摘要:

AbstractFamilial resemblance in bone mineral density at five skeletal sites was measured among 160 adult members of 40 families. Each family included a postmenopausal mother, one premenopausal daughter, one son, and the children's father. Similarities in selected life‐style factors thought to influence bone density, such as physical activity, smoking, alcohol use, and diet, were also evaluated. Bone density was measured by dual‐energy (total body, femoral neck, and lumbar spine) or single‐photon (radius and os calcis) absorptiometry. Correlation coefficients between the midparentZscore and offspringZscores of bone mineral density ranged from 0.22 to 0.52 among daughters and from 0.27 to 0.58 among sons. Adjustment of bone density for age, height, weight, and significant life‐style or environmental factors yielded heritability estimates for the five skeletal sites between 0.46 and 0.62. That is, 46–62% of variance in bone density was attributable to heredity. Most estimates derived from the group of daughters were similar to those from the sons. These observations provide support for a significant contribution of heredity to bone density. However, an individual's life‐style may account for a potentially large proportion of the nonheritable variance in b

ISSN:0884-0431    

DOI:10.1002/jbmr.5650080102

出版商:John Wiley and Sons and The American Society for Bone and Mineral Research (ASBMR)    

年代:1993

数据来源: WILEY

摘要:

AbstractBone mineral density in adult life, which is an important determinant of fracture risk, is determined by peak adult bone density, achieved in early adulthood and subsequent rates of change during adult life. Cross‐sectional twin and family studies indicate that the majority of population variation in bone density may be explained by genetic factors. Although there is evidence for a genetic effect on peak bone mass, it is unknown whether there is a genetic effect on rates of changes in bone density with age. Changes in lumbar spine and femoral neck bone density determined by dual‐photon absorptiometry (Lunar DP3) were examined in a cohort of monozygotic (MZ,n= 21, 3 male and 18 female pairs, median age, range, 46; 24–75 years) and dizygotic twins (DZ,n= 19; 43, 25–65 years). The median follow‐up was 3 years (range 1.1–5.5 years), with each subject having at least two and up to four bone density assessments. In these twins, genetic factors determine variation in rates of change (% change/year) in lumbar spine bone density,rMZ= 0.93 andrDZ= 0.51,p<0.02 (one tailed), and Ward's triangle,rMZ = 0–60.rDZ = 0.11,p<0.05 (one tailed). Model‐fitting analysis was also consistent with a genetic effect on rates of change in bone density at the trochanteric site, although such an effect was not shown at the femoral neck. These data demonstrate, for the first time, the possible existence of genetic determinants of rates of change in bone mineral de

ISSN:0884-0431    

DOI:10.1002/jbmr.5650080103

出版商:John Wiley and Sons and The American Society for Bone and Mineral Research (ASBMR)    

年代:1993

数据来源: WILEY

摘要:

AbstractControversy exists regarding the effect of fluoride on human osteoblast proliferation. To learn more of the cellular action of fluoride, we chose the clonal osteoblast cell line HOS TE85 as a model system. In these phenotypically osteoblast‐like cells, sodium fluoride stimulated [3H]thymidine incorporation in a dose‐dependent manner over the concentration range 1 × 10−5‐2 × 10−4M. The fluoride‐induced stimulation of [3H]thymidine uptake was dependent on cell density, being optimal at subconfluent cell numbers. Stimulation of [3H]thymidine uptake was inhibited by anti‐transforming growth factor β but not by antibody to insulin‐like growth factor I or β2‐microglobulin. Transforming growth factor β was shown to be a biphasic stimulator of [3H]thymidine uptake in HOS TE85, with maximal stimulation occurring at 0.5 nM transforming growth factor β. In the presence of fluoride the cells were more sensitive to stimulation by this growth factor, with maximum effect occurring at 0.1 nM. Fluoride did not increase mRNA for transforming growth factor β following either 8 or 24 h of exposure. We conclude that fluoride activates osteoblast proliferation by modulating the cellular sensitivity to transforming growth factor β, a known

ISSN:0884-0431    

DOI:10.1002/jbmr.5650080104

出版商:John Wiley and Sons and The American Society for Bone and Mineral Research (ASBMR)    

年代:1993

数据来源: WILEY

摘要:

AbstractMonkeys in a number of different New World primate genera express a form of compensated target organ resistance to steroid hormones, including 1,25‐dihydroxyvitamin D3[1,25‐(OH)2D3]. Characterization of these phenotypes has previously relied upon the study of the 1,25‐(OH)2D3‐receptor (VDR) interaction in cultured dermal fibroblasts from affected primates. In this report, we show that three of these prototypic phenotypes can be faithfully reproduced in previously established cultured cell lines: B95–8, EBV‐transformed B lymphoblasts from the marmoset (Callithrix jacchus), a New World primate with recognized vitamin D resistance; OMK, renal tubular epithelial cells from the owl monkey (Aotus trivergatus), a New World primate with an Old World primate‐like VDR phenotype; and MLA144, transformed B lymphoblasts from a gibbon (Hylobates), an Old World primate that expresses the wild‐type VDR phenotype. The rank order of specific nuclear uptake and binding of [3H]1,25‐(OH)2D3to the VDR was OMK ≥ ML A144 » B95–8. Despite a 7‐ to 9‐fold difference in cellular VDR content according to ligand binding analyses, there was no discernible difference in the internalization constantKinfor specific cellular uptake of [3H]1,25‐(OH)2D3(0.12–0.26 nM) or in the quantity of VDR detected by immunoblot analysis. We now speculate that the discrepancy in VDR quantitation by binding and immunoblot analysis in the B95–8 New World primate cell line results from the presence of an intracellular, vitamin D metabolite binding moiety in this cell line that competes with the VDR for metabolite binding. Extracts of B95–8 cells, but not wild‐type MLA144 cells, exhibited a binding component that had a relatively low affinity (∼ 50 nM) but high capacity for 1,25‐(OH)2D3compared to the VDR. When mixed with extracts of OMK and MLA144 cells (containing the wild‐type VDR) of equivalent protein concentration, B95–8 cell extract inhibited specific 1,25‐(OH)2D3‐VDR binding 84–86%. Sephadex G‐100 gel filtration chromatography of the sterol binding component in the B95–8 cell extract detected a single peak of [3H]1,25‐(OH)2D3and [3H]25‐OHD3binding to a protein eluting with an apparent molecular mass of 58–60 kD. This 58–60 kD sterol binding component was also distinguished from the 50 kD VDR by its elution from DEAE‐cellulose anion‐exchange HPLC at 0.45 M KCl; the mammalian VDR eluted at 0.25 M KCl. These data suggest that the 1,25‐(OH)2D3‐resistant phenotype of B95–8 cells may be due to the presence of a relatively plentiful, 58–60 kD intracellular protein that binds 1,25‐(OH)2D3with low affinity but high capacity a

ISSN:0884-0431    

DOI:10.1002/jbmr.5650080105

出版商:John Wiley and Sons and The American Society for Bone and Mineral Research (ASBMR)    

年代:1993

数据来源: WILEY

摘要:

AbstractThe anabolic effects of sodium fluoride (NaF) on trabecular bone mass in osteoporosis is now well established. In vivo histologic studies performed in humans and other animals have shown that fluoride induces an increase in osteoblast number at the tissue level. To determine the mechanisms of action of fluoride on osteoblasts, we studied the effects of NaF on short‐ and long‐term cultures of human osteoblastic cells derived from bone explants obtained from 21 donors. In short‐term experiments, bone‐derived cells were exposed to NaF for 4 days. At doses ranging from 10−11to 10−5M, NaF did not modify the alkaline phosphatase (AP) activity or osteocalcin secretion. In long‐term experiments, half the bone samples from 15 donors were cultured for 4 months in the presence of 10−5M NaF and the other half were maintained in NaF‐free medium. Observations by light and electron microscopy disclosed no morphologic modification in bone ex‐plants after 4 months of exposure to NaF, despite an increase in the bone fluoride content. After the first month of culture, slight but not significant increases were noted in 6 of 10 cases for AP activity, 4 of 10 for osteocalcin secretion, and 5 of 7 for [3H]thymidine incorporation. After 4 months of culture in the presence of NaF, no change in AP activity or cell proliferation was noted. In contrast, the osteocalcin secretion significantly decreased (p<0.05). These data suggest that, in vitro, under the conditions of this study, there is no direct effect of fluoride on the proliferation or activity (AP activity and osteocalcin secretion) of human osteoblastic cells and that this effect is very likely med

ISSN:0884-0431    

DOI:10.1002/jbmr.5650080106

出版商:John Wiley and Sons and The American Society for Bone and Mineral Research (ASBMR)    

年代:1993

数据来源: WILEY

摘要:

