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ABSTRACT: We performed the whole-genome scan for quantitative trait loci (QTLs) in SAMP6 mice that exhibits a significantly low peak bone mass. We found two significant loci on Chrs 11 and 13 (designated Pbd1 and Pbd2, respectively) and one suggestive locus on Chr X (designated Pbd3 ) that were linked to the bone mass. Next, we clarified that Pbd1 is related to the bone geometry, Pbd2 to the formation of bone before maturation, and Pbd3 to the bone loss after maturation. In particular, we showed that secreted frizzled-related protein 4 (Sfrp4) encoded by a gene within the Pbd2 locus on Chr 13 was responsible, at least in part, for the lower bone mineral density (BMD) in the SAMP6 mice, by inhibiting the proliferation of osteoblasts.
Clinical calcium 01/2011; 21(2):209-16.
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ABSTRACT: Genetic programming is known to affect the peak bone mass and bone loss after maturation. However, little is known about how polymorphic genes on chromosome X (Chr X) modulate bone loss after maturation. We previously reported a quantitative trait locus (QTL) on Chr X, designated Pbd3, which had a suggestive linkage to bone mass, in male SAMP2 and SAMP6 mice. In this study, we aimed to clarify the effects of Pbd3 on the skeletal phenotype. We generated a congenic strain, P2.P6-X, carrying a 45.6-cM SAMP6-derived Chr X interval on a SAMP2 genetic background. The effects of Pbd3 on the bone phenotype were determined by microcomputed tomography (microCT), whole-body dual-energy X-ray absorptiometry (DXA), serum bone turnover markers, and histomorphometric parameters. Both the bone area fraction (BA/TA) on microCT and whole-body DXA revealed reduced bone loss in P2.P6-X compared with that in SAMP2. The serum concentrations of bone turnover markers at 4 months of age were significantly lower in P2.P6-X than in SAMP2, but did not differ at 8 months of age. These results were observed in female mice, but not in male mice. In conclusion, a QTL within a segregated 45.6-cM interval on Chr X is sex-specifically related to the rate of bone loss after maturation.
Journal of Bone and Mineral Metabolism 03/2010; 28(5):520-31. · 2.27 Impact Factor
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ABSTRACT: Transgenic mice overexpressing Sfrp4 in osteoblasts were established. These mice exhibited low bone mass caused by a decrease in bone formation.
We recently reported that single nucleotide polymorphisms in the secreted frizzled-related protein 4 (Sfrp4) gene are responsible for low peak BMD in senescence-accelerated mouse (SAM) P6. In vitro studies revealed inhibition of osteoblast proliferation by Sfrp4, which is supposed to be mediated by canonical Wnt signaling.
We examined the expression of Sfrp4 in neonate long bones by in situ hybridization and generated transgenic mice in which Sfrp4 was specifically overexpressed in osteoblasts under the control of a 2.3-kb Col1a1 osteoblast-specific promoter. Next, we compared the phenotype of Sfrp4 transgenic (Sfrp4 TG) mice with that of mice in which one allele of beta-catenin was conditionally disrupted in osteoblasts (betaChet), and administered lithium chloride (LiCl) to Sfrp4 TG mice.
Hemizygous Sfrp4 TG mice exhibited a 30% reduction of trabecular bone mass compared with that in wildtype littermates at 8 wk of age, and histomorphometrical analysis showed decreases in both osteoblast numbers and bone formation rate. betaChet mice exhibited a 17% reduction of trabecular bone mass in distal femora caused by an increase in the osteoclast number and a decrease in bone formation rate. Furthermore, LiCl administration rescued the bone phenotype of Sfrp4 TG mice.
Expression of Sfrp4 in periosteum and bone tissues suggested the role of Sfrp4 in osteoblasts, and we identified that overexpression of Sfrp4 in osteoblasts suppressed osteoblast proliferation, resulting in a decrease in bone formation in vivo. Partial suppression of beta-catenin/canonical Wnt signaling also impaired bone formation, and activation of the signaling restored low bone mass of Sfrp4 TG mice. Thus, these results indicate that Sfrp4 decreases bone formation at least in part by attenuating canonical Wnt signaling in vivo.
Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 03/2008; 23(2):271-7. · 6.04 Impact Factor
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ABSTRACT: To determine whether sensitivity to polyethylene particles varies among patients, we studied 25 patients who had undergone total hip arthroplasty. We used pelvic radiographs to measure annual polyethylene wear and the area of osteolysis. The ratio of the area of osteolysis to the volumetric polyethylene wear was defined as sensitivity index. Adherent cells from peripheral blood were cocultured with polyethylene particles, and the amount of bone-resorptive cytokines was measured. The amount of interleukin-6, but not of interleukin-1beta or tumor necrosis factor-alpha, released from adherent cells in the in vitro experiment correlated with the in vivo sensitivity indices. This technique appears capable of predicting the development of polyethylene-induced osteolysis, allowing surgeons to avoid using polyethylene as the bearing surface in patients at risk for osteolysis.
The Journal of Arthroplasty 11/2007; 22(7):966-73. · 2.38 Impact Factor
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ABSTRACT: We segregated a QTL on chromosome 11 that affects femoral cross-sectional shape during growth by generating a congenic strain and an additional 16 subcongenic strains of the senescence-accelerated mouse strain, SAMP6. The QTL region was narrowed down to a 10.0-Mbp region.
Genetic background is known to affect bone characteristics. However, little is known about how polymorphic genes modulate bone shape. In a previous study using SAMP2 and SAMP6 mice, we reported a quantitative trait locus (QTL) on chromosome (Chr) 11 that had significant linkage to peak relative bone mass in terms of cortical thickness index (CTI) in male mice. We named it Pbd1. Here we aimed to clarify the effects of Pbd1 on skeletal phenotype in male mice and to narrow down the QTL region.
We generated a congenic strain named P6.P2-Pbd1(b), carrying a 39-cM SAMP2-derived Chr11 interval on a SAMP6 genetic background. Sixteen subcongenic strains with smaller overlapping intervals on the SAMP6 background were generated from P6.P2-Pbd1(b) to narrow the region of interest. The effects of Pbd1 on bone properties were determined. Gene expression analysis of all candidate genes in Pbd1 was performed using real-time RT-PCR.
The CTI of strain P6.P2-Pbd1(b) at 16 wk was higher than that of SAMP6. This was not caused by differences in cortical thickness but by cross-sectional shape. Morphological analysis by microCT revealed that the femoral cross-sectional shape of P6.P2-Pbd1(b) (and the other subcongenic strains with higher CTI or bone area fraction [BA/TA]) was more compressed anteroposteriorly than that of SAMP6, which was associated with superior mechanical properties. This feature was formed during bone modeling up to 16 wk of age. Subcongenic strains with a higher CTI showed significant increases in endocortical mineral apposition rate and significant reductions in periosteal mineral apposition rate at 8 wk compared with those of the SAMP6. The Pbd1 locus was successfully narrowed down to a 10.0-Mbp region, and the expression analysis suggested a candidate gene, Cacng4.
The Pbd1 affects femoral cross-sectional shape by regulating the rate of endocortical and periosteal bone formation of the femur during postnatal growth.
Journal of Bone and Mineral Research 06/2007; 22(5):675-85. · 6.37 Impact Factor
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Rika Nakanishi, Motoyuki Shimizu,
Masayuki Mori,
Haruhiko Akiyama,
Shuzo Okudaira,
Bungo Otsuki,
Maiko Hashimoto,
Keiichi Higuchi,
Masanori Hosokawa,
Tadao Tsuboyama,
Takashi Nakamura
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ABSTRACT: We segregated a QTL for peak BMD on Chr 13 by generating congenic sublines of the senescence-accelerated mouse SAMP6. Sfrp 4 within this locus was responsible for lower BMD of SAMP6.
Our genome-wide linkage study using SAMP6 and SAMP2 showed a significant quantitative trait locus (QTL) for peak BMD on chromosome (Chr) 13. To verify the gene that regulates peak BMD, we generated a congenic strain, P6.P2-Pbd2(b), which carried a 15-cM SAMP2 interval on an osteoporotic SAMP6 background, and showed that this Pbd2 locus increased peak BMD in SAMP6.
To narrow down this interval, we generated a new congenic subline P6.P2-13. We studied the effect of this locus on morphological and histomorphological features in vivo and on osteoblasts in vitro. The levels of expression of all genes in the segregated interval were examined, and we clarified the effect of the candidate gene, secreted frizzled-related protein (Sfrp4), on osteoblasts in vitro.
