Biomedical subjects

J S Thomsen

Publications and source records attributed to J S Thomsen.

At least 19 recordsLinked to original sources

PubMed2006

The anabolic effect of PTH on bone is attenuated by simultaneous glucocorticoid treatment.

Glucocorticoids (GC) are used for the treatment of a wide spectrum of diseases because of their potent anti-inflammatory and immunosuppressive effects, and they are serious and common causes of secondary osteoporosis. Administration of intermittent parathyroid hormone (PTH) may induce formation of new bone and may counteract the bone loss induced by GC treatment. Effects of simultaneous PTH and GC treatment were investigated on bone biomechanics, static and dynamic histomorphometry, and bone metabolism. Twenty-seven-month-old female rats were divided randomly into the following groups: baseline, vehicle, PTH, GC, and PTH + GC. PTH (1-34) 25 mug/kg and GC (methylprednisolone) 2.5 mg/kg were injected subcutaneously each day for a treatment period of 8 weeks. The rats were labeled with fluorochromes 3 times during the experiment. Bone sections were studied by fluorescence microscopy. The PTH injections resulted in a 5-fold increase in cancellous bone volume. At the proximal tibia, PTH induced a pronounced formation of new cancellous bone which originated from the endocortical bone surfaces and from thin trabeculae. Formation and modeling of connections between trabeculae were observed. Similar but less pronounced structural changes were seen in the PTH + GC group. The compressive strength of the cancellous bone was increased by 6-fold in the PTH group compared with the vehicle group. GC partially inhibited the increase in compressive strength induced by PTH. Concerning cortical bone, PTH induced a pronounced increase in the endocortical bone formation rate (BFR) and a smaller increase in periosteal BFR. The combination of PTH + GC resulted in a partial inhibition of the PTH-induced increase in bone formation. Serum-osteocalcin was increased by 65% in the PTH group and reduced by 39% in the GC group. The pronounced anabolic effect of PTH injections on the endocortical and trabecular bone surfaces and less pronounced anabolic effect on periosteal surfaces were partially inhibited, but not prevented, by simultaneous GC treatment in old rats. Both cortical and cancellous bone possessed full mechanical competence after treatment with PTH + GC.

Animals↗

PubMed2005

Stereological measures of trabecular bone structure: comparison of 3D micro computed tomography with 2D histological sections in human proximal tibial bone biopsies.

Stereology applied on histological sections is the 'gold standard' for obtaining quantitative information on cancellous bone structure. Recent advances in micro computed tomography (microCT) have made it possible to acquire three-dimensional (3D) data non-destructively. However, before the 3D methods can be used as a substitute for the current 'gold standard' they have to be verified against the existing standard. The aim of this study was to compare bone structural measures obtained from 3D microCT data sets with those obtained by stereology performed on conventional histological sections using human tibial bone biopsies. Furthermore, this study forms the first step in introducing the proximal tibia as a potential bone examination location by peripheral quantitative CT and CT. Twenty-nine trabecular bone biopsies were obtained from autopsy material at the medial side of the proximal tibial metaphysis. The biopsies were embedded in methylmetacrylate before microCT scanning in a Scanco microCT 40 scanner at a resolution of 20 x 20 x 20 microm3, and the 3D data sets were analysed with a computer program. After microCT scanning, 16 sections were cut from the central 2 mm of each biopsy and analysed with a computerized method. Trabecular bone volume (BV/TV) and connectivity density (CD) were estimated in both modalities, whereas trabecular bone pattern factor (TBPf) was estimated on the histological sections only. Trabecular thickness (Tb.Th), number (Tb.N) and separation (Tb.Sp), and structure model index (SMI) were estimated with the microCT method only. Excellent correlations were found between the two techniques for BV/TV (r = 0.95) and CD (r = 0.95). Additionally, an excellent relationship (r = 0.95) was ascertained between TBPf and SMI. The study revealed high correlations between measures of bone structure obtained from conventional 2D sections and 3D microCT data. This indicates that 3D microCT data sets can be used as a substitute for conventional histological sections for bone structural evaluations.

Aged↗

PubMed2005

The hypomagnesic rat model: dermatitis-prone hairless rats with mild magnesium depletion fed a diet low in lipids did not develop pruritic dermatitis.

