Postnatal and Pubertal Skeletal Changes Contribute Predominantly to the Differences in Peak Bone Density Between C3H/HeJ and C57BL/6J Mice

Abstract

Previous studies have shown that 60 -70% of variance in peak bone density is determined genetically. The higher the peak bone density, the less likely an individual is to eventually develop osteoporosis. Therefore, the amount of bone accrued during postnatal and pubertal growth is an important determining factor in the development of osteoporosis. We evaluated the contribution of skeletal changes before, during, and after puberty to the development of peak bone density in C3H/HeJ (C3H) and C57BL/6J (B6) mice. Volumetric bone density and geometric parameters at the middiaphysis of femora were measured by peripheral quantitative computed tomography (pQCT) from days 7 to 56. Additionally, biochemical markers of bone remodeling in serum and bone extracts were quantified. Both B6 and C3H mice showed similar body and femoral weights. B6 mice had greater middiaphyseal total bone area and thinner cortices than did C3H mice. Within strains, males had thicker cortices than did females. C3H mice accumulated more minerals throughout the study, with the most rapid accumulation occurring postnatally (days 7-23) and during pubertal maturation (days 23-31). C3H mice had higher volumetric bone density as early as day 7, compared with B6 mice. Higher serum insulin-like growth factor I (IGF-I) was present in C3H mice postnatally at day 7 and day 14. Until day 31, B6 male and female mice had significantly higher serum osteocalcin than C3H male and female mice, respectively. Alkaline phosphatase (ALP) was found to be significantly higher in the bone extract of C3H mice compared with B6 mice at day 14. These data are consistent with and support the hypothesis that the greater amount of bone accrued during postnatal and pubertal growth in C3H mice compared with B6 mice may be caused by increased cortical thickness, increased endosteal bone formation, and decreased endosteal bone resorption. (1,2) About 60 -70% of variance in peak bone density is determined genetically, (3) and 40 -50% of peak bone density is accumulated during puberty.(4) Elucidation of the mechanisms regulating this dramatic increase in skeletal mass during puberty is important in the effort to identify potential preventive or interventive measures that would lower the risk of developing osteoporosis.*The view, opinions, and/or findings contained in this report are those of the author(s) and should not be construed as a position, policy, decision, or endorsement of the Federal Government or the National Medical Technology Testbed, Inc. 1 J.L. Pettis

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

“…Studies comparing the bone shape and quality of C3H/HeJ (C3) and C57BL/ 6J (B6) mice found several key differences in both geometry and femoral strength. C3 mice have higher femoral bone mineral density and thicker cortices compared to B6 mice, although both strains fall within the normal range of bone mineral densities for mice [19,38]. C3 mice also had a smaller cross-sectional area, but twice the bone volume as compared to B6 [20].…”

“…At E18.5 and P1, differences in bone size and shape between C3 and B6 femurs can already be seen [38,40]. By one month of age, C3 mice have a greater cortical bone width coupled with a smaller marrow cavity diameter than B6 femurs and these differences persist and become more exaggerated until one year of age [38,40]. Additionally, by 12 weeks of age, C3 femurs have thicker trabeculi and smaller trabecular separation compared to B6 femurs [41].…”

Impaired skeletal growth in mice with haploinsufficiency of IGF-I: genetic evidence that differences in IGF-I expression could contribute to peak bone mineral density differences

“…less than corresponding age-matched normal children (Woods et al 1997). Furthermore, we and others have shown that serum levels of IGF-I increase during puberty and correlate with BMD (Moreira-Andres et al 1995, Libanati et al 1999, Thorsen et al 1999, Richman et al 2001, Kasukawa et al 2003. Although recent studies provide evidence that both the variation in peak BMD and circulating levels of IGF-I are largely determined genetically (Harrela et al 1996, Recker & Deng 2002, Baldock & Eisman 2004, the direct experimental evidence for the hypothesis that genetic-dependent variation in IGF-I production is a major determinant of the variation in peak BMD seen in normal healthy individuals is lacking at the present time.…”

Osteoblast-specific Knockout of the Insulin-like Growth Factor (IGF) Receptor Gene Reveals an Essential Role of IGF Signaling in Bone Matrix Mineralization

“…To assess quantitatively bone mass, architecture, and turnover, static and dynamic histomorphometric analyses were performed on female ⌬Igf1r and control littermates at 3 and 6 weeks of age, when the skeletal modeling in the mouse is very active (33). At these ages, the mutant and normal animals were indistinguishable in size and weight.…”