Post-weaning epiphysiolysis causes distal femur dysplasia and foreshortened hindlimbs in fetuin-A-deficient mice.

Abstract

Fetuin-A / α2-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.

• Authors: Laura J Brylka, Sina Köppert, Anne Babler, Beate Kratz, Bernd Denecke, Timur A Yorgan, Julia Etich, Ivan G Costa, Bent Brachvogel, Peter Boor, Thorsten Schinke, Willi Jahnen-Dechent
• Journal: PloS one (PLoS One) Vol. 12 Issue 10 Pg. e0187030 ( 2017) ISSN: 1932-6203 [Electronic] United States
• PMID: 29088242 (Publication Type: Journal Article)

Chemical References

• Ahsg protein, mouse
• alpha-2-HS-Glycoprotein

Topics

• Animals
• Bone Diseases, Developmental (genetics)
• Epiphyses, Slipped (genetics)
• Female
• Femur (abnormalities)
• Fluorescent Antibody Technique
• Gene Expression Profiling (methods)
• Growth Plate (abnormalities)
• Hindlimb (abnormalities)
• Male
• Mice, Inbred C57BL
• Mice, Knockout
• Reverse Transcriptase Polymerase Chain Reaction
• Weaning
• alpha-2-HS-Glycoprotein (deficiency, genetics)