BACKGROUND/PURPOSE: In the hypomagnesic dermatosis of rats, low-dietary magnesium leads to lowered serum Mg2+, universal dermatitis and scratching. The model is postulated to work better if the diet also has a low content of lipids. Pruritus is seen in patients suffering from anorexia nervosa and resolves on weight restoration. Lipid depletion of the diet and/or lowered body weight may therefore be important in developing pruritus. The purpose of the present study was to investigate whether a diet low in lipids can induce pruritus in dermatitis prone rats because of mild magnesium depletion thereby focusing on the role of lipids in the hypomagnesic dermatosis rat model. METHODS: Fourteen male hairless rats, 3 weeks of age, were fed a diet deficient in lipids and with a lower content of magnesium for a 4-week period and compared with 11 controls fed a normal diet. The skin was inspected daily and transepidermal water loss (TEWL), serum Mg2+ and scratching activity were measured. At the end, skin biopsies were taken from the flank and ears. RESULTS: Serum Mg2+ was significantly lowered in the diet group (P<0.001) but the rats developed no dermatitis or increased TEWL compared with 11 rats in a control group. Biopsies were normal with no sign of inflammation. Rats in the diet group had inferior weight gain, were less active and spent more time asleep than control rats (P<0.01). Furthermore, scratching activity monitored in the last week of the study as the number of scratch-sequences per awake minute was reduced in the diet group (P<0.001). CONCLUSION: The lipid-deficient diet was not able to induce pruritic dermatitis despite the fact that the rats were dermatitis prone because of mild magnesium depletion. It is not confirmed that dietary lipid depletion plays any significant role in the hypomagnesic dermatitis rat model. The dermatitis and the model appear to be strictly dependent on efficient magnesium depletion manufactured with very low magnesium levels.

Animals↗

PubMed2004

Autometallographic tracing of zinc ions in growing bone.

It has previously been established that zinc (Zn) supplementation increases bone dimensions and strength in growing rats. The present study aims at describing differences in the localization of loosely bound or free zinc ions, as revealed by autometallography (AMG), that might take place in the skeleton of growing rats following alimentary zinc depletion and supplementation. Male Wistar rats, 4 weeks old, were randomly divided into three groups. The rats had free access to a semi-synthetic diet with different amounts of zinc added. Group 1 was given a zinc-free (2 mg zinc/kg) diet, group 2 a 47 mg zinc/kg diet, and group 3 a 60 mg zinc/kg diet. All animals were killed after 4 weeks. Animals from each group were transcardially perfused with a 0.1 % sodium sulphide solution according to the zinc specific Neo-Timm method causing zinc ions to be bound in AMG catalytic zinc-sulphur clusters. We found clusters of zinc ions localized in the mineralizing osteoid in all groups. No immediate differences in AMG staining intensity could be observed between the groups neither in the uncalcified bone nor in the osteoblasts. However, alimentary zinc supply resulted in an increase in the height of the total growth plate in a dose-dependent manner. Zinc ions were also observed in chondrocytes throughout the whole thickness of the articular and the epiphyseal cartilage as well as in the inner layer of the synovial membrane.

Animals↗

PubMed2003

The effect of enterocystoplasty on bone strength assessed at four different skeletal sites in a rat model.

The objective of the study was to investigate bone strength at four different skeletal sites in a chronic animal model of urinary diversion. Young male Wistar rats (120) were allocated randomly to four groups undergoing ileocystoplasty; ileocystoplasty and resection of the ileocecal segment; colocystoplasty; or sham operation (controls). After 8 months the lumbar vertebrae, femora, and tibiae were harvested at necropsy. Bone strength was assessed biomechanically at four different skeletal sites: vertebra L3, femoral middiaphysis, femoral neck, and distal femoral metaphysis. Bone mass and architecture were assessed using standard static histomorphometry of the proximal tibial metaphysis (trabecular bone volume [BV/TV]; trabecular number [Tb.N]) and ash weight. Statistically significant differences of biomechanical parameters between groups were observed at three skeletal sites with corresponding changes in tibial histomorphometry. Isolated ileocystoplasty resulted in decreased maximum load values of L3 (-16.4%; p < 0.0035) and a substantial reduction in tibial BV/TV (-34.7%; p < 0.05). Ileocystoplasty combined with resection of the ileocecal segment led to a significant loss of bone strength of L3 (-32.4%; p < 0.0015) and a dramatic reduction of tibial BV/TV (-45.9%; p < 0.01). Loss of tibial metaphyseal bone mass was predominantly caused by a decrease in Tb.N. (p < 0.01). Colonic augmentation had no significant effect on bone strength or histomorphometric values. In conclusion, this is the first experimental study to demonstrate the relevance of histomorphometrically proven bone loss after enterocystoplasty in terms of biomechanical variables.

