Genetic variability in adult bone density among inbred strains of mice

Beamer, Wesley G.; Donahue, Leah-Rae; Rosen, Clifford J.; Baylink, David J.

doi:10.1016/8756-3282(96)00047-6

Cited by 570 publications

(472 citation statements)

References 30 publications

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“…Knockout and transgenic mouse models have contributed significantly to knowledge of the effects of single genes in bone regulation, such as the insulin-like growth factor-1 and bone morphogenetic protein-4 genes [65,66]. Highly inbred strains of mice provide a powerful means for investigating genetic influences over bone phenotypes [1,5,26,31,62]. A substantial genetic influence on peak bone mass has also been demonstrated by this study design [32,45].…”

Section: Introductionmentioning

confidence: 75%

Quantitative genetics of cortical bone mass in healthy 10-year-old children from the Fels Longitudinal Study

Duren

Sherwood

Choh

et al. 2007

Bone

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The genetic influences on bone mass likely change throughout the life span, but most genetic studies of bone mass regulation have focused on adults. There is, however, a growing awareness of the importance of genes influencing the acquisition of bone mass during childhood on lifelong bone health. The present investigation examines genetic influences on childhood bone mass by estimating the residual heritabilities of different measures of second metacarpal bone mass in a sample of 600 10-year-old participants from 144 families in the Fels Longitudinal Study. Bivariate quantitative genetic analyses were conducted to estimate genetic correlations between cortical bone mass measures, and measures of bone growth and development. Using a maximum likelihood-based variance components method for pedigree data, we found a residual heritability estimate of 0.71 for second metacarpal cortical index. Residual heritability estimates for individual measures of cortical bone (e.g., lateral cortical thickness, medial cortical thickness) ranged from 0.47 to 0.58, at this prepubertal childhood age. Low genetic correlations were found between cortical bone measures and both bone length and skeletal age. However, after Bonferonni adjustment for multiple testing, ρ G was not significantly different from 0 for any of these pairs of traits. Results of this investigation provide evidence of significant genetic control over bone mass largely independent of maturation while bones are actively growing and before rapid accrual of bone that typically occurs during puberty.

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Section: Introductionmentioning

confidence: 75%

Quantitative genetics of cortical bone mass in healthy 10-year-old children from the Fels Longitudinal Study

Duren

Sherwood

Choh

et al. 2007

Bone

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“…Bone density varies greatly among the mouse inbred strains, particularly between the C3H and B6 strains. Total density is approximately 50% higher in C3H femora compared to B6, and cortical bone properties are consistently higher in C3H mice [49,50]. Osteoblasts from C3H mice exhibit higher alkaline phosphatase activity and greater mineralization compared to cultured B6 osteoblasts, which contributes to the increased bone formation rate observed in the C3H inbred strain [51].…”

