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Biomedical subjects

W G Beamer

Publications and source records attributed to W G Beamer.

At least 37 records · Page 2Linked to original sources
PubMed2000

Exercise and mechanical loading increase periosteal bone formation and whole bone strength in C57BL/6J mice but not in C3H/Hej mice.

To identify the genes, and the mechanisms that account for the 53% higher peak bone density in C3H/HeJ (C3H) mice compared with C57BL/6J (B6) mice, we are performing quantitative trait locus and phenotypic analyses. The phenotypic studies revealed differences in bone formation and resorption, and showed that hindlimb immobilization (by sciatic neurectomy) caused a greater increase in endosteal resorption in the tibiae of B6 compared with C3H mice. The current studies were intended to examine the hypothesis that the bones of C3H mice are less sensitive to mechanical loading than the bones of B6 mice. To increase mechanical loading, 9-week-old female B6 and C3H mice (n = 10-13 mice/group) were subjected to a jumping exercise (20 jumps/day, 5 days/week, to heights of 20-30 cm) for a total of 4 weeks. Control mice did not jump. Osteocalcin, alkaline phosphatase (ALP) activity, and IGF-I were measured in serum. The left tibiae were used for histomorphometry (ground cross-sections prepared at the tibiofibular junction) and the right tibiae and femora were used for determinations of bone breaking strength (3-point bending). The results of these studies revealed (1) significant effects of both mouse strain (B6 and C3H) and the jumping exercise on tibial strength; (2) an exercise-dependent increase in serum IGF-I in C3H, but not B6 mice; and (3) no effects on serum ALP or osteocalcin. The histomorphometric analyses showed no effect of exercise on C3H tibiae, but significant exercise-dependent increases in total bone area, periosteal perimeter, periosteal mineral apposition rate (MAR), and periosteal bone formation (P < 0.02 for each) in B6 tibiae. There were no effects of exercise on periosteal resorption or any endosteal measurement in either C3H or B6 mice. Since the jumping exercise was designed to cause a two-three fold increase in muscular-skeletal loading at the tibio-fibular junction, and the calculated stress (g/mm2) at this sampling site was only 16% greater for B6 compared with C3H mice, we had anticipated that both strains of mice would show exercise-dependent increases in periosteal bone formation, with a greater response in the B6 mice. The lack of a response in the C3H tibiae demonstrates that the bones of C3H mice are less sensitive to mechanical loading (and unloading) than the bones of B6 mice.

Alkaline Phosphatase↗
PubMed2000

Insulin-like growth factor I and bone: from mouse to man.

Serum insulin-like growth factor I (IGF-I) is regulated by numerous variables, including growth hormone (GH), nutritional status, gonadal steroids and other hormones. However, the circulating IGF-I phenotype is also under heritable regulation, and several genetic determinants may be important in defining tissue-specific expression of the gene encoding this peptide. A very strong correlation has been found between serum IGF-I concentration and bone acquisition in both mice and humans. Based on previous studies as well as ongoing work with mice, it has been hypothesized that regulation of the serum IGF-I phenotype includes non-GH-dependent factors and, furthermore, that these determinants are also involved in the acquisition of bone mass. This paper reports that, by performing intercrosses between two inbred strains of mice of similar age, size and length, but with different serum levels of IGF-I, we have identified regulatory loci for serum IGF-I and established their relationship to putative quantitative trait loci for bone mineral density. Mapping these quantitative trait loci will help refine our understanding of disorders related to IGF-I.

Animals↗
PubMed2000

Mapping quantitative trait loci for serum insulin-like growth factor-1 levels in mice.