Acidosis↗

PubMed2003

Skeletal growth and long-term bone turnover after enterocystoplasty in a chronic rat model.

OBJECTIVE: To investigate skeletal growth and bone metabolism in a chronic animal model of urinary diversion. MATERIALS AND METHODS: Young male Wistar rats (120) were allocated randomly to four groups undergoing: ileocystoplasty, ileocystoplasty and resection of the ileocaecal segment, colocystoplasty, and controls. All animals received antibiotics for 1 week after surgery; half of each group remained on oral antibiotics. Bone-related biochemistry was measured in serum and urine. Dual-energy X-ray absorptiometry and peripheral quantitative computed tomography (pQCT) were used to determine bone mass ex vivo. RESULTS: Most (90%) of the rats survived the study period (8 months); six rats died from bowel obstruction at the level of the entero-anastomosis and four had to be killed because of persistent severe diarrhoea. Vital intestinal mucosa was found in all augmented bladders. There were no differences in bone length and volume. Loss of bone mass was almost exclusively in rats with ileocystoplasty and resection of the ileocaecal segment (-37.5%, pQCT, P < 0.01). There was no hyperchloraemic metabolic acidosis or gross impairment of renal function. Hypomagnesaemia, hypocalcaemia and decreased insulin-like growth factor-binding protein 3 were the only significant findings on blood analysis. Deoxypyridinoline crosslinks in urine were higher in rats with an enterocystoplasty than in controls. CONCLUSIONS: Enterocystoplasty in rats neither impairs skeletal growth nor bone quantity, but leads to significant loss of bone mass when combined with resection of the ileocaecal segment. Rarefaction of the trabecular network is confined to the metabolically highly active cancellous compartment, most likely as a consequence of intestinal malabsorption.

Absorptiometry, Photon↗

PubMed2002

Static histomorphometry of human iliac crest and vertebral trabecular bone: a comparative study.

We recently developed a new, rapid method for conducting static histomorphometry on large histologic sections. This method has now been applied on both iliac crest and lumbar vertebral bone to compare the age-related changes at these two skeletal sites and to investigate the correlation between the histomorphometric measures at the iliac crest and the vertebral body. The material comprised matched sets of unilateral transiliac crest bone biopsies and lumbar vertebral bodies (L-2) from 24 women (19-96 years) and 24 men (23-95 years) selected from a larger autopsy material. Three female subjects (80, 88, and 90 years) had a known vertebral fracture of L-2. The iliac crest biopsies and 9-mm-thick mediolateral slices of half the entire vertebral bodies were embedded in methylmetacrylate, stained with aniline blue, and scanned into a computer with a flatbed image scanner at a high resolution. With a custom-made computer program the following static histomorphometric measures were determined: trabecular bone volume; marrow and bone space star volume; node-strut analysis; trabecular bone pattern factor; trabecular thickness; trabecular number; trabecular separation; and anisotropy of bone and marrow phase. In addition, connectivity density was measured (ConnEulor method). The results showed that the age-related changes in the static histomorphometric measures are generally similar in the iliac crest and the vertebral body, and that these age-related changes are independent of gender. An exception, however, is connectivity density, where the age-related changes are similar for women and men in the vertebral body but significantly different in the iliac crest. Furthermore, the results showed that the histomorphometric measures were weakly intercorrelated between the iliac crest and the vertebral body, despite the generally similar pattern in age-related changes at these two skeletal sites. The highest correlation coefficient was found for trabecular separation (Tb.Sp; r = 0.63). Trabecular bone volume showed a correlation coefficient of r = 0.59. It is concluded that static histomorphometry performed on one skeletal site does not automatically predict static histomorphometric measures at another skeletal site. Therefore, it is recommended that static histomorphometry be performed at the skeletal site of interest-if at all possible.

