title: 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.affiliation: Department of Orthopaedic Surgery, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Machiko
authors.initials: M
authors.lastname: Arita
authors.affiliation: Department of Orthopaedic Surgery, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Jolanta
authors.initials: J
authors.lastname: Fertala
authors.affiliation: Department of Orthopaedic Surgery, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Cheryl
authors.initials: C
authors.lastname: Hou
authors.affiliation: Department of Orthopaedic Surgery, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Steplewski
authors.affiliation: Department of Orthopaedic Surgery, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania. Electronic address: andrzej.fertala@jefferson.edu.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Fertala
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D002356:Cartilage / Q000378:metabolism; D049109:Cell Proliferation; D019902:Chondrocytes / Q000166:cytology; D002923:Cilia / Q000378:metabolism; D024043:Collagen Type II / Q000235:genetics* / Q000378:metabolism; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress; D014644:Genetic Variation; D005838:Genotype; D006132:Growth Plate / Q000002:abnormalities* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010009:Osteochondrodysplasias / Q000235:genetics*; D019076:Transgenes
chemical_list: C447413:Col2a1 protein, mouse; D024043:Collagen Type II