The Material Basis for Reduced Mechanical Properties in oim Mice Bones

Abstract

Osteogenesis imperfecta (OI), a heritable disease caused by molecular defects in type I collagen, is characterized by skeletal deformities and brittle bones. The heterozygous and homozygous oim mice (oim/+ and oim/oim) exhibit mild and severe OI phenotypes, respectively, serving as controlled animal models of this disease. In the current study, bone geometry, mechanics, and material properties of 1-year-old mice were evaluated to determine factors that influence the severity of phenotype in OI. The oim/oim mice exhibited significantly smaller body size, femur length, and moment of area compared with oim/+ and wild-type (+/+) controls. The oim/oim femur mechanical properties of failure torque and stiffness were 40% and 30%, respectively, of the +/+ values, and 53% and 36% of the oim/+ values.

Bone Material Properties in Osteogenesis Imperfecta

“…At a tissue level, cortical thinning and reductions in trabecular number are observed on light microscopy, along with a lack of lamellar architecture and increased osteocyte density. (21) At an ultrastructural level, collagen content is reduced by 20% (22) and a reduction in the size of the D-space within oim-/-collagen fibrils of approximately 1% versus wild type across a range of D-space sizes from 60 to 70 nm has been observed using atomic force microscopy. (23) The individual tropocollagen molecules are more prone to kinking, (24) and there is more water associated with the tropocollagen and between the microfibrils.…”

Osteogenesis imperfecta

“…The increased vulnerability to frac tures might be explained by abnormalities of the miner alized matrix at different levels, affecting structures that normally hinder crack propagation 126 . First, compared with controls, the alignment of collagen fibrils was found to be more disordered and less lamellar in both oim mouse models 124,127 and biopsy samples from patients with osteo genesis imperfecta 128 ; second, the collagenous matrix is not only reduced in amount 129 but also showed more non enzymatic crosslinks 124 ; third, unmineral ized collagen fibrils from the oim mouse model showed reduced strength under tensioning 130 and more affinity to water 131 . By contrast, less tissue water was found in fully mineralized bone of the oim mice 132 and in bone biop sies from patients with osteogenesis imperfecta 121 .…”

Role of genetic background in determining phenotypic severity throughout postnatal development and at peak bone mass in Col1a2 deficient mice (oim)

“…The µCT image slices were reconstructed to give a cubic voxel dimension of 0.103 mm and analyzed using the Amira 3.1 software package (Mercury Computer Systems/TGS, Chelmsford, MA) to measure total femur length and locate the mid-shaft slice. The mid-shaft slice was modeled as a hollow elliptical cross-section with periosteal ( p ) and endosteal ( e ) anterior-posterior (d p and d e ; minor diameters) and medio-lateral (D p and D e ; major diameters) [12]. Their numerical values were determined by drawing a bone density histogram along the ellipse axes and reproducibly locating the edges of cortical bone defined as having a bone density threshold of [P max + (P max −P min )/3].…”

“…The osteogenesis imperfecta murine (oim) model exhibits an OI type III-like phenotype due to a single nucleotide deletion in the Col1a2 gene leading to exclusion of the α2(I) chain from the type I collagen molecule, producing solely homotrimeric type I collagen [10]. This mouse model has been shown to have reduced biomechanical integrity in bones [11,12] and aorta [13], altered bone mineral composition [14] and reduced amounts of type I collagen in bones [12], aorta [13], tendon [15] and left ventricle [16].…”

“…Although the skeletal fragility of the oim mouse model has been well studied, the impact of developmental stage on femoral geometry and biomechanical strength during postnatal development prior to three months of age has not been evaluated [11,12]. Prior to four months of age the femur grows in both length and diameter, which impacts its geometry and biomechanical properties.…”