Adult↗

PubMed2002

Predicting human vertebral bone strength by vertebral static histomorphometry.

The study investigates the relationship between static histomorphometry and bone strength of human lumbar vertebral bone. The ability of vertebral histomorphometry to predict vertebral bone strength was compared with that of vertebral densitometry, and also with histomorphometry and bone strength of iliac crest bone biopsies. The material comprised matched sets of second lumbar vertebrae, third lumbar vertebrae, and two iliac crest bone biopsies from each of 21 women (19--96 years) and 24 men (23--95 years). One of the iliac crest biopsies and 9-mm-thick mediolateral slices of half of each of the entire vertebral bodies (L-2) were used for histomorphometry. The other iliac crest biopsies and the L-3 were destructively tested by compression. High correlation was found between BV/TV or Tb.Sp and vertebral bone strength (absolute value of r = 0.86 in both cases). Addition of Tb.Th significantly improved the correlation between BV/TV and bone strength, and the addition of bone space star volume significantly improved the correlation between Tb.Sp and bone strength (from absolute value of r = 0.86 to absolute value of r = 0.89 in both cases). Bone structure (connectivity density) was not capable of improving the prediction of bone strength of the vertebral body. The correlations between BV/TV of L-2 and bone strength of L-3 were comparable with the correlation obtained by quantitative computed tomography (QCT), peripheral QCT (pQCT), and dual-energy X-ray absorptrometry (DEXA) of L-3 and bone strength of L-3. The iliac crest was found to have low predictive power of vertebral bone strength (iliac BV/TV: r = 0.62; iliac bone strength: r = 0.67). No gender-related differences were found in any of the relationships. It was shown that trabecular bone volume BV/TV and mean trabecular plate separation Tb.Sp are good predictors of vertebral bone strength. The ability of histomorphometry to predict vertebral bone strength was comparable to that of densitometry. Bone structure assessed by connectivity density did not improve the correlation between static histomorphometric measures and vertebral bone strength. No gender-related differences were found in any of the relationships. Neither static histomorphometry nor biomechanical testing of iliac crest bone biopsies is a good predictor of vertebral bone strength.

Adolescent↗

PubMed2002

Age-related differences between thinning of horizontal and vertical trabeculae in human lumbar bone as assessed by a new computerized method.

To investigate whether vertical trabeculae undergo compensatory thickening with age in the human vertebral body, a new computerized method was developed that is able to distinguish between horizontal and vertical trabeculae on normal histological sections. Study subjects included 48 individuals (24 women aged 19-97 years, and 24 men aged 23-95 years). From each L-2, thick frontal sections of half of the vertebra were embedded undecalcified in methylmetacrylate and cut into 10-microm-thick sections. A simple method able to classify image pixels as belonging to either vertical or horizontal trabeculae was developed and implemented in a computer program. The parallel-plate model was modified so that it was able to determine trabecular thickness, number, and separation (Tb.Th, Tb.N, and Tb.Sp) for horizontal and vertical trabeculae separately. The histomorphometric parameters were measured in three different regions: whole section, mid-third, and sub-endplate, for both horizontal and vertical trabeculae. It was found that the trabecular thickness of vertical trabeculae was independent of age in all investigated regions. The thickness of the horizontal trabeculae, in contrast, decreased significantly with age in all these regions. Tb.N decreased significantly with age for both horizontal and vertical trabeculae in all regions. However, the relative loss of trabeculae per unit length was largest for the horizontal trabeculae, whereas the absolute loss of trabeculae per unit length was largest for the vertical trabeculae. Tb.Sp was found to increase significantly with age for both vertical and horizontal trabeculae in all regions. No significant gender-related differences were found. In conclusion, in this study we describe a new, simple method for separation of horizontal and vertical bone tissue. This method has been applied on frontal vertebral sections. Trabecular bone thickness measured with the parallel-plate model showed that the thickness of horizontal trabeculae decreases significantly with age, whereas the thickness of vertical trabeculae did not decrease significantly with age. Furthermore, although the relative loss of trabeculae was larger for horizontal trabeculae than for vertical trabeculae, the absolute loss of vertical trabeculae was higher than that of horizontal trabeculae.

