A murine skeletal adaptation that significantly increases cortical bone mechanical properties. Implications for human skeletal fragility.

Abstract

Movl3 mice carry a provirus that prevents transcription initiation of the al (I) collagen gene. Mutant mice homozygous for the null mutation produce no type I collagen and die at mid-gestation, whereas heterozygotes survive to adulthood. Dermal fibroblasts from heterozygous mice produce -50% less type I collagen than normal littermates, and the partial deficiency in collagen production results in a phenotype similar to osteogenesis imperfecta type I (an inherited form of skeletal fragility). In this study, we have identified an adaptation of Movl3 skeletal tissue that significantly improves the bending strength of long bone. The adaptive response occurred over a 2-mo period, during which time a small number of newly proliferated osteogenic cells produced a significant amount of matrix components and thus generated new bone along periosteal surfaces. New bone deposition resulted in a measurable increase in cross-sectional geometry which, in turn, led to a dramatic increase in long bone bending strength. (J. Clin. Invest. 1993. 92:1697-1705

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

“…This is consistent with observations that post-pubertal fracture number tends to decrease in OI patients [23]. The Mov-13 mouse model also demonstrated age-associated improvements in bone strength as well as geometry [32]. Though oim/oim mice represent type III OI patients, the current data are consistent with findings in mouse models of type I (Mov-13) and type IV (Brtl) OI, which both demonstrated age-associated improvements in femoral geometry and strength [25,32].…”

“…This is consistent with the observation that bone from OI patients plays "catch-up" with increasing age in an attempt to compensate for the reduction in the amount and integrity of the bone [24]. The Brtl and Mov-13 mouse models of OI have also shown age-associated changes in bone integrity [25,32]. Both of these models carry mutations in the α1(I) chain and only the heterozygote animals have been evaluated.…”

“…Bone biomechanical integrity can be partitioned into the following contributing components: the amount, architecture and distribution, and bone material composition and strength [32,33]. The experimental approach we took was to examine bone biomechanical integrity of femurs from two distinct mouse strains and three genotypes at three age points.…”

Osteogenesis Imperfecta

“…The retroviral insertion blocks the initiation of transcription and inactivates the Col1a1 allele (Hartung et al, 1986). The insertion is lethal at midgestation in homozygous mice (comparable to a type II OI though causing earlier lethality) while heterozygous mice are viable and constitute a model for the mild type I OI with increased skeletal fragility but also interesting adaptations that lead to improved cortical mechanical properties (Bonadio et al, 1993). The use of Cre-lox recombination technology made it possible to obtain the first knock-in mouse model for OI.…”

Whole Bone Mechanics and Bone Quality

“…Cellular metabolic activity distinguishes the skeleton from manmade structures and not only creates but also adapts and repairs the structural characteristics during growth and aging and with other conditions such as exercise, injury, and disease. In some animal models, for example, reduced tissue material properties are compensated for by altered geometry, resulting in comparable structural properties and minimizing the risk of fracture [13,61].…”