability of tendons.Cell and tissue research · 2025Article
- Induction of cardiac fibulin-4 protects against pressure overload-induced cardiac hypertrophy and heart failure.Communications biology · 2025Article
- Novel Insights into the Aortic Mechanical Properties of Mice Modeling Hereditary Aortic Diseases.Thrombosis and haemostasis · 2025Article
- Transcriptional regulation of postnatal aortic development.Cells & development · 2024Article
- Article
- Patient-derived extracellular matrix demonstrates role of COL3A1 in blood vessel mechanics.Acta biomaterialia · 2023Article
- Characterization of a spontaneous mouse model of mild, accelerated aging via ECM degradation in emphysematous lungs.Scientific reports · 2023Article
- EMILIN1 deficiency causes arterial tortuosity with osteopenia and connects impaired elastogenesis with defective collagen fibrillogenesis.American journal of human genetics · 2022Article
- Autosomal recessive cutis laxa type Ib-Successful redo aortic root and arch replacement.Clinical case reports · 2022Article
- Inter-donor variability of extracellular matrix production in long-term cultures of human fibroblasts.Biomaterials science · 2022Article
- A multi-omics study to characterize the transdifferentiation of human dermal fibroblasts to osteoblast-like cells.Frontiers in molecular biosciences · 2022Article
- Procollagen C-proteinase enhancer-1 (PCPE-1), a potential biomarker and therapeutic target for fibrosis.Matrix biology plus · 2021Article
- Raman microspectroscopy and Raman imaging reveal biomarkers specific for thoracic aortic aneurysms.Cell reports. Medicine · 2021Article
- Predicting Proteolysis in Complex Proteomes Using Deep Learning.International journal of molecular sciences · 2021Article
- Clinical and Molecular Delineation of Cutis Laxa Syndromes: Paradigms for Homeostasis.Advances in experimental medicine and biology · 2021Review
- Numerical knockouts-In silico assessment of factors predisposing to thoracic aortic aneurysms.PLoS computational biology · 2020Article
- The "other" 15-40%: The Role of Non-Collagenous Extracellular Matrix Proteins and Minor Collagens in Tendon.Journal of orthopaedic research : official publication of the Orthopaedic Research Society · 2020Review
- Elastic fibers and biomechanics of the aorta: Insights from mouse studies.Matrix biology : journal of the International Society for Matrix Biology · 2020Review
- EFEMP2 Inhibits Breast Cancer Invasion And Metastasis In Vitro And In Vivo.OncoTargets and therapy · 2019Article
- Functional importance of lysyl oxidase family propeptide regions.Journal of cell communication and signaling · 2018Review
Corrections and comments
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Authors and funding
10 authors at 3 institutions in 3 countries.
Funding
Abstract
Homozygous recessive mutations in either EFEMP2 (encoding fibulin-4) or FBLN5 (encoding fibulin-5), critical genes for elastogenesis, lead to autosomal recessive cutis laxa types 1B and 1A, respectively. Previously, fibulin-4 was shown to bind lysyl oxidase (LOX), an elastin/collagen cross-linking enzyme, in vitro. Consistently, reported defects in humans with EFEMP2 mutations are more severe and broad in range than those due to FBLN5 mutations and encompass both elastin-rich and collagen-rich tissues. However, the underlying disease mechanism in EFEMP2 mutations has not been fully addressed. Here, we show that fibulin-4 is important for the integrity of aortic collagen in addition to elastin. Smooth muscle-specific Efemp2 loss in mouse (termed SMKO) resulted in altered fibrillar collagen localization with larger, poorly organized fibrils. LOX activity was decreased in Efemp2-null cells, and collagen cross-linking was diminished in SMKO aortas; however, elastin cross-linking was unaffected and the level of mature LOX was maintained to that of wild-type aortas. Proteomic screening identified multiple proteins involved in procollagen processing and maturation as potential fibulin-4-binding partners. We showed that fibulin-4 binds procollagen C-endopeptidase enhancer 1 (Pcolce), which enhances proteolytic cleavage of the procollagen C-terminal propeptide during procollagen processing. Interestingly, however, procollagen cleavage was not affected by the presence or absence of fibulin-4 in vitro. Thus, our data indicate that fibulin-4 serves as a potential scaffolding protein during collagen maturation in the extracellular space. Analysis of collagen in other tissues affected by fibulin-4 loss should further increase our understanding of underlying pathologic mechanisms in patients with EFEMP2 mutations.
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