Adolescent↗

PubMed2002

The effect of topically applied salicylic compounds on serotonin-induced scratching behaviour in hairless rats.

There is a strong need for antipruritic substances for treating itch in clinical dermatology. In one recent human study, topically applied acetylsalicylic acid has been described to rapidly decrease histamine-induced itch. We have established a model for periferally elicited pruritus by injecting serotonin into the rostral back area (neck) in rats. Using this model, we aimed to investigate the antipruritic potential of four different salicylic compounds, which all possess different skin penetration characteristics. Eighteen rats were studied for 6 weeks. Prior to serotonin injections (2 mg/ml, 50 micro l), 10 micro l of test substances was applied to a circular area 18 mm in diameter. The four substances were salicylic acid, butyl salicylate, diethylamine salicylate and salicylamide, all solubilized in dimethyl isosorbide to a concentration of 5% w/w. Diethylamine salicylate and salicylamide were previously shown to be slowly absorbed through rat skin in contrast to salicylic acid and butyl salicylate. After serotonin injections, scratching was monitored by video recording for 1.5 h. Compared with the vehicle, a lower number of scratch sequences were seen when diethylamine salicylate (P < 0.001) and salicylamide (P = 0.005) had been applied. The numbers of scratch sequences were lower with diethylamine salicylate and salicylamide than with the vehicle throughout the 1.5-h study period. We conclude that topical application of diethylamine salicylate and salicylamide could suppress serotonin-induced scratching in rats. The antipruritic effect seems to be related to the slow drug release of the two substances. The results may be clinically relevant as serotonin induces itch in humans.

Administration, Topical↗

PubMed2002

Experimental itch in sodium lauryl sulphate-inflamed and normal skin in humans: a randomized, double-blind, placebo-controlled study of histamine and other inducers of itch.

BACKGROUND: Investigations of pruritogenic substances in humans have involved intradermal injections in normal skin; itching of inflamed skin has been little studied. OBJECTIVES: To develop an itch model with provocation of itch in experimentally inflamed skin as well as in normal skin, using subjects as self-controls. METHODS: In 32 non-atopic volunteers aged 21-30 years, the skin of five selected test sites on one volar forearm was pretreated for 24 h with large Finn chambers containing 1% sodium lauryl sulphate (SLS) used as a standard contact irritant to induce inflammation. Twenty microlitres of different pruritogenic substances [histamine, substance P, neurokinin A, neurokinin B, trypsin, platelet-activating factor (PAF) and serotonin] and saline as control were injected intradermally into the inflamed test sites and in corresponding non-treated sites on the opposite forearm. The test individuals scored itch intensity on a visual analogue scale for 20 min, and weal area was then measured. : RESULTS: Histamine and substance P induced itch in both normal and inflamed skin compared with a saline reference. Neurokinin A, trypsin, PAF and serotonin only elicited itch in normal skin, and neurokinin B neither elicited itch in normal skin nor in inflamed skin. Itch was induced in normal and SLS-inflamed skin to a similar magnitude. However, weal area after histamine was significantly (P < 0.001) larger in inflamed skin when compared with normal skin. CONCLUSIONS: Histamine and substance P elicited itch to the same degree in normal skin and inflamed skin pretreated with SLS despite a stronger weal response in inflamed skin. Mediators present in inflamed skin did not potentiate itch, a c-fibre-mediated neuronal response. The weal reaction is based on enhanced vascular permeability (protein extravasation). A greater skin perfusion in inflamed skin may therefore have increased the weal size. We propose an experimental model in humans for testing of itch involving both normal and inflamed skin. The model has the potential for use in evaluating new topical and systemic treatments of itch.

Adult↗

PubMed2002

Decreased trabecular bone biomechanical competence, apparent density, IGF-II and IGFBP-5 content in acromegaly.