Serum insulin-like growth factor-1 (IGF-1) and femoral bone mineral density (BMD) differ between two inbred strains of mice, C3H/HeJ (C3H) and C57BL/6J (B6), by approximately 30% and 50%, respectively. Similarly, skeletal IGF-1 content, bone formation, mineral apposition, and marrow stromal cell numbers are higher in C3H than in B6 mice. Because IGF-1 and several bone parameters cosegregate, we hypothesize that the serum IGF-1 phenotype has a strong heritable component and that genetic determinants for serum IGF-1 are involved in the regulation of bone mass. We intercrossed (B6 x C3H)F1 hybrids and analyzed 682 F2 female offspring at 4 months of age for serum IGF-1 by radioimmunoassay and femoral BMD by peripheral quantitative computerized tomography (pQCT). Genomic DNA was assayed by polymerase chain reaction (PCR) to determine alleles for 114 Mit markers inherited in F2 mice at average distances of 14 centimorgans (cM) along each chromosome (Chr). Serum IGF-1 levels in the F2 progeny were relatively normal in distribution, but showed a greater range than either progenitor, indicating that serum IGF-1 level is a polygenic trait with an estimated heritability of 52%. Serum IGF-1 correlated with femoral length (r = 0.266, p < 0.0001) and femoral BMD (r = 0.267, p < 0.0001). Whole genome scans for main effects associated with serum IGF-1 levels revealed three significant QTLs (in order of significance) on mouse Chrs 6, 15, and 10. The QTL on Chr 6 showed a significant reduction in IGF-1 associated with increasing C3H allele number, whereas the Chr 15 and Chr 10 loci showed additive effects with increasing C3H allele number. A genome-wide search for interacting marker pairs identified a significant interaction between the Chr 6 QTL and a locus on Chr 11. This interactive effect suggested that when the Chr 11 locus was homozygous for C3H, there was no effect of the Chr 6 locus on serum IGF-1; however, the combination of C3H alleles on Chr 6 with B6 alleles on Chr 11 was associated with reduced serum IGF-1 concentrations. To test this in vivo, we tested congenic mice carrying the Chr 6 QTL region from C3H on a B6 background (B6.C3H-6). Both serum IGF-1 and femoral BMD were significantly lower in female congenic than progenitor B6 mice. In summary, we identified three major QTLs on mouse Chrs 6, 10, and 15, and noted a major locus-locus interaction between Chrs 6 and 11. We named these QTLs IGF-1 serum levels (Igf1sl1 to Igf1sl4). Functional isolation of the Igf1sl1 QTL on Chr 6 for IGF-1 in B6.C3H-6 congenic mice demonstrated effects on both the IGF-1 and BMD phenotypes. The genetic determinants of these Igf1sl QTLs will provide much insight into the regulation of IGF-1 and the subsequent acquisition of peak bone mass.

Animals↗
PubMed2000

Comparison of bone formation responses to parathyroid hormone(1-34), (1-31), and (2-34) in mice.

In this study we used a mouse model system to compare the in vivo effects of parathyroid hormone(1-34) [PTH(1-34)] with that of PTH(1-31) or PTH(2-34) analogs. Daily subcutaneous administration of PTH(1-34) for 15 days caused a dose-dependent increase in the serum osteocalcin level and bone extract alkaline phosphatase activity, markers of bone formation. PTH(2-34) was much less potent, whereas PTH(1-31) was equipotent in stimulating bone formation parameters in mice. PTH(1-34) caused significant increases in serum calcium (after 4 h) and tartrate-resistant acid phosphatase activity in bone extract (after 4 h), whereas PTH(2-34) and PTH(1-31) were less potent. Because PTH(1-31) caused a smaller increase in bone resorption parameters compared to PTH(1-34), despite similar effects on bone formation parameters, we evaluated the long-term anabolic effects of PTH(1-31) and PTH(1-34) in mice. Weekly evaluations of serum osteocalcin levels demonstrated that daily injections of PTH(1-34) and PTH(1-31) at 80 microg/kg body weight increased serum osteocalcin levels within 1 week of the start of treatment, which were maintained during the entire 22 week treatment. Assessment of bone density at the end of the treatment period with peripheral quantitated computed tomography (pQCT) revealed that PTH(1-34) caused a significantly greater increase in femoral bone density compared to PTH(1-31) at the middiaphysis (18% vs. 9% over vehicle control; p < 0.001). Both PTH(1-34) and PTH(1-31) increased periosteal circumference compared to vehicle (p < 0.01) without a significant difference between the two treatments. In contrast, PTH(1-34) caused a significantly greater reduction in endosteal circumference than PTH(1-31) (p < 0.001). Both analogs significantly increased maximum load and area of moment of inertia over the vehicle group. In conclusion, our findings suggest that PTH(1-34) and PTH(1-31) may exhibit different anabolic effects at the periosteum vs. endosteum in the long bones of mice.

