摘要:

AbstractAn inbred strain of transgenic mice that expressed a mutated gene for type I procollagen and that developed spontaneous fractures was used to study the effects of age on the phenotype of fragile bones. The mutated gene has been shown to cause depletion of type I collagen in the transgenic mice because it generated shortened proα1(I) chains that bound to and produced degradation of normal proα1(I) chains synthesized from the endogenous mouse COL1A1 gene. For this study, femurs from transgenic mice ranging in age from 0.5–24 months were examined. The results demonstrated that the level of expression of the transgene was independent of age. Femurs from the transgenic mice were more fragile than controls at 0.5 and 1.5 months, they were biomechanically normal at 6 months, and then they were more fragile at 24 months. The normal biomechanical properties of the bones from the transgenic mice at 6 months were accompanied by periosteal thickening of the bones together with an increase in the collagen content that was not associated with a proportional increase in mineral content. The results indicated that the effects of age, mechanical stress, and hormonal action produced a biological compensation for the mutated gene by either increasing collagen synthesis of bone, decreasing collagen degradation, or both. The biological compensation was apparently lost by 24 months when the outer diameters of the femurs were again less than in controls, the cortical thickness was about the same as in controls, and both the collagen and mineral contents were less than controls. The results demonstrated that bone fragility in the transgenic mice paralleled the age‐dependent phenotype of human osteogenesis imperfecta. Therefore the transgenic mice appeared to be useful models for osteogenesis imperfecta. They also may be useful models for some forms of osteopo

ISSN:0884-0431    

DOI:10.1002/jbmr.5650101202

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

年代:1995

数据来源: WILEY

摘要:

AbstractWe evaluated the effects of recombinant insulin‐like growth factor‐I (IGF‐I) and growth hormone (GH) on calciotropic hormones and bone turnover markers in 16 healthy elderly women 71.9 ± 1.3 years of age (mean ± SEM). Subjects consumed a fixed diet providing 1000 mg of calcium and 0.9 g/kg of protein for 10 days before starting baseline 24‐h urine and blood collections. Specimens were collected for 6 consecutive days before initiating subcutaneous injections of GH (25 μg/kg/day,n= 5) and IGF‐I at 60 μg/kg b.i.d. (high‐dose,n= 5) or at 15 μg/kg b.i.d. (low‐dose,n= 6) for 28 days. Resorption markers included urine hydroxyproline (OHP), total pyridinolines (PYD), and N‐telopeptide; formation markers included osteocalcin, skeletal alkaline phosphatase (sALP), and type I procollagen carboxy‐terminal extension peptide (CICP). For each subject, baseline daily turnover markers varied substantially (CV = 16–22%). With GH and high‐dose IGF‐I, resorption and formation markers increased progressively to maximum levels at day 21. For GH, the increase in day 21 PYD, N‐telopeptide, osteocalcin, and CICP was 143, 111, 53, and 81%, respectively (p<0.06–0.02). For high‐dose IGF‐I, these increases were 108, 81, 77, and 111% (p<0.02–0.002). However, with low‐dose IGF‐I, no change was observed in resorption markers while osteocalcin and CICP increased progressively (day 21, % increases = 88 ± 51, 36 ± 14). Twenty‐four hour urine collections during the last days of baseline and of study drug were taken as six 4 h aliquots. When deoxyPYD was measured on these samples in the low‐dose IGF‐I group, a significant increase was observed only on the 0800–1200 h aliquot. Serum phosphorus concentrations increased with GH (21.2 ± 3.3%) and high‐dose IGF‐I (8.8 ± 3.6%) by day 21 but actually decreased by day 28 (−9.7 ± 2.7,p<0.02) with low‐dose IGF‐I. Urinary phosphorus excretion decreased with high‐dose IGF‐I only. Twenty‐four hour calcium excretion increased with all treatments. These results indicate that both GH and high‐dose IGF‐I activate remodeling osteons. By contrast, low‐dose IGF‐I may directly increase osteoblastic function with only a minimal increase in bone resorption and may therefore provide a useful means to increase bone mass. The results also suggest some of the GH action on renal phosphorus handling represents a direct action of GH on the nephron which does not involve the intermediacy of IGF‐I. Finally, even under controlled conditions bone turnover markers exhibit substantial daily variation so that a very l

ISSN:0884-0431    

DOI:10.1002/jbmr.5650101203

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

年代:1995

数据来源: WILEY

摘要:

AbstractWe compared the effect of administration of recombinant human insulin‐like growth factor‐1 (rhIGF‐1) alone or the rhIGF‐1/IGF binding protein‐3 (IGFBP‐3) complex on osteopenia in rats. Female Sprague‐Dawley rats (8 months old) underwent combined ovariectomy and bilateral sciatic neurectomy (OVX‐NX) or sham operation only. After 2 months, the OVX‐NX animals were injected subcutaneously with rhIGF‐1 alone or with rhIGF‐1/IGFBP‐3 equimolar complex for 4 weeks. The IGF‐1 contents and dose were 0.3 mg/kg of body weight (BW) three times/week, 3 mg/kg of BW once/week, or 3 mg/kg of BW three times/week. At the end of the experiment, the 4th and 5th lumbar vertebrae (L4, L5) and the proximal tibiae were removed after tetracycline labeling, and histomorphometrical analyses were performed on undecalcified sections using Villanueva's staining. The cancellous bone volume at L5 significantly increased by thickening of the trabecular width in rats treated with the complex. However, the increase in the values at the proximal tibia was not significant. The bone formation rates (BFR/BS) in the lumbar vertebrae of rats treated with the complex three times a week at doses of 0.3 mg/kg of BW and 3 mg/kg of BW were both significantly increased but the parameter increase was less marked with the dose of 3 mg/kg of BW once/week. The BFR/BS did not increase significantly in animals treated with IGF‐1 alone. These findings clearly demonstrated that the effect of systemically administered rhIGF‐1 on bone formation was markedly potentiated when combined with IGFBP‐3 in estrogen deficiency combined with reduced activity. The action of IGF‐1 was less potent on the bone in paralyzed limbs. The action of rhIGF‐1/IGFBP‐3 on trabecular bone appeared to depend not only on the dose but also on the frequency of administration