BACKGROUND: Earlier studies on the effect of excess growth hormone (GH) on trabecular bone have been conflicting. Since insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) in part mediate the effects of GH, the present study aimed to investigate trabecular bone composition of these growth factors in relation to biomechanical properties in acromegaly. MATERIALS AND METHODS: Trabecular bone biomechanical competence (compression test), apparent density (peripheral quantitative computed tomography, pQCT), and bone matrix contents of calcium (HCl hydrolysis) and IGFs (guanidinium-HCl extraction) were measured in iliac crest biopsies from 13 patients with active acromegaly (two women and 11 men, aged 21-61 years) and 21 age- and sex-matched controls (four women and 17 men, aged 23-64 years). RESULTS: Trabecular bone pQCT was reduced in acromegalic patients compared with controls (P = 0.005), as was biomechanical competence (P < 0.05 for all measures). These parameters were significantly positively correlated in both acromegalic patients and controls. The calcium content of trabecular bone was significantly increased in patients compared with controls. No significant differences were found in trabecular bone content of IGF-I, IGFBP-3, or osteocalcin. However, IGF-II and IGFBP-5 content was decreased (P < 0.001 and P < 0.05, respectively). CONCLUSIONS: The present study demonstrates reduced trabecular biomechanical competence and apparent density in acromegaly, supporting previous observations of an unfavourable effect of chronic excess GH on the axial skeleton. Furthermore, we demonstrate decreased trabecular bone content of IGF-II and IGFBP-5 in these patients. However, we found no direct causal relationship between trabecular bone density and bone content of IGF-system components.

Acromegaly↗

PubMed2002

Topically applied aspirin decreases histamine-induced wheal and flare reactions in normal and SLS-inflamed skin, but does not decrease itch. A randomized, double-blind and placebo-controlled human study.

Topically applied aspirin has recently been reported to decrease histamine-induced itch in human volunteers. Our aim is to confirm this and to study the antipruritic ability of topical aspirin in inflamed skin. In 24 non-atopic volunteers, an inflammatory skin reaction was induced in forearm skin at 5 different sites by sodium lauryl sulphate contained in Finn Chambers. Aspirin 10%, aspirin 1%, mepyramine 5% and vehicle were applied to the inflamed and corresponding non-inflamed areas 20 min before itch induction with intradermal histamine injection. Itch and pain were scored on a visual analogue scale at regular intervals. Wheal and flare areas were measured. No difference in itch intensities was found after application of aspirin, mepyramine and vehicle, but more itch was induced in aspirin and mepyramine pretreated sites in inflamed skin compared to normal skin (p<0.05). In normal skin, flare areas were smaller after pretreatment with aspirin 10% (p<0.05) and mepyramine (p<0.001), as were wheal areas after mepyramine (p<0.01), compared to vehicle pretreatments. In inflamed skin, flare areas were smaller after pretreatment with aspirin 10% (p<0.01) and mepyramine (p<0.001), as were wheal areas after aspirin 10% (p<0.01), aspirin 1% (p<0.05) and mepyramine (p<0.001). We conclude that despite a significant skin penetration as measured by the influence on wheal and flare reactions, topically applied aspirin did not decrease histamine-induced itch in the model used.

Administration, Topical↗

PubMed2002

Sequential treatment with basic fibroblast growth factor and PTH is more efficacious than treatment with PTH alone for increasing vertebral bone mass and strength in osteopenic ovariectomized rats.