AbstractSevere deficiency of osteoclasts inop/opmice, caused by the absence of functional macrophage colony‐stimulating factor (M‐CSF), is cured by daily injections of purified recombinant human M‐CSF (rhM‐CSF). In this study, we found that a single injection of 5 μgrhM‐CSF is enough for recruitment of osteoclasts in mutant mice. Osteoclast number increased during the period between 2 and 4 days after the single rhM‐CSF injection. When YM175, a new derivative of bisphosphonate, was administered to the mice 4 days after rhM‐CSF injection or later, osteoclasts disappeared by 3 days after YM175 administration. However, a significant number of osteoclasts were detected even at 3 days after YM175 administration when YM175 was administered 3 days after rhM‐CSF injection or earlier. These results indicate that YM175 is cytotoxic only to functioning osteoclasts and that recruitment of osteoclasts is finished 4 days after a single rhM‐CSF injection. The osteoclasts actively resorbed bone trabeculae for a prolonged period, demonstrating that M‐CSF is not requisite for the functioning o

ISSN:0884-0431    

DOI:10.1002/jbmr.5650080107

出版商:John Wiley and Sons and The American Society for Bone and Mineral Research (ASBMR)    

年代:1993

数据来源: WILEY

摘要:

AbstractIt was reported earlier that IL‐1 production by cultured monocytes and the ratio of helper (CD4) to suppressor (CD8) lymphocytes in peripheral blood are different in osteoporotic compared to nonosteoporotic subjects. We examined these and several other parameters related to the biosynthetic activity and differentiation status of peripheral blood mononuclear cells (PBMC) in untreated osteoporotic postmenopausal women (age 65 ± 7,n= 46), nonosteoporotic postmenopausal women (age 55 ± 3,n= 20), and nonosteoporotic premenopausal women (age 37 ± 7,n= 8), as defined by spine density. We found that unstimulated monocytes from osteoporotics did not produce detectable IL‐1β as determined by ELISA. In addition, there were no significant differences between osteoporotics and nonosteoporotics in IL‐1β or IFN‐γ production by PBMC stimulated with OKT3, a monoclonal antibody to the T cell‐receptor complex. The proliferative response of lymphocytes to OKT3 was significantly less (p<0.02) in osteoporotics compared to nonosteoporotic post‐ and premenopausal women; multiple‐regression analysis, however, indicated that this difference was not due to bone density but to age. Flow cytometric analysis of PBMC revealed no difference between osteoporotics and nonosteoporotics in the distribution of 18 phenotypic subsets determined, including CD4‐or CD8‐positive lymphocytes or the ratio of CD4 to CD8 cells. Further, there was no correlation of the surface markers with bone density, the exceptions being the subsets expressing the CD3/CD56 and CD8/CD56 markers, which were inversely related to spine density in the osteoporotic women. Nonetheless, in the osteoporotic women, the CD8/CD56 and CD14/CD13 cells were positively correlated with the levels of plasma 1,25‐(OH)2D3(r= 0.33,p<0.04;r= 0.39,p= 0.028, respectively), whereas the CD4 cells were negatively correlated with 1,25‐(OH)2D3(r= −0.35,p= 0.026). These data suggest that cytokine production by peripheral blood mononuclear cells and the distribution of the various subsets of these cells in the peripheral blood are not related to bone mass in osteoporosis. Distribution of PBMC subsets in the peripheral blood, however, may be influenced by circu

ISSN:0884-0431    

DOI:10.1002/jbmr.5650080108

出版商:John Wiley and Sons and The American Society for Bone and Mineral Research (ASBMR)    

年代:1993

数据来源: WILEY

摘要:

AbstractMalignant osteopetrosis is characterized by impaired osteoclast activity. Osteoclasts derive from hematopoietic stem cells. In osteopetrosis, marrow cavities fail to develop, resulting in extramedullary hematopoiesis and the presence of stem cells in the bloodstream. Resistance to 1,25‐(OH)2D3may be involved in the pathogenesis of the disease. Sensitivity to 1,25‐(OH)2D3, calcitonin sensitivity, and expression of the osteoclast‐associated vitronectin receptor (VR) was examined in cultures of circulating mononuclear cells of seven osteopetrotic infants (1.5–6 months old). Since peripheral blood from age‐matched children contains few stem cells, umbilical cord blood was used as control. Mononucleated cells were isolated by the Ficoll‐Hypaque method and cultured (106cells per ml) in α‐MEM containing 20% horse serum in presence or absence of added 1,25‐(OH)2D3. VR was identified by immunochemical staining with MAb 23C6. 1,25‐(OH)2D3at 10−8M significantly stimulated the formation of multinucleated cells (MNC) in cultures from all osteopetrotic patients and cord blood samples. Cells from three of five patients responded to 10−9M 1,25‐(OH)2D3, the minimal stimulatory concentration for cord blood. Salmon calcitonin (100 ng/ml) partially inhibited the 10−8M 1,25‐(OH)2D3‐induced MNC formation in cultures from three of six patients and in cultures of all cord blood samples. In both types of cultures mononuclear cells and MNC cross‐reacted with MAb 23C6, and 1,25‐(OH)2D3concentration did not influence the number and percentage of these cells. This study does not support the hypothesis of 1,25‐(OH)2D3resistance in osteopetrotic infants and shows that mononuclear cells expressing VR, possibly osteoclast progenitors, develop in cultures of circulating mononuclear cells from these infants. 1,25‐(OH)2D3may no