The new congenic strain, P6.P2-13, retained the 2.4-Mb SAMP2 interval on the SAMP6 background, and 11 genes existed in this interval. In morphometrical analysis, P6.P2-13 increased the bone area fraction (BA/TA) by 6.6% at the diaphysial cortex (p < 0.001) and increased the trabecular bone volume (BV/TV) by 54.2% at the distal metaphysis (p < 0.05) in the femora compared with those of SAMP6. The bone formation rate of P6.P2-13 was markedly increased at the periosteal surface of femoral cortex and that was caused by a higher proliferation rate of osteoblasts in P6.P2-13 compared with those in SAMP6. Quantitative RT-PCR analysis of calvaria tissue showed approximately 40-fold higher levels of expression of Sfrp4 in SAMP6 than in P6.P2-13. Taken together with the result that recombinant Sfrp4 suppressed the proliferation of osteoblasts, we hypothesized that Sfrp4 inhibited the proliferation of osteoblasts through its antagonistic effect on Wnt signaling. TCF/beta-catenin-dependent reporter activity in osteoblasts derived from SAMP6 showed lower responsiveness for the Wnt ligand, Wnt3A, than that in osteoblasts from P6.P2-13.
In SAMP6 mice, Sfrp4 negatively regulates bone formation and decreases BMD through the inhibition of Wnt signaling.
Journal of Bone and Mineral Research 11/2006; 21(11):1713-21. · 6.37 Impact Factor
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ABSTRACT: The wear rate of polyethylene against alumina was demonstrated to be lower than against metal, and the results of early clinical studies of alumina-on-polyethylene combination were as good as expected, but the long-term results of alumina ceramic heads were not as good, as reported by several authors. The purpose of this study was to assess the clinical results over 10 years of cemented total hip arthroplasty (THA) with two types of alumina head: old and current alumina.
We compared the clinical results of these two types of alumina used for cemented THA. The first type was old alumina (containing 7% yttria), and 77 hips with a 28-mm head (group I) were included. The second type was current alumina (highly purified alumina), and 50 hips with a 26-mm head (group II) and 88 hips with a 22-mm head (group III) were included. The mean follow-up was 17 years 4 months in group I, 12 years 3 months in group II, and 10 years in group III.
The Kaplan-Meier survival analysis, with revision for any reason as the endpoint, predicted 10-year survival rates of 90.8%, 100%, and 97.5% for groups I, II, and III, respectively. The survival curves differed significantly only between groups I and II. The probabilities of 10-year survival of the pros-theses with radiological loosening as the endpoint were 77.2%, 91.6%, and 96.5%, respectively. The survival curves showed significant differences only between groups II and III.
The old alumina showed a higher wear rate and rougher surface on the femoral head than did the current alumina in our previous study. The clinical results also indicated superiority of current alumina over old alumina. The difference in the size of the femoral head (26 vs. 22 mm) did not affect the clinical results.
Journal of Orthopaedic Science 08/2005; 10(4):378-84. · 0.84 Impact Factor
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ABSTRACT: Acute displacement of the cemented acetabular component of a hip arthroplasty after attempted reduction of a dislocation is described. The causes of displacement of the socket, which was not radiologically loose, are discussed. Potential causes include impingement of the femoral head and the ceramic screw head overhanging the acetabular bone, which was used to fix the bone graft.
The Journal of Arthroplasty 03/2004; 19(2):240-3. · 2.38 Impact Factor
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ABSTRACT: The development of bone densitometry has made it clear that there are discrepancies in bone density at various measurement sites in a given individual. This study examined the consistency of bone density measurements across various sites in a strain of laboratory mouse (senescence-accelerated mouse; SAM). A systemic evaluation of the bone density was performed by dual-energy X-ray absorptiometry (DXA) on SAMP6 (P6) mice, a strain with low peak bone density, as measured by microphotodensitometry of the femoral bones, whereas the SAMP2 (P2) and SAMR1 (R1) strains have high peak bone density. We modified Jilka's method to more comprehensively measure the whole body and additional regions of interest (ROIs; head, right foreleg, left foreleg, right hindleg, left hindleg, spine, and tail). The age-related changes in the total (whole-body) BMD showed a common pattern among the strains studied, and the peak value was seen at 4 months old. P6 showed the lowest peak BMD. A detailed comparison of the bone density between P6 and P2 at the age of 4 months revealed significantly lower regional BMD values for P6 in all seven ROIs. The strain difference in BMD could not be attributed to a difference in size. In conclusion, P6 mice showed low bone density not only in their femurs but also in the subregions and over their entire body. This strain can be potentially useful in the investigation of the genetic basis of senile osteoporosis.