The study was designed 1) to determine whether treatment with basic fibroblast growth factor (bFGF) and PTH is more efficacious than treatment with PTH alone for increasing bone mass and strength and improving trabecular microarchitecture in osteopenic ovariectomized rats, and 2) to assess whether prior and concurrent administration of the antiresorptive agents estrogen and risedronate suppresses the bone anabolic response to treatment with bFGF alone and sequential treatment with bFGF and PTH. Three-month-old female Sprague Dawley rats were ovariectomized (OVX) or sham-operated (sham) and maintained untreated for 1 yr. Baseline sham and OVX rats were killed at this time (15 months of age). Groups of rats were injected sc with estrogen (10 microg/kg, 4 d/wk), risedronate (5 microg/kg, 2 d/wk), or vehicle. At the end of the second week of antiresorptive treatment, catheters were inserted into the jugular veins of all rats, and vehicle or bFGF at a dose of 250 microg/kg was injected daily for 14 d. Three groups of rats were killed at the end of bFGF treatment. The remaining rats were continued on their respective antiresorptive therapy and injected sc with vehicle or synthetic human PTH-(1-34) at a dose of 80 microg/kg, 5 d/wk, for 8 wk. Lumbar vertebrae were processed for cancellous bone histomorphometry and biomechanical testing. Ovariectomy resulted in a decrease in vertebral bone mass and strength. Treatment of OVX rats for 14 d with bFGF markedly increased osteoblast surface, osteoid surface, and osteoid volume compared with vehicle treatment of sham and OVX rats. Furthermore, osteoid bridges were observed extending between preexisting trabeculae in bFGF-treated OVX rats. Prior and concurrent administration of estrogen and risedronate did not suppress these bone anabolic effects of bFGF. Treatment of OVX rats with PTH alone increased vertebral cancellous bone mass and strength to the level of vehicle-treated sham rats. Sequential treatment of OVX rats with bFGF and PTH further augmented vertebral bone mass and strength to a level above that observed in OVX rats treated with PTH alone. The improvements in bone mass and strength were associated with an increase in trabecular thickness in OVX rats treated with PTH alone and with an increase in trabecular thickness and node to terminus ratio, an index of trabecular connectivity, in OVX rats treated sequentially with bFGF and PTH. Cotreatment with estrogen and risedronate did not suppress the anabolic response of bone to bFGF and PTH. In fact, a trend for an even greater increase in cancellous bone mass and node to terminus ratio was observed in OVX rats treated with risedronate, bFGF, and PTH. These findings indicate that sequential treatment with bFGF and PTH is more efficacious than treatment with PTH alone for increasing bone mass and strength and improving trabecular microarchitecture in osteopenic OVX rats.

Aging↗

PubMed2001

Influence of a low calcium and phosphorus diet on the anabolic effect of human parathyroid hormone (1-38) in female rats.

Parathyroid hormone (PTH) or synthetic N-terminal PTH fragments administered intermittently have been established as anabolic agents in animal and human bones. In the present study, the influence of a low calcium diet on the anabolic effect of human PTH(1-38) [hPTH(1-38)] was investigated. Forty-eight 10-week-old female Sprague-Dawley rats were randomly assigned to a diet with a low calcium content (LCa) or a diet with the recommended amount of calcium (RCa). After an adaptation period of 15 days, the rats were randomly assigned to hPTH(1-38) treatment (+LCa/+RCa) or vehicle only (-LCa/-RCa) for an additional 14 days. Total bone mineral density (BMD) values of several bones were determined using quantitative computed tomography and from ratios of ash weight to volume. Biomechanical competence of the fourth lumbar vertebrae and of the right femora was assessed. An anabolic effect could be detected in both PTH-treated groups. However, the bones of the +LCa group showed significantly lower BMD and also a diminished increase in maximal breaking force compared with those of the +RCa group. The study demonstrates that the anabolic effect of hPTH(1-38) is blunted by the LCa diet. This suggests that, during PTH treatment, dietary calcium intake is critical.

Animals↗

PubMed2001

The positive effects of zinc on skeletal strength in growing rats.

The aim of the present study was to assess the skeletal effects of alimentary zinc depletion and supplementation in an animal model of intact, growing rats. The study was planned as a dose-response study. Thirty-six male Wistar rats, 4 weeks old, were divided into three groups of 12 rats each. The rats had free access to a semisynthetic diet with different amounts of zinc added. Group 1 was given a zinc-free diet containing 2 mg zinc/kg, group 2 was given a normal-zinc diet containing 47 mg zinc/kg; and group 3 was given a zinc-supplemented diet containing 60 mg zinc/kg. All animals were killed 4 weeks after initiation of the experiment and the right femora were removed. The biomechanical effects were measured at the following skeletal sites: femoral diaphysis; femoral neck; and distal femoral metaphysis. In addition, static histomorphometry was performed at the middiaphyseal region. Biomechanical testing revealed a significant zinc-induced increase in bone strength at all sites investigated. It also showed that zinc influenced bone strength in a dose-dependent manner except at the distal metaphysis, where there was no significant difference between the group fed normal-zinc diet and the group fed a hyper-zinc diet. Zinc also improved the rates of growth in the rats. The body weights and length of femora increased dose-dependently. Static histomorphometry showed that zinc exerted its main effect on the periosteal envelope, thereby increasing bone area, tissue area, and axial moment of inertia. We conclude that alimentary zinc supplementation in growing rats induces an increase of bone strength in both the femoral neck and the femoral diaphysis. These results further support the view that zinc has a positive effect on bone metabolism which mimics that of growth hormone (GH) or insulin-like growth factor 1 (IGF-1).

