Open AccessPost-weaning epiphysiolysis causes distal femur dysplasia and foreshortened hindlimbs in fetuin-A-deficient mice
Author(s) -
Laura Brylka,
Sina Köppert,
Anne Babler,
Beate Kratz,
Bernd Denecke,
Timur Alexander Yorgan,
Julia Etich,
Ivan G. Costa,
Bent Brachvogel,
Peter Boor,
Thorsten Schinke,
Willi JahnenDechent
Publication year - 2017
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0187030
Subject(s) - slipped capital femoral epiphysis , ectopic calcification , epiphysis , epiphysiolysis , endocrinology , medicine , femur , cartilage , biology , calcification , anatomy , femoral head , paleontology
Fetuin-A / α 2 -Heremans-Schmid-glycoprotein (gene name Ahsg ) is a systemic inhibitor of ectopic calcification. Due to its high affinity for calcium phosphate, fetuin-A is highly abundant in mineralized bone matrix. Foreshortened femora in fetuin-A-deficient Ahsg -/- mice indicated a role for fetuin-A in bone formation. We studied early postnatal bone development in fetuin-A-deficient mice and discovered that femora from Ahsg -/- mice exhibited severely displaced distal epiphyses and deformed growth plates, similar to the human disease slipped capital femoral epiphysis (SCFE). The growth plate slippage occurred in 70% of Ahsg -/- mice of both sexes around three weeks postnatal. At this time point, mice weaned and rapidly gained weight and mobility. Epiphysis slippage never occurred in wildtype and heterozygous Ahsg +/- mice. Homozygous fetuin-A-deficient Ahsg -/- mice and, to a lesser degree, heterozygous Ahsg +/- mice showed lesions separating the proliferative zone from the hypertrophic zone of the growth plate. The hypertrophic growth plate cartilage in long bones from Ahsg -/- mice was significantly elongated and V-shaped until three weeks of age and thus prior to the slippage. Genome-wide transcriptome analysis of laser-dissected distal femoral growth plates from 13-day-old Ahsg -/- mice revealed a JAK-STAT-mediated inflammatory response including a 550-fold induction of the chemokine Cxcl9 . At this stage, vascularization of the elongated growth plates was impaired, which was visualized by immunofluorescence staining. Thus, fetuin-A-deficient mice may serve as a rodent model of growth plate pathologies including SCFE and inflammatory cartilage degradation.