Mechanisms of aberrant organization of growth plates in conditional transgenic mouse model of spondyloepiphyseal dysplasia associated with the R992C substitution in collagen II.

Abstract

Mutations in collagen II, a main structural protein of cartilage, are associated with various forms of spondyloepiphyseal dysplasia (SED), whose main features include aberrations of linear growth. Here, we analyzed the pathomechanisms responsible for growth alterations in transgenic mice with conditional expression of the R992C collagen II mutation. Specifically, we studied the alterations of the growth plates of mutant mice in which chondrocytes lacked their typical columnar arrangement. Our studies demonstrated that chondrocytes expressing the thermolabile R992C mutant collagen II molecules endured endoplasmic reticulum stress, had atypical polarization, and had reduced proliferation. Moreover, we demonstrated aberrant organization and morphology of primary cilia. Analyses of the extracellular collagenous deposits in mice expressing the R992C mutant collagen II molecules indicated their poor formation and distribution. By contrast, transgenic mice expressing wild-type collagen II and mice in which the expression of the transgene encoding the R992C collagen II was switched off were characterized by normal growth, and the morphology of their growth plates was correct. Our study with the use of a conditional mouse SED model not only indicates a direct relation between the observed aberration of skeletal tissues and the presence of mutant collagen II, but also identifies cellular and matrix elements of the pathomechanism of SED.

• Authors: Machiko Arita, Jolanta Fertala, Cheryl Hou, Andrzej Steplewski, Andrzej Fertala
• Journal: The American journal of pathology (Am J Pathol) Vol. 185 Issue 1 Pg. 214-29 (Jan 2015) ISSN: 1525-2191 [Electronic] United States
• PMID: 25451152 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Chemical References

• Col2a1 protein, mouse
• Collagen Type II

Topics

• Amino Acid Substitution
• Animals
• Cartilage (metabolism)
• Cell Proliferation
• Chondrocytes (cytology)
• Cilia (metabolism)
• Collagen Type II (genetics, metabolism)
• Crosses, Genetic
• Disease Models, Animal
• Endoplasmic Reticulum Stress
• Genetic Variation
• Genotype
• Growth Plate (abnormalities, metabolism)
• Mice
• Mice, Transgenic
• Mutation
• Osteochondrodysplasias (genetics)
• Transgenes