Animals↗

PubMed2001

Sequential treatment with basic fibroblast growth factor and parathyroid hormone restores lost cancellous bone mass and strength in the proximal tibia of aged ovariectomized rats.

This study was designed to determine whether sequential treatment with basic fibroblast growth factor (bFGF) and parathyroid hormone (PTH) can restore lost cancellous bone mass and strength at a severely osteopenic skeletal site in aged ovariectomized (OVX) rats. Female Sprague-Dawley rats were subjected to sham surgery or ovariectomy at 3 months of age and maintained untreated for the first year after surgery. At 15 months of age, groups of baseline control and OVX rats were killed and catheters were inserted in the jugular veins of all remaining rats. Two groups of OVX rats were injected intravenously (iv) daily with bFGF for 14 days at a dose of 200 microg/kg body weight. At the end of bFGF treatment, one group was killed whereas the other group was subjected to 8 weeks of treatment with synthetic human PTH 1-34 [hPTH(1-34)] consisting of subcutaneous (sc) injections 5 days/week at a dose of 80 microg/kg. Another group of OVX rats was treated iv with vehicle for 2 weeks followed by treatment with PTH alone for 8 weeks. Other groups of sham-operated control rats and OVX rats were treated iv and sc with vehicle alone. The right proximal tibia from each rat was processed undecalcified for quantitative bone histomorphometry and the left proximal tibia was subjected to biomechanical testing. Baseline and vehicle-treated OVX rats were severely osteopenic because their tibial cancellous bone volumes were less than 5% compared with mean values of 20.3% and 15.0% in baseline and vehicle-treated control rats, respectively. Treatment of OVX rats for 2 weeks with bFGF alone did not significantly increase tibial cancellous bone volume but induced marked increases in osteoid volume, osteoblast surface, and osteoid surface. Sequential treatment of aged OVX rats with bFGF and PTH increased tibial cancellous bone volume (15.1%) and load to failure to at least the level of vehicle-treated control rats. Tibial cancellous bone volume (10.8%) and load to failure also were significantly increased by treatment with PTH alone, and these variables were not significantly different from those of OVX rats treated with bFGF + PTH. However, tibial ash density was significantly greater in OVX rats treated sequentially with bFGF and PTH compared with OVX rats treated with PTH alone. Our findings suggest that sequential treatment with bFGF and PTH may be useful for restoration of lost cancellous bone in the severely osteopenic, estrogen-deplete skeleton, but it cannot be concluded with certainty that this sequential treatment has a greater bone restorative effect than treatment with PTH alone.

Aging↗

PubMed2000

DAX-1 functions as an LXXLL-containing corepressor for activated estrogen receptors.

We have discovered that the orphan receptor DAX-1 (NROB1) interacts with the estrogen receptors ERalpha and ERbeta. Interaction occurs with ligand-activated ERs in solution and on DNA and is mediated by the unique DAX-1 N-terminal repeat domain. Each of the three repeats contains a leucine-rich receptor-binding motif, known as the LXXLL motif, which is usually found in nuclear receptor coactivators. We have demonstrated that DAX-1 functions as an inhibitor of ER activation in mammalian cells and suggest a mechanism involving two sequential events, occupation of the ligand-induced coactivator-binding surface and subsequent recruitment of corepressors. Accordingly, we propose that DAX-1 itself acts as a corepressor for ERs. Because DAX-1 is coexpressed with ERs in reproductive tissues, these interactions could play significant roles by influencing estrogen signaling pathways. Our results point at functional similarities between DAX-1 and the orphan receptor SHP (NROB2) in that they have acquired features of transcriptional coregulators that are unique for members of the nuclear receptor family.

DAX-1 Orphan Nuclear Receptor↗