title: Forelimb contractures and abnormal tendon collagen fibrillogenesis in fibulin-4 null mice.
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.
authors.affiliation: Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College, Thomas Jefferson University, 233 South 10th Street, Philadelphia, PA 19107, USA.|Department of Orthopaedic Surgery, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Dessislava Z
authors.initials: DZ
authors.lastname: Markova
authors.affiliation: Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College, Thomas Jefferson University, 233 South 10th Street, Philadelphia, PA 19107, USA.
authors.forename: Te-Cheng
authors.initials: TC
authors.lastname: Pan
authors.affiliation: Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College, Thomas Jefferson University, 233 South 10th Street, Philadelphia, PA 19107, USA.
authors.forename: Rui-Zhu
authors.initials: RZ
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Anatomy and Cell Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Guiyun
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Oita University, Oita, Japan.
authors.forename: Takako
authors.initials: T
authors.lastname: Sasaki
authors.affiliation: Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College, Thomas Jefferson University, 233 South 10th Street, Philadelphia, PA 19107, USA.|Department of Orthopaedic Surgery, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Machiko
authors.initials: M
authors.lastname: Arita
authors.affiliation: Department of Molecular Pharmacology & Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Birk
authors.affiliation: Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College, Thomas Jefferson University, 233 South 10th Street, Philadelphia, PA 19107, USA. mon-li.chu@jefferson.edu.
authors.forename: Mon-Li
authors.initials: ML
authors.lastname: Chu
mesh_terms: D000818:Animals; D003094:Collagen / Q000378:metabolism*; D003286:Contracture / Q000150:complications / Q000378:metabolism* / Q000473:pathology*; D016326:Extracellular Matrix Proteins / Q000172:deficiency* / Q000378:metabolism; D000071837:Fibrillins / Q000378:metabolism; D005552:Forelimb / Q000473:pathology*; D006547:Hernia / Q000150:complications / Q000473:pathology; D010641:Phenotype; D021381:Protein Transport; D013710:Tendons / Q000002:abnormalities* / Q000378:metabolism / Q000648:ultrastructure
chemical_list: C403672:EFEMP2 protein, human; D016326:Extracellular Matrix Proteins; D000071837:Fibrillins; D003094:Collagen
keywords: Collagen fibrillogenesis; Cutis laxa; Elastic fiber; Fibrillin; Tendon