摘要:

Abstract“For this is not [that] which we can hope, that no grievance ever should arise …; but when complaints are freely heard, deeply considered, and speedily reformed then is the utmost bound … attained that wise men look for.” —Areopagit

ISSN:0884-0431    

DOI:10.1002/jbmr.5650110302

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

年代:1996

数据来源: WILEY

摘要:

AbstractNitric oxide (NO), a mediator of cardiovascular homeostasis, neurotransmission, and immune function, has recently been found to have important effects in bone. Both constitutive and inducible forms of NO synthase are expressed by bone‐derived cells, and cytokines such as interleukin‐1 (IL‐1), tumor necrosis factor (TNF), and interferon gamma (IFN‐γ), are potent stimulators of NO production. When combined with other cytokines, IFN‐γ markedly induces NO production, which suppresses osteoclast formation and activity of mature osteoclasts. This “superinduction” of NO is largely responsible for the selective inhibitory effect of IFN‐γ on cytokine‐induced bone resorption. High concentrations of NO are also inhibitory for cells of the osteoblast lineage, and NO production appears to be partly responsible for the inhibitory effects of cytokines on osteoblast proliferation. At lower concentrations, however, NO has different effects. Moderate induction of NO potentiates bone resorption, and the constitutive production of NO at low concentrations promotes the proliferation of osteoblast‐like cells and modulates osteoblast function. NO therefore appears to be an important regulatory molecule in bone with effects on cells of the osteoblast and osteoclast lineage and represents one of the molecules produced by osteoblasts which directly regulate osteoclastic activity. Stimulation of NO production in bone by proinflammatory cytokines raises the possibility that NO may be involved as a mediator of bone disease in conditions associated with cytokine activation, such as rheumatoid arthritis, tumor associated osteolysis, and postm

ISSN:0884-0431    

DOI:10.1002/jbmr.5650110303

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

年代:1996

数据来源: WILEY

摘要:

AbstractPvuII andXbaI restriction fragment length polymorphisms (RFLPs) of the estrogen receptor (ER) gene and its relation to bone mineral density (BMD) were examined in 238 postmenopausal healthy women aged 45–91 years (66.3 ± 0.6 years, mean ± standard error of the mean [SEM]) in Japan. The RFLPs were represented as Pp (PvuII) and Xx (XbaI), with capital letters signifying the absence of and small letters the presence of restriction sites. In the PPxx genotype (n= 18), Z score values of BMD were significantly lower than those for other genotypes (n= 220) (lumbar spine, −0.746 vs. −0.065 [p= 0.022]; total body, −0.482 vs. 0.308 [p= 0.002]). We classified the subjects into three genotypes with allelic haplotype: homozygote of the Px haplotype was expressed as the 11 genotype, heterozygote of the Px haplotype as the 10 genotype, and the one lacking the Px haplotype as the 00 genotype. The PpXx genotype was not included in this analysis because the allelic haplotypes are uncertain. The Px haplotype was associated with a low BMD in postmenopausal women (Z score for the lumbar spine, −0.746 vs. −0.279 vs. 0.083, for the 11, 10, 00 genotypes, respectively [p= 0.029]; Z score for the total body, −0.482 vs. 0.164 vs. 0.427, respectively [p= 0.003]). We suggest that some variation of the ER gene linked to these RFLPs is associated with low BMD and that this at least partly explains the cause of postmenopausal osteoporosis in

ISSN:0884-0431    

DOI:10.1002/jbmr.5650110304

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

年代:1996

数据来源: WILEY

摘要:

AbstractOsteoblasts are derived from precursor cells present in low frequency in the stromal element of bone marrow. Because of the lack of a practical procedure to isolate osteoblast precursors from early cultures of plastic adherent cells from bone marrow, previous studies of marrow stromal cells have been made in confluent cultures of bone marrow when the osteoblast (OB) precursors are already differentiated. Also these studies utilized cultures containing mixed populations of cells including hematopoietic cells. Thus we have employed a negative immunoselection procedure to remove contaminating hematopoietic cells and to isolate nearly homogeneous populations of early human stromal cells derived from the plastic‐adherent mononuclear marrow cells cultured in the presence of serum. By reverse transcriptase polymerase chain reaction (RT‐PCR) analysis for mRNA, and by immunocytochemical study for protein, we studied the sequential expression in culture of multiple markers of the osteoblast phenotype‐alkaline phosphatase, osteopontin, parathyroid hormone receptor, types I and III procollagen, and osteocalcin‐as well as lipoprotein lipase (LPL), a marker of the adipocyte phenotype. At an early stage of culture (7‐9 days), human OB precursors formed colonies of variable sizes that expressed low levels of mRNA and protein concentrations of OB markers, and their concentration increased on growth to a confluent monolayer (approximately 14 days). LPL mRNA was expressed at high levels in the colony stage, and its level decreased upon confluency, suggesting a loss of potential for commitment to the adipocyte lineage. Interestingly, treatment with dexamethasone at 10−8M increased the expression for some of the osteoblast markers and for the LPL gene and was required for the deposition of mineralized matrix and for the formation of adipocytes containing cytoplasmic lipid droplets in confluent cultures. Cloned single early colonies were able to coexpress the osteoblast and adipocyte markers (as assessed by RT‐PCR). Thus these immunoselected marrow stromal cells have the characteristics of authentic human osteoblast precursor cells which also are capable of differentiating in

ISSN:0884-0431    

DOI:10.1002/jbmr.5650110305

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

年代:1996

数据来源: WILEY

摘要:

AbstractTo determine the action of corticosteroid on bone metabolism and assess the effects of a synthetic vitamin D analog, ED‐71, on them, 56 SD rats, 8 weeks of age, were assigned to seven groups of eight animals each. Group 1 was the basal control. Group 2 was the nontreated control. Groups 3–7 were given prednisolone at 30 mg/kg of body weight (BW) twice a week and concomitantly administered ED‐71 with respective doses of 0, 0.0125, 0.025, 0.05, and 0.1 μg/kg of BW for 12 weeks. In group 3, urinary calcium (U‐Ca) and deoxypyridinoline (U‐Dpy) were significantly increased compared with group 2. In groups 4–7, U‐Ca values were increased but U‐Dpy values were dose‐dependently decreased. Age‐dependent increases in the parameter values of BMD, compressive strength, trabecular bone volume (BV/TV), and trabecular thickness (Tb.Th) of the lumbar body were significantly suppressed in group 3 but dose‐dependently increased in groups 4–7, and the values of group 7 exceeded those of group 2. The parameters of bone mineral density (BMD) and the bending strength of the femur in groups 4–7 were larger than the values in group 3 but did not reach the levels of group 2. The trabecular bone formation rate (BFR/BS) of the lumbar body measured by calcein labeling in group 3 was reduced when compared with group 2, but the values were not further decreased in groups 4–7. The perimeter ratios of double labels over single labels (dLS/sLS) greatly decreased by prednisolone, were dose‐dependently increased to the level of the normal control by ED‐71. Double‐labeled perimeters and the dLS/sLS ratios were also increased in the periosteal envelope of the midfemur. These findings clearly demonstrate that prednisolone administration affects the age‐related changes in bone metabolism, and ED‐71 administration counteracts the effects by increasing intestinal calcium absorption, reducing bone resorption, and enhancing mineralization. The action of ED‐71, however, seem

ISSN:0884-0431    

DOI:10.1002/jbmr.5650110306

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

年代:1996

数据来源: WILEY

摘要:

AbstractChanges of bone turnover with aging are responsible for bone loss and play a major role in osteoporosis. Although an increase of bone turnover has been documented at the time of menopause, the subsequent abnormalities of bone resorption and formation and their potential role in determining bone mass in the elderly have not been investigated. To address this issue, we have measured a battery of new sensitive and specific markers of bone turnover in a population‐based study of 653 healthy women analyzed cross‐sectionally, including 432 women postmenopausal from 1 to 40 years, and the data were correlated with bone mineral density (BMD) measured by dual‐energy X‐ray absorptiometry (DXA) at different skeletal sites. Bone formation was assessed by serum osteocalcin (OC), serum bone‐specific alkaline phosphatase (B‐ALP), serum C‐propeptide of type I collagen (PICP), and bone resorption by the urinary excretion of two pyridinoline cross‐linked peptides (NTX and CTX). Bone turnover increased in perimenopausal women with both irregular menses and elevated serum follicle stimulating hormone (FSH). Menopause induced a 37–52% and 79–97% increase in the bone formation and bone resorption marker levels, respectively (p<0.0001 except for PICP). In postmenopausal women, bone formation markers did not decrease with age. When resorption markers were corrected by whole body bone mineral content (BMC), the fraction of bone resorbed per day was not correlated with age in postmenopausal women and remained elevated for up to 40 years after menopause. In premenopausal women, the bone turnover rate accounted for only 0–10% of the variation in whole body BMC, total hip, distal radius, and lumbar spine BMD. With increasing time after menopause, the importance of the bone turnover rate as a determinant of bone mass increased at all sites and accounted for up to 52% of the BMD variance in elderly women. Thus, in women 20 years or more postmenopause, bone turnover was higher in those in the lowest quartile than in those in the highest quartile of BMD. In elderly women, 20 years since menopause and over, but not in younger ones, serum PTH was negatively correlated with serum 25‐hydroxyvitamin D (r= −0.22,p<0.05) and explained only 5–8% of the bone turnover variance (p<0.01‐0.001). These data indicate that the overall rates of both bone formation and bone resorption remain high in elderly women. The rate of bone turnover appears to play an increasing role as a determinant of bone mass with increasing time since menopause with a high bone turnover rate being associated with a low bone mass. Thus assessing bone marker levels may be useful in the evaluation of osteoporosis risk. In elderly women, secondary hyperparathyroidism caused in part by reduced serum 25‐hydroxyvitamin D appears to be a marginal determinant of

ISSN:0884-0431    

DOI:10.1002/jbmr.5650110307

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

年代:1996

数据来源: WILEY

摘要:

AbstractOsteocytes have been proposed to be the cells primarily responsible for sensing the effects of mechanical loading in bone. Osteocytes respond to loading in vivo, and have been shown to express osteotropic agents and their receptors, and cell/matrix adhesion molecules in vitro, but the functional significance of such findings is not clear. One obstacle to increased understanding of the role of osteocytes in the regulation of bone mass is that the cells are not easily accessible for study. In situ studies are difficult, and although it is possible to extract and culture osteocytes from neonatal bones, the responses of such cells might be very different from those in older bones in situ. We have developed a technique to investigate osteocyte gene expression in vivo, using the reverse transcriptase linked polymerase chain reaction (PCR), and have shown that they express mRNA for β‐actin (β‐ACT), osteocalcin (OC), connexin‐43 (Cx43), insulin‐like growth factor I (IGF‐I), c‐fos, and c‐jun, but not tumor necrosis factor alpha (TNF‐α) or tartrate‐resistant acid phosphatase (TRAP). The principle behind the method is that after removal of the periosteum, tangential cryostat sections of a tubular bone contain RNA only from osteocytes and a very small number of endothelial cells as long as the marrow cavity is not broached. Using this method, we have investigated gene expression in cells from rat ulnar cortical bone under forming and resorbing bone surfaces. In addition, we have investigated the effect on gene expression of mechanical loading which, if repeated daily, initiates new bone formation on quiescent or resorbing surfaces. Although the expression of the genes we have studied in osteocytes is different from those expressed by the periosteal surfaces overlying the cortex, we have not detected loading‐related changes in osteocyte gene expression in any cortical bones. This may be because of the extreme sensitivity of the PCR technique which can only resolve large differences in expression. The use of quantitative methods in the future may allow demonstration of regulated gene ex

ISSN:0884-0431    

DOI:10.1002/jbmr.5650110308

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

年代:1996

数据来源: WILEY

摘要:

AbstractWe have shown previously that prostaglandin (PG) production in 7‐day‐old neonatal mouse calvarial cultures is regulated largely by changes in prostaglandin G/H synthase‐2 (PGHS‐2) expression and to a lesser extent by changes in arachidonic acid (AA) release. In this study, we examined the effects of interleukin‐4 (IL‐4), and its interactions with other cytokines and with parathyroid hormone (PTH), on mRNA levels of PGHS‐2, PGHS‐1, and cytosolic phospholipase A2(cPLA2) and on medium protaglandin E2(PGE2) levels in calvarial cultures. IL‐1 and tumor necrosis factor‐α (TNF‐α), both at 1–100 ng/ml, and PTH at 0.1‐10 nM increased PGHS‐2 and cPLA2mRNA and medium PGE2levels dose‐dependently after 4 h of treatment. IL‐6 and IL‐11 at 1–100 ng/ml did not affect mRNA or PGE2levels. IL‐4 at 1–100 ng/ml decreased PGHS‐2 and cPLA2mRNA and PGE2levels in control as well as IL‐1, TNF‐α, and PTH‐stimulated cultures. The inhibition of PGHS‐2 and cPLA2mRNA expression by IL‐4 (10 ng/ml) was present at 1 h, reached a maximum at 4 h, and persisted for 24 h. The effects were maintained in the presence of cycloheximide. IL‐4 also decreased PGHS‐2 protein levels in control and IL‐1‐stimulated cultures. PGHS‐1 mRNA levels were not stimulated by any of the factors studied nor inhibited by IL‐4. IL‐4 partially inhibited control and PTH‐stimulated45Ca release from prelabeled mouse calvariae at 4 days. However, neither the inhibition of resorption by IL‐4 nor the stimulation by IL‐1 and PTH were altered by indomethacin (1 μM). We conclude that (1) IL‐1, TNF‐α, and PTH, but not IL‐6 nor IL‐11, can increase the expression of PGHS‐2, cPLA2, and PGE2production in cultured mouse calvariae; (2) IL‐4 inhibits PGE2production in both control and stimulated calvarial cultures by inhibiting PGHS‐2 and cPLA2; and

ISSN:0884-0431    

DOI:10.1002/jbmr.5650110309

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

年代:1996

数据来源: WILEY

摘要:

AbstractTo evaluate the osteoblastic function in patients with multiple pituitary hormone deficiencies (M‐PHD) and with isolated growth hormone deficiency (I‐GHD), bone cells were cultured and the effects of 10−8M 1,25‐dihydroxyvitamin D3(1,25[OH]2D3) on parameters of cell proliferation, osteoblastic differentiation, and local paracrine regulation were measured. Three days of 1,25(OH)2D3treatment increased alkaline phosphatase activity and osteocalcin release but inhibited [3H]thymidine incorporation in all cell cultures from patients as well as from controls. In addition, 1,25(OH)2D3increased the release of both total and active transforming growth factor‐β (TGF‐β) in bone cells from controls by, respectively, 4.9‐ and 3.2‐fold and in bone cells from I‐GHD by 5.1‐ and 1.5‐fold, respectively. However, in bone cells from M‐PHD, the stimulation of total TGF‐β release was significantly lower (1.3‐fold) than in control and I‐GHD cells, and active TGF‐β release was not stimulated at all. One year of supplementation with human growth hormone did not improve this deficient TGF‐β release in bone cells from M‐PHD. We conclude that cultured bone cells from I‐GHD and M‐PHD show a normal response to 1,25(OH)2D3regarding cell proliferation and osteoblastic differentiation, which implicates a normal l,25(OH)2D3‐receptor function. In cells from controls and I‐GHD, 1,25(OH)2D3enhanced both total and active TGF‐β release. However, bone cells from M‐PHD showed a deficient TGF‐β response to 1,25(OH)2D3. These results suggest that the regulation of TGF‐β product

ISSN:0884-0431    

DOI:10.1002/jbmr.5650110310

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

年代:1996

数据来源: WILEY

摘要:

AbstractAs with any structure, the structural capacity of the proximal femur depends on the applied loads and these can vary as a function of impact direction during a fall. However, despite its potential importance in hip fracture risk assessment, the relative importance of impact direction is unknown. To investigate the role of impact direction in hip fracture, we developed a detailed finite element model of the proximal femur. We analyzed four loading configurations that represent a range of possible falls on the greater trochanter. Our results indicate that a change in the angle between the line of action of the applied force and the axis of the femoral neck from 0° (representing a direct lateral impact) to 45° (representing a posterolateral impact) reduced structural capacity by 26%. This weakening of the femur with changes in impact direction is comparable to the weakening associated with 2–3 decades of age‐related bone loss. Our result elucidates the independent contribution of fall mechanics to hip fracture risk by identifying an aspect of the fall (the direction of impact) that is an important determinant of fall severity. The results can also be incorporated into a refined clinical method for assessment of hip fracture risk that accounts for the complex interactions between fall severity and bone frag

ISSN:0884-0431    

DOI:10.1002/jbmr.5650110311

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

年代:1996

数据来源: WILEY