ISSN:0884-0431    

DOI:10.1002/jbmr.5650080109

出版商:John Wiley and Sons and The American Society for Bone and Mineral Research (ASBMR)    

年代:1993

数据来源: WILEY

摘要:

AbstractThe noncollagenous matrix proteins, composing about 10% of the organic matrix of bone, are considered important for cell matrix organization and regulation of mineralization in bone. In the present study, seven of the major noncollagenous bone matrix proteins were localized immunohistochemically in serial sections of lumbar vertebrae from 24 (12 intact and 12 ovariectomized) adult female cynomolgus monkeys (Macaca fascicularis). Osteocalcin was the only protein restricted to bone cells and mineralized bone matrix. Bone sialoprotein was present in both bone and calcified cartilage, and all the other proteins were distributed in soft tissues as well as bone. Staining for both osteocalcin and bone sialoprotein was present diffusely throughout the bone matrix, but osteonectin, osteopontin, matrix gla protein, decorin, and biglycan staining was concentrated along bone surfaces. Osteoid was negative for osteocalcin and bone sialoprotein, but all other proteins had areas of positive immunostaining within osteoid. All proteins except biglycan exhibited strong immunostaining of a subset of active osteoblasts, suggesting that they may be markers of osteoblast maturity or state of activation. The pattern of immunostaining in intact and surgically menopausal monkeys was similar, except that staining for matrix proteins concentrated along bone surfaces appeared to be more widely distributed in the surgically menopausal monkeys, probably due to the higher rate of bone formation in these animals.

ISSN:0884-0431    

DOI:10.1002/jbmr.5650080110

出版商:John Wiley and Sons and The American Society for Bone and Mineral Research (ASBMR)    

年代:1993

数据来源: WILEY

摘要:

AbstractA young girl had tibial osteotomies at age 14 for genu valgum and then had recurrent tibia) cysts over a number of years. Hypocalcemia and hyperphosphatemia were first noted at age 21. The diagnosis of pseudohypoparathyroidism was made at age 28, when elevated plasma PTH was detected. Clinical and biochemical features, including a PTH response test and assay of RBC Gs, established the diagnosis of pseudohypoparathyroidism type lb. Failure to suppress plasma PTH with vitamin D therapy led to an exacerbation of her cystic bone disease; there were widespread lytic lesions radiologically, most of which took up [99mTc]diphosphonate on bone scan. Microradioscopy revealed evidence of resorption of phalangeal tufts. Bone biopsy showed osteitis fibrosa cystica. During an orthopedic procedure, trabecular bone fragments were taken from her right humerus, and bone‐derived cells cultured using an explant technique. The cultured cells were osteoblast‐like in morphology, fully responsive to PTH, cholera toxin, forskolin, and PGE1in vitro, and had an alkaline phosphatase and osteocalcin response to 1,25‐dihydroxyvitamin D3[1,25‐(OH)2D3]. Following this examination of skeletal responsiveness, attempts were made to suppress the elevated plasma PTH levels and symptomatic bone disease by optimizing therapy with oral 1,25‐(OH)2D3. When bone pain associated with the cystic bone disease failed to resolve, the patient underwent total parathyroidectomy, following which the bone pain gradually resolved. This is the first direct demonstration of PTH responsiveness in cultured bone cells in the syndrome of pseudohypoparathyroidism with osteitis fibros

ISSN:0884-0431    

DOI:10.1002/jbmr.5650080111

出版商:John Wiley and Sons and The American Society for Bone and Mineral Research (ASBMR)    

年代:1993

数据来源: WILEY