Chromosome X loci and spontaneous granulosa cell tumor development in SWR mice: epigenetics and epistasis at work for an ovarian phenotype.

Females of the SWR/Bm (SWR) inbred mouse strain possess a unique susceptibility to juvenile-onset tumors originating from the granulosa cells (GC) of the ovarian follicles. Tumor susceptibility is an inherited, polygenic trait in SWR females, minimally involving an oncogenic Granulosa cell tumor susceptibility (Gct) locus on chromosome (Chr) 4 (Gct1), and two GC tumor susceptibility modifier genes mapped to distinct regions of Chr X (Gct4 and Gct6). Shifts in the frequency of GC tumor initiation in the SWR female population from low penetrance to moderate penetrance, or phenotype switching between GC tumor-susceptible and GC tumor-resistant, is strongly influenced by the allelic contributions at Gct4 and Gct6.

Fine map of the Gct1 spontaneous ovarian granulosa cell tumor locus.

The spontaneous development of juvenile-onset, ovarian granulosa cell (GC) tumors in the SWR/Bm (SWR) inbred mouse strain is a model for juvenile-type GC tumors that appear in infants and young girls. GC tumor susceptibility is supported by multiple Granulosa cell tumor (Gct) loci, but the Gct1 locus on Chr 4 derived from SWR strain background is fundamental for GC tumor development and uniquely responsive to the androgenic precursor dehydroepiandrosterone (DHEA). To resolve the location of Gct1 independently from other susceptibility loci, Gct1 was isolated in a congenic strain that replaces the distal segment of Chr 4 in SWR mice with a 47 × 10(6)-bp genomic segment from the Castaneus/Ei (CAST) strain.

A novel animal model for bone metastasis in human lung cancer.

Metastases account for 90% of lung cancer mortalities, frequently target the skeleton and lead to rapid deterioration in quality of life. The molecular mechanism underlying bone metastases is largely unknown. Development of xenograft mouse models, such as the severe combined immunodeficient (SCID) CB-17 mouse and the non-obese diabetic (NOD)/SCID mouse, both of which lack functional B- and T-cells and are able to host allogeneic or xenogeneic tumor cells, has made great contributions in this area.

Low magnitude mechanical signals mitigate osteopenia without compromising longevity in an aged murine model of spontaneous granulosa cell ovarian cancer.

Cancer progression is often paralleled by a decline in bone mass, raising risk of fracture. Concerns persist regarding anabolic interventions for skeletal protection, as these may inadvertently exacerbate neoplastic tissue expansion. Given bone's inherent mechanosensitivity, low intensity vibration (LIV), a mechanical signal that encourages osteoblastogenesis, could possibly slow cancer-associated bone loss, but this goal must be achieved without fostering disease progression.

Genetic variation in TRPS1 may regulate hip geometry as well as bone mineral density.

Trps1 has been proposed as a candidate gene for a mouse bone mineral density (BMD) QTL on Chromosome (Chr) 15, but it remained unclear if this gene was associated with BMD in humans. We used newly available data and advanced bioinformatics techniques to confirm that Trps1 is the most likely candidate gene for the mouse QTL. In short, by combining the raw genetic mapping data from two F2 generation crosses of inbred strains of mice, we narrowed the 95% confidence interval of this QTL down to the Chr 15 region spanning from 6 to 24cM.

Bone morphogenetic protein receptor type Ia localization causes increased BMP2 signaling in mice exhibiting increased peak bone mass phenotype.

Bone morphogenetic protein 2 (BMP2) is a growth factor that initiates osteoblast differentiation. Recent studies show that BMP2 signaling regulates bone mineral density (BMD). BMP2 interacts with BMP receptor type Ia (BMPRIa) and type II receptor leading to the activation of the Smad signaling pathway.

Altered plasma membrane dynamics of bone morphogenetic protein receptor type Ia in a low bone mass mouse model.

Bone morphogenetic proteins (BMPs) are growth factors that initiate differentiation of bone marrow stromal cells to osteoblasts and adipocytes, yet the mechanism that decides which lineage the cell will follow is unknown. BMP2 is linked to the development of osteoporosis and variants of BMP2 gene have been reported to increase the development of osteoporosis. Intracellular signaling is transduced by BMP receptors (BMPRs) of type I and type II that are serine/threonine kinase receptors.