Animals↗
PubMed2000

Spontaneous fracture (sfx): a mouse genetic model of defective peripubertal bone formation.

A new mouse model of stage-specific bone growth failure and fracture has been recovered as an autosomal recessive mutation, designated spontaneous fracture (sfx). The sfx/sfx mice are phenotypically normal until shortly after weaning, when reduced mobility and impaired somatic growth are first noted. By 6 weeks of age, body, spleen, and thymus weights, as well as hematocrits and serum calcium, inorganic phosphate, total alkaline phosphatase, insulin-like growth factor-I, and osteocalcin levels are decreased. The sfx/sfx mice also show reduced femoral cortical density and diaphyseal circumference, as well as a paucity of mature osteoblasts on bone surfaces. Histological analyses of the femur and tibia in the mutants show subtle reduction of chondrocyte numbers in epiphyseal-plate columns, reduction of matrix, and near absence of osteoid below the differentiated chondrocytes. Trabeculae in proximal tibiae, iliacs, and vertebral bodies are sparse and thin. Cortical bone thickness of mutants is markedly thinned in all sites examined. By 7-8 weeks, radiographic films routinely show spontaneous impact fractures of the distal femur accompanied by callus formation, whereas complete fractures are less commonly observed. Volumetric bone mineral density (BMD) of mutant femurs is similar to +/? littermates in the center of the femoral diaphysis, but BMD declines as either end of the femoral diaphysis is approached. We have mapped the gene responsible for this phenotype to central Chromosome 14. Reduced bone mass, impaired bone formation, abnormalities of bone architecture, and a disposition to spontaneous fracture identify sfx/sfx mice as a useful model for understanding the mechanisms responsible for peripubertal bone formation.

Animals↗
PubMed2000

Genetic regulation of cortical and trabecular bone strength and microstructure in inbred strains of mice.

The inbred strains of mice C57BL/6J (B6) and C3H/HeJ (C3H) have very different femoral peak bone densities and may serve as models for studying the genetic regulation of bone mass. Our objective was to further define the bone biomechanics and microstructure of these two inbred strains. Microarchitecture of the proximal femur, femoral midshaft, and lumbar vertebrae were evaluated in three dimensions using microcomputed tomography (microCT) with an isotropic voxel size of 17 microm. Mineralization of the distal femur was determined using quantitative back-scatter electron (BSE) imaging. MicroCT images suggested that C3H mice had thicker femoral and vertebral cortices compared with B6. The C3H bone tissue also was more highly mineralized. However, C3H mice had few trabeculae in the vertebral bodies, femoral neck, and greater trochanter. The trabecular number (Tb.N) in the C3H vertebral bodies was about half of that in B6 vertebrae (2.8(-1) +/- 0.1 mm(-1) vs. 5.1(-1) +/- 0.2 mm(-1); p < 0.0001). The thick, more highly mineralized femoral cortex of C3H mice resulted in greater bending strength of the femoral diaphysis (62.1 +/- 1.2N vs. 27.4 +/- 0.5N, p < 0.0001). In contrast, strengths of the lumbar vertebra were not significantly different between inbred strains (p = 0.5), presumably because the thicker cortices were combined with inferior trabecular structure in the vertebrae of C3H mice. These results indicate that C3H mice benefit from alleles that enhance femoral strength but paradoxically are deficient in trabecular bone structure in the lumbar vertebrae.

Animals↗
PubMed1999

Androgenetic alopecia: in vivo models.

Androgenetic alopecia is the most common form of balding in humans. There is great interest in finding a reliable animal model to study the pathogenesis and treatment of this abnormality. The sump-tailed macaque (Macaca artoides) has been the standard model and appears to be useful homologue. These primates are reasonably good predictors of compound efficacy. Due to reduced size and expense, rodent models have been sought. Testosterone inducible models require more development but offer potential. Xenografts of human skin to immunodeficient mice, notably nude or severe combined immunodeficiency, are small, relatively inexpensive, and easy to work with if a source of human tissue is available. Xenografts to double mutant mice for severe combined immunodeficiency and a number of hormone receptor null mutations offer new refinements to these xenograft models.

Alopecia↗
PubMed1999

Quantitative trait loci for bone density in C57BL/6J and CAST/EiJ inbred mice.