Journal of Bone and Mineral Metabolism 02/2004; 22(3):207-14. · 2.27 Impact Factor
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Motoyuki Shimizu,
Keiichi Higuchi,
Soichiro Kasai,
Tadao Tsuboyama,
Mutsumi Matsushita,
Takuro Matsumura,
Shuzo Okudaira,
Masayuki Mori,
Akio Koizumi,
Takashi Nakamura,
Masanori Hosokawa
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ABSTRACT: Previously, we identified two significant quantitative trait loci (QTLs) specifying the peak relative bone mass (bone mass corrected for bone size) on chromosomes (Chrs) 11 and 13 by interval mapping in two mouse strains, SAMP2 and SAMP6. The latter strain is an established murine model of senile osteoporosis and exhibits a significantly lower peak relative bone mass than SAMP2 mice. We recently designated the Chr 13 locus as Pbd2 (Peak bone density 2) and constructed a congenic strain, P6.P2-Pbd2(b), which carried a single genomic interval from the Chr 13 of SAMP2 on a SAMP6-derived osteoporotic background. In this study, we have constructed a congenic strain, P2.P6-Pbd2(a), carrying a SAMP6-derived susceptible interval on a SAMP2-derived resistance background. This congenic strain had a lower bone density than the background strain, SAMP2, based on three measurement methods, each utilizing a different principle for evaluating bone density: MD, DXA, and pQCT. Next, a candidate gene approach was used to find polymorphisms of Bmp6 (bone morphogenetic protein 6). The CAG trinucleotide repeat numbers in exon 1 of this gene differ among SAM strains. We found an association of CAG repeat length with relative peak bone mass in mice.
Mammalian Genome 08/2002; 13(7):335-40. · 2.89 Impact Factor
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Motoyuki Shimizu,
Keiichi Higuchi,
Soichiro Kasai,
Tadao Tsuboyama,
Mutsumi Matsushita,
Takuro Matsumura,
Shuzo Okudaira,
Masayuki Mori,
Akio Koizumi,
Takashi Nakamura,
Masanori Hosokawa
Mammalian Genome 06/2002; 13(7):335-340. · 2.89 Impact Factor
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Motoyuki Shimizu,
Keiichi Higuchi,
Beth Bennett,
Chen Xia,
Tadao Tsuboyama,
Soichiro Kasai,
Takuya Chiba,
Hiromi Fujisawa,
Kumiko Kogishi,
Haruo Kitado,
Mitsutoshi Kimoto,
Norikazu Takeda,
Mutsumi Matsushita,
Hideo Okumura,
Tadao Serikawa,
Takashi Nakamura,
Thomas E. Johnson,
Masanori Hosokawa
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ABSTRACT: The whole genome scan for quantitative trait loci (QTLs) specifying peak bone mass was performed with the F2 intercrosses of SAMP6, an established murine model of senile osteoporosis, exhibiting a significantly lower peak bone mass,
and SAMP2, exhibiting a higher peak bone mass. Cortical thickness index (CTI), a parameter of bone mass of femurs, was measured
in 488 F2 progeny at 4 months of age, when the animals attained peak bone mass by microphotodensitometry. Genetic markers were typed
at 90 loci spanning all chromosomes except the Y. By interval mapping of 246 male F2 mice, two loci were identified with significant linkage to peak bone mass, one on Chromosome (Chr) 11 and another on Chr
13, with a maximum lod score of 10.8 (22.2% of the total variance) and 5.8 (10.0%), respectively. Another locus on the X Chr
was suggestive of a QTL associated oppositely with a low peak bone mass to the SAMP2 allele. This association was consistent
with the distribution of peak bone mass in the F1 and F2. These findings should be useful to elucidate the genetics of osteoporosis.
Mammalian Genome 01/1999; 10(2):81-87. · 2.89 Impact Factor