Section: Discussionmentioning

confidence: 96%

Bone mass is inversely proportional to Dkk1 levels in mice

MacDonald

Joiner

Oyserman

et al. 2007

Bone

156

106

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The Wnt/β-catenin signaling pathway has emerged as a key regulator in bone development and bone homeostasis. Loss-of-function mutations in the Wnt co-receptor LRP5 result in osteoporosis and "activating" mutations in LRP5 result in high bone mass. Dickkopf-1 (DKK1) is a secreted Wnt inhibitor that binds LRP5 and LRP6 during embryonic development, therefore it is expected that a decrease in DKK1 will result in an increase in Wnt activity and a high bone mass phenotype. Dkk1 −/− knockout mice are embryonic lethal, but mice with hypomorphic Dkk1 d (doubleridge) alleles that express low amounts of Dkk1 are viable. In this study we generated an allelic series by crossing Dkk1 +/− and Dkk1 +/d mice resulting in the following genotypes with decreasing Dkk1 expression levels: +/+, +/d, +/− and d/−. Using μCT imaging we scanned dissected left femora and calvariae from eight week old mice (n=60). We analyzed the distal femur to represent trabecular bone and the femur diaphysis for cortical endochondral bone. A region of the parietal bones was used to analyze intramembranous bone of the calvaria. We found that trabecular bone volume is increased in Dkk1 mutant mice in a manner that is inversely proportional to the level of Dkk1 expression. Trabeculae number and thickness were significantly higher in the low Dkk1 expressing genotypes from both female and male mice. Similar results were found in cortical bone with an increase in cortical thickness and cross sectional area of the femur diaphysis that correlated with lower Dkk1 expression. No consistent differences were found in the calvaria measurements. Our results indicate that the progressive Dkk1 reduction increases trabecular and cortical bone mass and that even a 25% reduction in Dkk1 expression could produce significant increases in trabecular bone volume fraction. Thus DKK1 is a negative regulator of normal bone homeostasis in vivo. Our study suggests that manipulation of DKK1 function or expression may have therapeutic significance for the treatment of low bone mass disorders.

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“…Male MRL/MpJ mice (n ϭ 22) were obtained from The Jackson Laboratory (Bar Harbor, ME) and male C57BL/6 mice (n ϭ 22) were obtained from Charles River (Wilmington, MA). Mice were housed until 22 weeks of age in order to ensure skeletal maturity (27), at which time 16 mice from each strain were subjected to intraarticular fracture (7). The mice were anesthetized using an intraperitoneal injection of pentobarbital, and positioned with the left lower limb in a custom cradle that held the limb at 90°of flexion and secured at the ankle.…”

Section: Methodsmentioning

confidence: 99%

Absence of posttraumatic arthritis following intraarticular fracture in the MRL/MpJ mouse

Ward¹,

Furman²,

Huebner³

et al. 2008

Arthritis & Rheumatism

112

127

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Objective. Posttraumatic arthritis is a frequent long-term complication of intraarticular fractures. A model of a closed intraarticular fracture in C57BL/6 mice that progresses to posttraumatic arthritis has been developed. The MRL/MpJ mouse has shown unique regenerative abilities in response to injury. The objective of this study was to determine if the MRL/MpJ mouse is protected from posttraumatic arthritis after intraarticular fractures.Methods. Intraarticular fractures were created in MRL/MpJ mice and C57BL/6 control mice (n ‫؍‬ 16 each). Limbs were analyzed for posttraumatic arthritis 4 and 8 weeks after fracture using microfocal computed tomography bone morphology, subchondral bone thickness evaluation, and histologic evaluation of cartilage degeneration. Serum cytokines and biomarkers were measured after the mice were killed.Results. Intraarticular fractures were successfully created in all 32 mice. In the experimental fractured limbs, C57BL/6 mice had a decrease in bone density, increased subchondral bone thickness, and increased cartilage degeneration compared with normal contralateral control limbs. In the MRL/MpJ mice, no differences in bone density, subchondral bone thickness, or histologic grading of cartilage degeneration were seen between fractured and contralateral control limbs. Cytokine analysis showed lower systemic levels of the proinflammatory cytokine interleukin-1␣ (IL-1␣) and higher levels of the antiinflammatory cytokines IL-4 and IL-10 in the MRL/MpJ mice.Conclusion. This study shows that the MRL/MpJ mouse is relatively protected from posttraumatic arthritis after intraarticular fracture. Further investigation into the mechanism involved in this response will hopefully provide new insight into the pathogenesis, prevention, and treatment of posttraumatic arthritis after intraarticular fracture.

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Genetic variability in adult bone density among inbred strains of mice

Cited by 570 publications

References 30 publications

Quantitative genetics of cortical bone mass in healthy 10-year-old children from the Fels Longitudinal Study

Quantitative genetics of cortical bone mass in healthy 10-year-old children from the Fels Longitudinal Study

Bone mass is inversely proportional to Dkk1 levels in mice

Absence of posttraumatic arthritis following intraarticular fracture in the MRL/MpJ mouse

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