Pathogenesis of Osteoarthritis in Col2a1 Mutant Mice

Brigham Young University, Provo UT

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Abstract

DESCRIPTION (provided by applicant): The application?s major objective is to develop an animal model for osteoarthritis (OA) to provide an understanding of the histopathology and mechanisms involved in the development of articular cartilage disease. Degeneration of synovial joint tissue in the form of OA is one of the leading causes of chronic disability in humans. For the most part, OA is idiopathic and, therefore, animal models are urgently needed for the understanding of the mechanisms involved and to lay the foundation for the development of drug and gene therapies used in the treatment and prevention of this skeletal disease. One class of proteins that plays an essential role in the structure and function of articular cartilage, triple helical collagen, appears to be involved in the pathogenesis of this disease, particularly those types of hereditary OA associated with mild chondrodysplasia. Disproportionate micromelia (Dmm) is a semidominant, type II collagen (Col2a1) mutation in mice that, in the heterozygous condition, causes mild dwarfism. Preliminary studies, including small histological studies on knee joints from 6- and 9-month-old mice, indicate the presence of OA as well. The purpose of the proposed research is to expand these preliminary studies to thoroughly characterize the development of OA in Dmm/+ mice. The use of light microscopy will permit examination of cellular changes within knee-joint as well as non-weight-bearing articular cartilages of various aged heterozygous mice. Electron microscopy will permit examination of subcellular and matrix changes in relation to the observed histological changes. Immunohistochemistry will allow documentation of the presence of type I collagen, as well as the appearance of such OA biomarkers as degraded collagen and degraded proteoglycan, and up-regulation of the corresponding metalloproteinases in relation to the time-of-onset of such histopathological changes. The overall objective is to establish Dmm/+ mice as an animal model of OA in which various therapies can be tested to determine whether they prevent OA initiation or progression.