Insulin-like growth factor-1 increases bone calcium accumulation only during rapid growth in female rats.

Calcium retention varies with developmental state, which may be partially under the control of insulin-like growth factor 1 (IGF-1). IGF-1 levels can be manipulated through dietary and therapeutic interventions. We investigated the relationship between IGF-1 endogenous production and calcium utilization and bone accretion during growth as well as the effects of IGF-1 treatment on calcium utilization during rapid and slowed growth in intact female Sprague-Dawley rats.

Casein kinase 2 regulates in vivo bone formation through its interaction with bone morphogenetic protein receptor type Ia.

Approximately 7.9 million fractures occur annually in the United States with 5-10% of these resulting in delayed or impaired healing. Nearly half of the trauma cost of $56 billion per year is used for the treatment of fractures.

The heparin-binding domain of IGFBP-2 has insulin-like growth factor binding-independent biologic activity in the growing skeleton.

Insulin-like growth factor-binding protein 2 (IGFBP-2) is a member of a family of six highly conserved IGFBPs that are carriers for the insulin-like growth factors (IGFs). IGFBP-2 levels rise during rapid neonatal growth and at the time of peak bone acquisition. In contrast, Igfbp2(-/-) mice have low bone mass accompanied by reduced osteoblast numbers, low bone formation rates, and increased PTEN expression.

Connective tissue growth factor is required for skeletal development and postnatal skeletal homeostasis in male mice.

Connective tissue growth factor (CTGF), a member of the cysteine-rich 61 (Cyr 61), CTGF, nephroblastoma overexpressed (NOV) (CCN) family of proteins, is synthesized by osteoblasts, and its overexpression inhibits osteoblastogenesis and causes osteopenia. The global inactivation of Ctgf leads to defective endochondral bone formation and perinatal lethality; therefore, the consequences of Ctgf inactivation on the postnatal skeleton are not known. To study the function of CTGF, we generated Ctgf(+/LacZ) heterozygous null mice and tissue-specific null Ctgf mice by mating Ctgf conditional mice, where Ctgf is flanked by lox sequences with mice expressing the Cre recombinase under the control of the paired-related homeobox gene 1 (Prx1) enhancer (Prx1-Cre) or the osteocalcin promoter (Oc-Cre).

Quantitative trait loci for tibial bone strength in C57BL/6J and C3H/HeJ inbred strains of mice.

Three-point bending technology has been widely used in the measurement of bone strength. Quantitative trait loci (QTLs) for bone strength have been identified using mouse femurs. In this study, we investigate the use of mouse tibiae in identification of QTLs that regulate bone strength.

A novel spontaneous mutation of Irs1 in mice results in hyperinsulinemia, reduced growth, low bone mass and impaired adipogenesis.

A spontaneous mouse mutant, designated 'small' (sml), was recognized by reduced body size suggesting a defect in the IGF1/GH axis. The mutation was mapped to the chromosome 1 region containing Irs1, a viable candidate gene whose sequence revealed a single nucleotide deletion resulting in a premature stop codon. Despite normal mRNA levels in mutant and control littermate livers, western blot analysis revealed no detectable protein in mutant liver lysates.

Nephroblastoma overexpressed (Nov) inactivation sensitizes osteoblasts to bone morphogenetic protein-2, but nov is dispensable for skeletal homeostasis.

Overexpression of nephroblastoma overexpressed (Nov), a member of the Cyr 61, connective tissue growth factor, Nov family of proteins, inhibits osteoblastogenesis and causes osteopenia. The consequences of Nov inactivation on osteoblastogenesis and the postnatal skeleton are not known. To study the function of Nov, we inactivated Nov by homologous recombination.

Quantitative trait loci, genes, and polymorphisms that regulate bone mineral density in mouse.

This is an in silico analysis of data available from genome-wide scans. Through analysis of QTL, genes and polymorphisms that regulate BMD, we identified 82 BMD QTL, 191 BMD-associated (BMDA) genes, and 83 genes containing known BMD-associated polymorphisms (BMDAP). The catalogue of all BMDA/BMDAP genes and relevant literatures are provided.

PPARG by dietary fat interaction influences bone mass in mice and humans.

