Phenotypic Characterization of Mice Bred for High and Low Peak Bone Mass

Klein, Robert F.; Shea, M; Gunness, M.; Pelz, Geoffrey B.; Belknap, John K.; Orwoll, Eric S.

doi:10.1359/jbmr.2001.16.1.63

Cited by 36 publications

(25 citation statements)

References 34 publications

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“…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: 67%

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: 67%

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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“…In light of other Cushing-like phenotypes, and because hypercorticosteronemia is known to favor bone resorption and limit bone deposition, bone properties were analyzed as previously described (27,28) in 28-to 32-wk-old male MC4-R −/− , MC3-R −/− , and WT mice. MC4-R deletion increased total whole-body BMD, cancellous area, and polar moment of inertia (Ip) ( Table 1).…”

Section: Mc3-r Deletion Results In Phenotypes Common To Cushing Syndrmentioning

confidence: 99%

Melanocortin-3 receptor regulates the normal fasting response

Renquist

Murphy

Larson

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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The melanocortin-3 receptor-deficient (MC3-R −/− ) mouse exhibits mild obesity without hyperphagia or hypometabolism. MC3-R deletion is reported to increase adiposity, reduce lean mass and white adipose tissue inflammation, and increase sensitivity to salt-induced hypertension. We show here that the MC3-R −/− mouse exhibits defective fasting-induced white adipose tissue lipolysis, fasting-induced liver triglyceride accumulation, fasting-induced refeeding, and fasting-induced regulation of the adipostatic and hypothalamic-adrenal-pituitary axes. Close examination of the hypothalamic-pituitary-adrenal axis showed that MC3-R −/− mice exhibit elevated nadir corticosterone as well as a blunted fasting-induced activation of the axis. The previously described phenotypes of this animal and the reduced bone density reported here parallel those of Cushing syndrome. Thus, MC3-R is required for communicating nutritional status to both central and peripheral tissues involved in nutrient partitioning, and this defect explains much of the metabolic phenotype in the model. energy homeostasis | nonesterified fatty acid | corticotrophin-releasing hormone | hormone-sensitive lipase R esearch on the central melanocortin system has focused on the role of the melanocortin-4 receptor (MC4-R) in energy homeostasis, particularly as a result of the hyperphagic obesity syndrome found in both mice and humans with mutations in this receptor (1-3). A large body of work has demonstrated that circuitry regulated by the MC4-R is essential for much of leptin action and coordinates energy intake with energy expenditure to maintain long-term energy homeostasis (4). In contrast, the melanocortin-3 receptor (MC3-R), expressed in ∼35 different nuclei in the CNS with a pattern distinct from that of the MC4-R

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“…Spine BMD was measured in WT, CD4dnTGFβIIR, CD4dnTGFβIIR/IFN-γ -/-, and IFN-γ -/-mice at 8, 12, and 16 weeks of age ( Figure 5A). At the latter time point, WT mice achieve their peak BMD, and bone remodeling ensues (38)(39)(40)(41).…”

Section: Figurementioning

confidence: 99%

IFN-γ stimulates osteoclast formation and bone loss in vivo via antigen-driven T cell activation

Gao¹,

Grassi²,

Ryan³

et al. 2007

J. Clin. Invest.

396

388

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T cell-produced cytokines play a pivotal role in the bone loss caused by inflammation, infection, and estrogen deficiency. IFN-γ is a major product of activated T helper cells that can function as a pro-or antiresorptive cytokine, but the reason why IFN-γ has variable effects in bone is unknown. Here we show that IFN-γ blunts osteoclast formation through direct targeting of osteoclast precursors but indirectly stimulates osteoclast formation and promotes bone resorption by stimulating antigen-dependent T cell activation and T cell secretion of the osteoclastogenic factors RANKL and TNF-α. Analysis of the in vivo effects of IFN-γ in 3 mouse models of bone loss -ovariectomy, LPS injection, and inflammation via silencing of TGF-β signaling in T cells -reveals that the net effect of IFN-γ in these conditions is that of stimulating bone resorption and bone loss. In summary, IFN-γ has both direct anti-osteoclastogenic and indirect pro-osteoclastogenic properties in vivo. Under conditions of estrogen deficiency, infection, and inflammation, the net balance of these 2 opposing forces is biased toward bone resorption. Inhibition of IFN-γ signaling may thus represent a novel strategy to simultaneously reduce inflammation and bone loss in common forms of osteoporosis.

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Phenotypic Characterization of Mice Bred for High and Low Peak Bone Mass

Cited by 36 publications

References 34 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

Melanocortin-3 receptor regulates the normal fasting response

IFN-γ stimulates osteoclast formation and bone loss in vivo via antigen-driven T cell activation

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