Genetic analyses for loci regulating bone mineral density have been conducted in a cohort of F(2) mice derived from intercross matings of (C57BL/6J x CAST/EiJ)F(1) parents. Femurs were isolated from 714 4-month-old females when peak adult bone density had been achieved. Bone mineral density (BMD) data were obtained by peripheral quantitative computed tomography (pQCT), and genotype data were obtained by Polymerase Chain Reaction (PCR) assays for polymorphic markers carried in genomic DNA of each mouse. Genome-wide scans for co-segregation of genetic marker data with high or low BMD revealed loci on eight different chromosomes, four of which (Chrs 1, 5, 13, and 15) achieved conservative statistical criteria for suggestive, significant, or highly significant linkage with BMD. These four quantitative trait loci (QTLs) were confirmed by a linear regression model developed to describe the main effects; none of the loci exhibited significant interaction effects by ANOVA. The four QTLs have been named Bmd1 (Chr 1), Bmd2 (Chr 5), Bmd3 (Chr 13), and Bmd4 (Chr 15). Additive effects were observed for Bmd1, recessive for Bmd3, and dominant effects for Bmd2 and Bmd4. The current large size of the QTL regions (6-->31 cM) renders premature any discussion of candidate genes at this time. Fine mapping of these QTLs is in progress to refine their genetic positions and to evaluate human homologies.

Age Factors↗
PubMed1999

Deficiency of SHP-1 protein-tyrosine phosphatase activity results in heightened osteoclast function and decreased bone density.

Mice homozygous for the motheaten (Hcphme) or viable motheaten (Hcphme-v) mutations are deficient in functional SHP-1 protein-tyrosine phosphatase and show severe defects in hematopoiesis. Comparison of femurs from mev/mev mice revealed significant decreases in bone mineral density (0.33 +/- 0.03 mg/mm3 for mev/mevversus 0.41 +/- 0.01 mg/mm3 for controls) and mineral content (1.97 +/- 0.36 mg for mev/mevversus 10.64 +/- 0.67 for controls) compared with littermate controls. Viable motheaten mice also showed reduced amounts of trabecular bone and decreased cortical thickness. These bone abnormalities were associated with a 14% increase in numbers of multinucleated osteoclasts and an increase in osteoclast resorption activity. In co-cultures of normal osteoblasts with mutant or control bone marrow cells, numbers of osteoclasts developing from mutant mice were increased compared with littermate control mice. Although mev/mev osteoclasts develop in the absence of colony-stimulating factor (CSF)-1, nevertheless cultured osteoclasts show increased size in the presence of CSF-1. CSF-1-deficient osteopetrosis (op/op) mutant mice develop severe osteosclerosis. However, doubly homozygous mev/mevop/op mice show an expansion of bone marrow cavities and reduced trabecular bone mass compared with op/op mice. Western blot analysis showed that several proteins that were markedly hyperphosphorylated on tyrosine residues were detected in the motheaten osteoclasts, including a novel 126-kd phosphotyrosine protein. The marked hyperphosphorylation of a 126-kd protein in motheaten osteoclasts suggests that this protein depends on SHP-1 for dephosphorylation. These findings demonstrate that the decreased SHP-1 catalytic activity in me/me and mev/mev mice results in an increased population of activated osteoclasts and consequent reduction in bone density.

Animals↗
PubMed1999

Histomorphometric studies show that bone formation and bone mineral apposition rates are greater in C3H/HeJ (high-density) than C57BL/6J (low-density) mice during growth.

