Bone Matrix Maturation in a Rat Model of Intra-Cortical Bone Remodeling

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 DESCRIPTION (provided by applicant): The purpose of this project is to develop rat and mouse analogs of Haversian remodeling to facilitate improved understanding of matrix maturation during adult cortical bone turnover. Our objective is to develop and validate a rodent model in which multiple skeletal sites can be interrogated using a hierarchical evaluation strategy from genes to mechanics. Variations in the organic and inorganic phases of the bone matrix affect material properties. These properties, in combination with the distribution of the matrix in space, determine the overall strength, stiffness and energy-to-failure of the bone as a tissue and organ. Cortical bone makes up ~80% of the total skeletal mass and contributes significantly to the mechanical strength of long bones. Because bone remodeling continues throughout life it is important to examine how the new bone which forms in the adult skeleton matures, particularly in light of the existence of treatments for various metabolic bone diseases including osteoporosis, some of which may negatively affect bone matrix material properties. While we now have considerable knowledge of how osteoporosis drugs affect bone resorption, formation and structure, we have little information on how these drugs affect bone as a material. In particular, the maturation process of the bone matrix from osteoid to fully mineralized matrix is incompletely understood. A major limitation for the research community is the lack of mouse or rat models for studying cortical bone remodeling. We propose to screen three rat models in which cortical resorption is induced followed by a recovery phase when lamellar bone fills in the induced cortical resorption spaces. Based on strict a priori criteria for model selection, we will carefully validate the model and will determine if it can be translated to mice so that future studies can take advantage of mouse genetic tools. The primary focus is on matrix maturation (e.g., the rate of mineralization) as determined by combined fluorochrome labeling, backscatter scanning electron microscopy, and Fourier transform infrared imaging. Other endpoints include micro-computed tomography, polarized light microscopy, gene and protein expression, serum markers, nanoindentation, and whole bone mechanical testing. The model will be validated by comparison with rabbits, a species in which Haversian remodeling normally occurs and in rats and mice in which Haversian remodeling is induced by other means. To demonstrate utility we will determine if the model replicates acceleration of Haversian bone mineralization during sclerostin antibody treatment, which we recently found in a non-human primate model. Successful completion of the project will offer researchers a new way to study Haversian bone matrix maturation in vivo, thereby providing a novel approach to screen drugs or other treatments affecting the skeleton and to study mechanisms of matrix maturation and how alterations in the matrix contribute to bone strength. Thus, we anticipate the new model will facilitate in vivo research into mechanisms of how bone quality is maintained in the adult skeleton.