Influence of a collagen mutation of the mechanical nature of bone: Governing factors in a disease model for osteogenesis imperfecta type IV.

Bone relies on multiple orders of organization to properly fulfill its functional requirements. At its most fundamental level, collagen and mineral combine in a precisely defined manner and contribute to the mechanical properties of bone. However, the precise way in which collagen fulfills this role remains incompletely understood. A greater understanding is needed to define the contribution of collagen to normal bone function in order to understand what happens when circumstances arise causing these systems to fail. The purpose of this thesis was to evaluate the consequences of a collagen mutation on bone structure, strength, ductility, and ultrastructure. Interventions and perturbations, including natural changes due to aging, induced changes in cellular activity, and allelic alterations at the level of the genome were examined. Specifically, changes in collagen structure were hypothesized to alter bone ultrastructure, changing elastic properties and post-yield ductility. While elastic properties are proposed to be altered through changes in bone cell activity and thus bone mass, changes in ductility are hypothesized to require a fundamental intervention at the ultrastructural level. An animal model established to replicate a typical osteogenesis imperfecta-producing collagen mutation was used to address these questions. As a result of a G349C substitution in one col1a1 allele, Brtl/+ mice demonstrate reduced bone strength and ductility due to deficiencies in bone size and collagen organization. With age, Brtl/+ compensates for deficiencies in bone strength at least in part through enhanced mineralization and thus enhanced tissue elastic modulus. A 12 week bisphosphonate intervention designed to target Brtl/+ cellular activity improved bone strength through changes in bone structure, but failed to rescue bone brittleness. This low ductility phenotype was rescued through additional mutation of the second col1a1 allele in the Brtl/Brtl mouse. In addition to whole bone properties, impaired ultrastructural phenotype, including hypermineralization and impaired collagen cross-linking were rescued in the Brtl/Brtl mouse. Mechanisms responsible for the Brtl/+ phenotype may involve disruption of normal collagen processing, altered collagen secretion, heterogeneity of secreted collagen, or differential organization of collagen in the extracellular matrix. A disulfide bond present in Brtl/Brtl collagen may play a critical role in rescue of its phenotype.Ph.D.Animal PhysiologyApplied SciencesBiological SciencesBiomedical engineeringCellular biologyGeneticsHealth and Environmental SciencesPathologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/124849/2/3163852.pd