High-density C3H/HeJ (C3H) and low-density C57BL/6J (B6) mice, with femoral bone density differing by 50%, were chosen as a model to investigate the mechanisms controlling peak bone density and to map peak bone density genes. The present longitudinal study was undertaken to further establish the bone biologic phenotypes of these two inbred strains of mice. To evaluate phenotypic differences in bone formation parameters in C3H and B6 mice between the ages of 6 and 26 weeks, undecalcified ground sections from the diaphyses of the tibia and femur were prepared from mice receiving two injections of tetracycline. Histomorphometric analyses revealed that the cortical bone area was significantly greater (16%-56%, p < 0.001) in both the femur and tibia of the C3H mice than in the B6 mice at all timepoints. This difference in cortical bone area was due to significantly smaller medullary areas in the C3H mice than in the B6 mice. The bone formation rates (BFR) at the endosteum in both the femur and tibia were significantly greater (28%-117%,p < 0.001) in the young C3H mice (6-12 weeks old) than in B6 mice. The higher bone formation in C3H mice was associated with higher values of the bone mineral apposition rate (25%-94%, p < 0.001), and was not associated with higher values of the forming surface length as measured by tetracycline label length. Similar interstrain differences in mineral apposition and bone formation rates were observed in the periosteum of the femur and tibia. In conclusion, the greater bone area in the high-density C3H mice vs. the low-density B6 mice was, in part, due to the greater periosteal and endosteal bone formation rates during growth in the C3H mice. Because the C3H and B6 mice were maintained under identical environmental conditions (diet, lighting, etc.), the observed interstrain differences in bone parameters were the result of the action of genetic factors. Consequently, these two inbred strains of mice are suitable as a model to identify genetic factors responsible for high bone formation rates.

Animals↗
PubMed1999

Osteoclast formation in bone marrow cultures from two inbred strains of mice with different bone densities.

For the purpose of identifying genes that affect bone volume, we previously identified two inbred mouse strains (C57BL/6J and C3H/HeJ) with large differences in femoral bone density and medullary cavity volume. The lower density and larger medullary cavity volume in C57BL/6J mice could result from either decreased formation or increased resorption or both. We recently reported evidence suggesting that bone formation was increased in vivo and that osteoblast progenitor cells are more numerous in the bone marrow of C3H/HeJ compared with C57BL/6J mice. In the present study, we determined whether osteoclast numbers in vivo and osteoclast formation from bone marrow cells in vitro might also differ between the two mouse strains. We have found that the number of osteoclasts on bone surfaces of distal humerus secondary spongiosa was 2-fold higher in 5.5-week-old C57BL/6J mice than in C3H/HeJ mice of the same age (p < 0.001). Bone marrow cells of C57BL/6J mice cocultured with Swiss/Webster mouse osteoblasts consistently produced more osteoclasts than did C3H/HeJ bone marrow cells at all ages tested from 3.5-14 weeks of age (p < 0.001). Osteoclast formation was also greater from spleen cells of 3.5-week-old C57BL/6J mice than C3H/HeJ mice. The distribution of nuclei per osteoclast and the 1, 25-dihydroxyvitamin D3 dose dependence of osteoclast production from bone marrow cells were similar. Osteoclasts that developed from both C57BL/6J and C3H/HeJ marrow cells formed pits in dentin slices. Cultures from C57BL/6J marrow cells formed 2.5-fold more pits than cultures from C3H/HeJ marrow cells (p < 0.02). We compared the abilities of C57BL/6J and C3H/HeJ osteoblasts to support osteoclast formation. When bone marrow cells from either C57BL/6J or C3H/HeJ mice were cocultured with osteoblasts from either C57BL/6J or C3H/HeJ newborn calvaria, the strain from which osteoblasts were derived did not affect the number of osteoclasts formed from marrow cells of either strain. Together, these observations suggest that genes affecting the bone marrow osteoclast precursor population may contribute to the relative differences in bone density that occur between C3H/HeJ and C57BL/6J mouse strains.

Animals↗
PubMed1999

Physiologic and endocrinologic characterization of male sex-biased diabetes in C57BLKS/J mice congenic for the fat mutation at the carboxypeptidease E locus.

The fat gene in mice represents a recessive mutation at the carboxypeptidase E (Cpe) locus. The mutant allele (Cpe(fat)) encodes a highly unstable enzyme and produces an obesity phenotype characterized by attenuated processing of prohormones such as proinsulin that require this exopeptidase for full maturation. This article presents a preliminary physiologic and endocrinologic characterization of the stock of C57BLKS/LtJ-Cpe(fat)/Cpe(fat) mice at the backcross generation (N10) currently distributed by The Jackson Laboratory. Although previously reported not to be diabetogenic at N5, an additional five backcrosses to the C57BLKS/J background resulted in a male-biased development of both obesity and diabetes. Major differences distinguishing this mutant stock from the phenotypes produced by either the diabetes (Lepr(db)) or obese (Lep(ob)) mutations on the same inbred strain background are lack of hyperphagia and hypercorticism, sensitivity of diabetic males to exogenous insulin, and a milder and male-biased diabetes syndrome that is not associated with widespread beta-cell necrosis and islet atrophy, and that often remits with age.

