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Forelimb contractures and abnormal tendon collagen fibrillogenesis in fibulin-4 null mice

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Abstract

Fibulin-4 is an extracellular matrix glycoprotein essential for elastic fiber formation. Mice deficient in fibulin-4 die perinatally because of severe pulmonary and vascular defects associated with the lack of intact elastic fibers. Patients with fibulin-4 mutations demonstrate similar defects, and a significant number die shortly after birth or in early childhood from cardiopulmonary failure. The patients also demonstrate skeletal and other systemic connective tissue abnormalities, including joint laxity and flexion contractures of the wrist. A fibulin-4 null mouse strain was generated and used to analyze the roles of fibulin-4 in tendon fibrillogenesis. This mouse model displayed bilateral forelimb contractures, in addition to pulmonary and cardiovascular defects. The forelimb and hindlimb tendons exhibited disruption in collagen fibrillogenesis in the absence of fibulin-4 as analyzed by transmission electron microscopy. Fewer fibrils were assembled, and fibrils were disorganized compared with wild-type controls. The organization of developing tenocytes and compartmentalization of the extracellular space was also disrupted. Fibulin-4 was co-localized with fibrillin-1 and fibrillin-2 in limb tendons by using immunofluorescence microscopy. Thus, fibulin-4 seems to play a role in regulating tendon collagen fibrillogenesis, in addition to its essential function in elastogenesis.

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Abbreviations

ARCL:

Autosomal recessive cutis laxa

BMP:

Bone morphogenetic protein

FDL:

Flexor digitorum longus

LOX:

Lysyl oxidase

LTBP:

Latent TGF-β-binding protein

TGF:

Transforming growth factor

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Acknowledgments

We thank the late Dr. Günter Kostka for graciously providing the mouse fibulin-4 genomic subclone, and Dr. Lynn Sakai for providing the antibodies for fibrillin-1 and -2.

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Author notes

  1. Dessislava Z. Markova & Machiko Arita

    Present address: Department of Orthopaedic Surgery, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA

Authors and Affiliations

  1. Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College, Thomas Jefferson University, 233 South 10th Street, Philadelphia, PA 19107, USA

    Dessislava Z. Markova, Te-Cheng Pan, Rui-Zhu Zhang, Machiko Arita & Mon-Li Chu

  2. Department of Pathology, Anatomy and Cell Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA

    Guiyun Zhang

  3. Department of Biochemistry, Faculty of Medicine, Oita University, Oita, Japan

    Takako Sasaki

  4. Department of Molecular Pharmacology & Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA

    David E. Birk

Authors
  1. Dessislava Z. Markova
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  2. Te-Cheng Pan
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  3. Rui-Zhu Zhang
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  4. Guiyun Zhang
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Corresponding author

Correspondence to Mon-Li Chu.

Additional information

Dessislava Z. Markova and Te-Cheng Pan contributed equally to this work.

Research reported in this publication was supported by the National Institutes of Health under Award Number GM55625 (MLC) and AR44745 (DEB). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Markova, D.Z., Pan, TC., Zhang, RZ. et al. Forelimb contractures and abnormal tendon collagen fibrillogenesis in fibulin-4 null mice. Cell Tissue Res 364, 637–646 (2016). https://doi.org/10.1007/s00441-015-2346-x

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  • DOI: https://doi.org/10.1007/s00441-015-2346-x

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