Genetic Variation in Bone Growth Patterns Defines Adult Mouse Bone Fragility

Abstract

Femoral morphology and composition were determined for three inbred mouse strains between ages E18.5 and 1 year. Genotype-specific variation in postnatal, pubertal, and postpubertal growth patterns and mineral accrual explained differences in adult bone trait combinations and thus bone fragility.Introduction: Fracture risk is strongly regulated by genetic factors. However, this regulation is generally considered complex and polygenic. Therefore, the development of effective genetic-based diagnostic and treatment tools hinges on understanding how multiple genes and multiple cell types interact to create mechanically functional structures. The goal of this study was to connect variability in whole bone mechanical function, including measures of fragility, to variability in the biological processes underlying skeletal development. We accomplished this by testing for variation in bone morphology and composition among three inbred mouse strains from E18.5 to 1 year of age. Materials and Methods: Mid-diaphyseal cross-sectional areas, diameters, moments of inertia, and ash content were determined for three strains of mice with widely differing adult whole bone femoral mechanical properties (A/J, C57BL/6J, and C3H/HeJ) at E18.5 and postnatal days 1, 7, 14, 28, 56, 112, 182, and 365 (n ‫ס‬ 5-15 mice/strain/age). Results: Significant differences in the magnitude and rate of change in morphological and compositional bone traits were observed among the three strains at each phase of growth, including prenatal, postnatal, pubertal, and adult ages. These genotype-specific variations in growth patterns mathematically determined how variation in adult bone trait combinations and mechanical properties arose. Furthermore, six bone traits were identified that characterize phenotypic variability in femoral growth. These include (1) bone size and shape at postnatal day 1, (2) periosteal and (3) endosteal expansion during early growth, (4) periosteal expansion and (5) endosteal contraction in later growth, and (6) ash content. These results show that genetic variability in adult bone traits arises from variation in biological processes at each phase of growth. Conclusions: Inbred mice achieve different combinations of adult bone traits through genotype-specific regulation of bone surface activity, growth patterns, and whole bone mineral accrual throughout femoral development. This study provides a systematic approach, which can be applied to the human skeleton, to uncover genetic control mechanisms influencing bone fragility.

Delayed pubertal development by hypothalamic suppression causes an increase in periosteal modeling but a reduction in bone strength in growing female rats

“…The preservation of the total subperiosteal area could have maintained the bone strength; however, the calculated stress and Young's modulus values were significantly lower in the experimental groups. Tthe ash fraction of the tibial diaphysis, a measure of mineral content in bone was not different between groups; not a surprising result as Price et al (2005) (18) reported that the variability in ash content is established early in life and thus is not a major accommodation strategy to alter stiffness during pubertal delay. Factors such as collagen cross-linking, mineral crystal size, collagen fiber orientation and microstructure organization may affect bone strength (35).…”

“…The relative cellular activity on the periosteal and endocortical bone surfaces specifically during puberty affects bone size, a critical element of bone strength (18). Increased estrogen levels during puberty have been hypothesized to inhibit periosteal modeling in females (19) and thus result in smaller and weaker bones compared to males.…”

Differential Adaptive Response of Growing Bones From Two Female Inbred Mouse Strains to Voluntary Cage‐Wheel Running

“…Finally, because the amount of voluntary cage‐wheel running is expected to vary among exercised mice, we tested for associations between distance run and each of the morphological and mechanical properties to identify parameters that may be sensitive to the amount of cage‐wheel activity during growth. Though this study does not specifically test for in situ tissue‐level strain differences in the femora of growing A/J and B6 mice, we anticipate that mechanical strain levels will be similar between the two running mouse strains because they both have similar body mass and long bones of near equivalent stiffness 13. Thus, any differential phenotypic response to voluntary cage‐wheel running should be more applicable to either a difference in the number of loading cycles (ie, wheel revolutions) sustained, or may reflect a difference in the normal strain distribution pattern between these two mouse strains.…”

Bone microstructure and its associated genetic variability in 12 inbred mouse strains: μCT study and in silico genome scan

“…The Lewis and Fischer inbred rat strains have been used as a model of human aging-related traits [10][11][12] including an intercross genome screening study of bone properties [13]. The power of the mouse as a genetic tool has been utilized to uncover genes whose normal allelic variation regulates BMD and other skeletal traits such as bone geometry, microarchitecture and strength [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28]. An inbred strain survey is a useful step in a thorough genetic analysis of a complex quantitative trait like BMD in mice [23].…”