Animals↗
PubMed1998

Multigenic and imprinting control of ovarian granulosa cell tumorigenesis in mice.

Spontaneous juvenile ovarian granulosa cell (GC) tumors that occur in young girls are similar to GC carcinomas that develop in SWR-derived inbred mice. We analyzed female offspring from a series of matings among SWR and SJL inbred mice for chromosomal loci underlying tumor susceptibility. Intercross F2 female mice were produced by reciprocal matings of (SWR x SJL)F1 and (SJL x SWR)F1 parents. Tumorigenesis in these F2 mice as well as in SWXJ recombinant inbred and congenic strains of mice derived from SWR and SJL showed significant (P < 0.001) association with Gct1, a dominant susceptibility locus on chromosome (CHR) 4 and with Gct2 on CHR 12. Suggestive (P < 0.01) association was found with Gct3 on CHR 15. A fourth susceptibility locus, Gct4 on CHR X, was demonstrated with a strong parent-of-origin effect associated with the paternal genotype. Imprinting and complex interactions among these four loci combine to establish the probability for GC tumorigenesis in this mouse model.

Alleles↗
PubMed1998

Lymphadenopathy, elevated serum IgE levels, autoimmunity, and mast cell accumulation in flaky skin mutant mice.

The autosomal recessive mutation "flaky skin" (fsn) causes pleiotropic abnormalities in the immune and hematopoietic systems accompanied by pathologic changes in the skin. Homozygotes (fsn/fsn) showed increased size and histological alterations in the spleen and lymph nodes. Abnormalities in lymphoid architecture of the spleen in fsn/fsn mice were accompanied by marked increases in total numbers of B cells, macrophages, and immature erythroid cells. Splenic B cells displayed elevated MHC class II expression. Serum IgE levels were greater than 100 microg/ml by 10 weeks of age, representing > 7000-fold increase compared with normal littermates. This increased IgE level was associated with elevated IL-4 production by spleen cells and with increased amounts of serum IL-4. Serum IgM, IgG1, and IgG2b levels were also increased in fsn/fsn mice while IgG3 was decreased. Autoimmunity in fsn/fsn mice was evidenced by glomerulonephritis accompanied by immune complex deposition in the kidneys, increased serum blood urea nitrogen levels, and the presence of circulating anti-double-stranded DNA autoantibodies. Pathological changes in the skin of fsn/fsn mice were characterized by epidermal hyperplasia and mixed dermal inflammation. Increased numbers of mast cells were also observed in the dermis of the truncal skin as well as in the epithelial stomach. These marked immunological abnormalities suggest that the fsn locus encodes a major immunoregulatory molecule important in multiple immune and hematopoietic functions.

Abnormalities, Multiple↗
PubMed1998

Alkaline phosphatase levels and osteoprogenitor cell numbers suggest bone formation may contribute to peak bone density differences between two inbred strains of mice.

Previous studies have shown that C3H/HeJ (C3H) mice have higher peak bone density than C57BL/6J (B6) mice, at least in part because of differences in rates of bone resorption. The current studies were intended to examine the alternative, additional hypothesis that the greater bone density in C3H mice might also be a consequence of increased bone formation. To that end, we measured two presumptive, indirect indices of bone formation and osteoblast number in these inbred strains of mice: alkaline phosphatase (ALP) activity in serum, bones, and bone cells; and the number of ALP-positive colony-forming units (CFU) in bone marrow stromal cell cultures. We found that C3H mice had higher serum levels of ALP activity than B6 mice at 6 (118 vs. 100 U/L, p < 0.03) and 32 weeks of age (22.2 vs. 17.2 U/L, p < 0.001). Tibiae from C3H mice also contained higher levels of ALP activity than tibiae from B6 mice at 6 (417 vs. 254 mU/mg protein, p < 0.02) and 14 weeks of age (132 vs. 79 mU/mg protein, p < 0.001), as did monolayer cultures of bone-derived cells from explants of 7.5-week-old C3H calvariae and femora (8.2 times more, p < 0.02, and 4.6 times more, p < 0.001, respectively). Monolayer cell cultures prepared by collagenase digestion of calvariae from newborn and 6-week-old mice also showed similar strain-dependent differences in ALP-specific activity (p < 0.001 for each). Our studies also showed more ALP-positive CFU in bone marrow stromal cell cultures from 8-week-old C3H mice, compared with B6 mice (72.3 vs. 26.1 ALP-positive CFU/culture dish, p < 0.001). A similar result was seen for ALP-positive CFU production at 6 and 14 weeks of age, and the difference was greatest for the CFU that contained the greatest numbers of ALP-positive cells. Because skeletal ALP activity is a product of osteoblasts and has been shown to correlate with rates of bone formation, and because the number of ALP-positive CFU is believed to reflect the number of osteoprogenitor cells, the current data are consistent with the general hypothesis that bone formation may be greater in C3H than B6 mice because of a difference in osteoblast number. Our data further suggest that peak bone density may be greater in C3H mice than B6 mice due to a combination of decreased bone resorption and increased bone formation.