Adult BMD, an important risk factor for fracture, is the result of genetic and environmental interactions. A quantitative trait locus (QTL) for the phenotype of volumetric BMD (vBMD), named Bmd8, was found on mid-distal chromosome (Chr) 6 in mice. This region is homologous to human Chr 3p25.

A close examination of genes within quantitative trait loci of bone mineral density in whole mouse genome.

Bone mineral density (BMD) is one of the strongest determinants of osteoporotic fracture risk. Over the last decade, a large number of quantitative trait loci (QTL) that regulate BMD have been identified using the mouse model. In an attempt to examine the relationship between those QTL and gene distribution in the mouse genome, we searched PubMed with keywords bone and QTL for every publication up to January 2007; we obtained a total of 75 QTL of BMD.

Quantitative trait loci for BMD in an SM/J by NZB/BlNJ intercross population and identification of Trps1 as a probable candidate gene.

Identification of genes that regulate BMD will enhance our understanding of osteoporosis and could provide novel molecular targets for treatment or prevention. We generated a mouse intercross population and carried out a quantitative trait locus (QTL) analysis of 143 female and 124 male F(2) progeny from progenitor strains SM/J and NZB/BlNJ using whole body and vertebral areal BMD (aBMD) as measured by DXA. We found that both whole body and vertebral aBMD was affected by two loci on chromosome 9: one with a significant epistatic interaction on distal chromosome 8 and the other with a sex-specific effect.

Evaluation of gene expression profiling in a mouse model of L-gulonolactone oxidase gene deficiency.

Humans and guinea pigs are species which are unable to synthesize ascorbic acid (vitamin C) because, unlike rodents, they lack the enzyme L-gulonolactone oxidase (Gulo). Although the phenotype of lacking vitamin C in humans, named scurvy, has long been well known, information on the impact of lacking Gulo on the gene expression profiles of different tissues is still missing. This knowledge could improve our understanding of molecular pathways in which Gulo may be involved.

LH analog and dietary isoflavones support ovarian granulosa cell tumor development in a spontaneous mouse model.

The reproductive hormone environment is an important influence upon spontaneous ovarian granulosa cell (GC) tumor development in genetically susceptible (SWR x SWXJ-9) F1 female mice: androgenic support during puberty stimulates tumorigenesis, while exposure to 17beta-estradiol (E(2)) suppresses tumor initiation. We sought to determine whether gonadotropic stimulation was sufficient to initiate GC tumors in a grafted model system, and to determine the potential for dietary isoflavones (genistein and daidzein) as alternatives to E(2) for tumor chemoprevention in vivo. Isolated ovaries from pre-pubertal (SWR x SWXJ-9) F1 females were transferred to the kidney capsule of host mice homozygous for the hypogonadal (hpg/hpg) and severe combined immunodeficiency (scid/scid) mutations.

Quantitative trait loci that determine mouse tibial nanoindentation properties in an F2 population derived from C57BL/6J x C3H/HeJ.

Use of nanoindentation technology to identify quantitative trait loci (QTL) that regulate bone properties represents a novel approach to improving our understanding of molecular mechanisms that control bone matrix properties. Tibiae for QTL mapping were from an F2 population derived from C57BL/6J and C3H/HeJ. A nanoindenter (Triboindenter; Hysitron, Minneapolis, MN) was used to conduct indentation tests on transverse sections.

Mapping genetic loci that regulate lipid levels in a NZB/B1NJxRF/J intercross and a combined intercross involving NZB/B1NJ, RF/J, MRL/MpJ, and SJL/J mouse strains.

The NZB/B1NJ (NZB) mouse strain exhibits high cholesterol and HDL levels in blood compared with several other strains of mice. To study the genetic regulation of blood lipid levels, we performed a genome-wide linkage analysis in 542 chow-fed F2 female mice from an NZBxRF/J (RF) intercross and in a combined data set that included NZBxRF and MRL/MpJxSJL/J intercrosses. In the NZBxRF F2 mice, the cholesterol and HDL concentrations were influenced by quantitative trait loci (QTL) on chromosome (Chr) 5 [logarithm of odds (LOD) 17-19; D5Mit10] that was in the region identified earlier in crosses involving NZB mice, but two QTLs on Chr 12 (LOD 4.