Alkaline Phosphatase↗
PubMed1997

Comparison of chemical carcinogen skin tumor induction efficacy in inbred, mutant, and hybrid strains of mice: morphologic variations of induced tumors and absence of a papillomavirus cocarcinogen.

Chemical carcinogen induction of skin tumors in mice was investigated to determine (i) if tumor induction efficacy was modified by single gene mutations, (ii) if the histologic types of the tumors varied with these mutations, and (iii) if a novel papillomavirus was involved as a cocarcinogen. A two-stage carcinogenesis protocol (7,12-dimethylbenz[a]anthracene followed by 12-O-tetradecanoylphorbol-13-acetate) was used to induce papillomas in 14 inbred, two hybrid, and 15 other genetic stocks of mice with inherited, single-gene mutations causing skin abnormalities. Histopathological, immunohistochemical, and Southern blot analyses were performed to determine tumor type and to detect the presence of papillomaviruses. The histologic types of tumors induced included early follicular papillomas, mixed papillomas, exophytic papillomas, hyperplastic papillomas, fibropapillomas, squamous cell carcinomas, and mast cell tumors. The efficacy of tumor induction was influenced by strain background, as seen by the clustering of mice into high-, intermediate-, and nonresponding groups. Similarly, tumor induction efficacy was affected by specific mutant genes that cause skin abnormalities. No evidence of papillomavirus structural antigens or viral genomic DNA was identified in 547 induced tumors. These observations indicate that numerous modifier genes but not papillomaviruses are involved in cutaneous chemical carcinogenesis.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1997

Hormone synthesis and responsiveness of spontaneous granulosa cell tumors in (SWR x SWXJ-9) F1 mice.

Granulosa cell tumors spontaneously occur in approximately 10-25% of female (SWR x SWXJ-9) F1 mice. The present studies were designed to test whether tumor-bearing mice produce a distinct hormonal profile by which they could be identified and determine whether cultured tumor cells are responsive to hormones and growth factors that regulate normal granulosa cells. Samples of female mouse blood taken from age 3 to 10 weeks allowed estimation of serum FSH, 17beta-estradiol, and inhibin levels for normal mice and for mice destined to develop tumors. These studies indicated that FSH and 17beta-estradiol values differed between normal and tumor-bearing animals, but overlapped sufficiently that such values could not accurately predict the tumor-bearing state. Inhibin concentrations did differentiate normal from tumor-bearing animals in all cases. Increased levels of inhibin were observed coincident in time with visibly detectable tumors within the ovaries. Compared to inhibin synthesis in vivo, hormonal responsiveness in vitro was much more variable. Steroidogenesis was stimulated in all tumors by dibutyryl-cAMP and low-density lipoprotein (LDL). Some, but not all, tumors responded to IGF1, EGF, FSH, and hCG. In about one-half of the tumors tested, FSH could induce hCG or dibutyryl-cAMP responsiveness. IGF1 pretreatment consistently increased the responsiveness of tumor cells stimulated by dibutyryl-cAMP and LDL. Production of inhibin by isolated tumor cells was detectable and decreased by EGF or dibutyryl-cAMP treatments. We conclude that granulosa tumor cell secretion of inhibin may be under different control than secretion from normal granulosa cells and acts as an excellent marker for these tumors.

Animals↗