ISSN:0884-0431    

DOI:10.1002/jbmr.5650101204

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

年代:1995

数据来源: WILEY

摘要:

AbstractTo investigate the potential use of growth hormone (GH) in Activate‐Depress‐Free‐Repeat treatment of postmenopausal osteoporosis, we measured changes in serum levels of biochemical markers of bone turnover, insulin‐like growth factor‐I (IGF‐I), calciotropic hormones, and bone mineral density in 40 postmenopausal women with osteopenia (ages 52–73 years) in response to 7 days of treatment with either placebo or GH (0.05, 0.10, or 0.20 IU/kg/day) administered subcutaneously in the evening. GH treatment increased serum osteocalcin (p<0.01) and C‐terminal type‐I procollagen propeptide (p<0.01) and also serum levels of type‐I collagen telopeptide (p<0.001), fasting urinary hydroxyproline/creatinine (p<0.05), pyridinoline/creatinine (p<0.05), and deoxypyridinoline/creatinine (p<0.01) in a dose‐dependent fashion. Even the lowest dose of GH tested induced a significant increase in these parameters; however, the effects were transient lasting only 1–2 weeks. In the highest dose group, however, a somewhat prolonged effect (30 days) on serum osteocalcin was observed. Furthermore, GH increased serum levels of IGF‐I, insulin, and tri‐iodothyronin. No effect on serum 1,25‐dihydroxyvitamin D3or parathyroid hormone could be demonstrated. Adverse effects were mainly related to fluid retention. They were clearly dose‐dependent and rapidly reversible. In conclusion, short‐term GH treatment stimulates bone formation and bone resorption in pos

ISSN:0884-0431    

DOI:10.1002/jbmr.5650101205

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

年代:1995

数据来源: WILEY

摘要:

AbstractParathyroid hormone‐related protein (PTHrP), a likely mediator for humoral hypercalcemia of malignancy, is also synthesized in various normal tissues. In the kidney, PTHrP, mainly detected in proximal and distal tubules, has been shown to stimulate proliferation of rat mesangial cells in culture. Experiments were carried out to investigate the possible mitogenic effect of PTHrP in cultures of rabbit proximal tubule cells (PTC). Immunocytochemical analysis, using antihuman (h)PTHrP antibodies to (38–64) and (107–111) epitopes in the PTHrP molecule, showed strong cytoplasmic staining in PTC and in proximal tubule‐like LLC‐PK1cells. PTC secreted immunoreactive PTHrP (54.8 ± 7.0 fmol/106cells) into the culture medium. Human PTHrP(1–141) stimulated proliferation in subconfluent cultures of these cells dose‐dependently. This effect was similar to that induced by [Tyr34]hPTHrP(1–34) amide (hPTHrP[1–34]), hPTHrP(1–86), and bovine (b)PTH(1–34), while hPTHrP(38–64) amide, hPTHrP(107–111) amide, and hPTHrP(107–139) amide were ineffective. Addition of anti‐hPTHrP neutralizing antibodies to (1–34), (38–64), and (107–111) epitopes of PTHrP decreased PTC growth. The mitogenic effect of these agonists was abolished in confluent PTC. In contrast, [Nle8,18, Tyr34]bPTH(3–34) amide (bPTH[3–34]) increased DNA synthesis in either subconfluent or confluent PTC. In LLC‐PK1cells, which also secreted PTHrP and are devoid of PTH receptors, none of these peptides affected proliferation. Forskolin (10 μM) or H‐8 (2 μM), a protein kinase A inhibitor, did not affect basal or hPTHrP(1–34)‐stimulated DNA synthesis, respectively, in subconfluent PTC. On the other hand, 10 nM staurosporine and 100 nM calphostin C, protein kinase C (PKC) inhibitors, blunted the effects of hPTHrP(1–34) or bPTH(3–34) on DNA synthesis in these cells. These studies suggest that PTHrP may function as an autocrine factor in the regulation of p

ISSN:0884-0431    

DOI:10.1002/jbmr.5650101206

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

年代:1995

数据来源: WILEY

摘要:

AbstractBone resorption can be evaluated by measuring the urinary excretion of collagen type I cross‐linked N telopeptides (NTx). Since it is difficult to obtain (and verify) 24 h urine collections from patients, untimed spot urines are more practical. Such measurements, however, need correction for urine dilution and potentially may vary with collection time since a circadian rhythm in bone metabolism has been reported. This study examined cross‐link excretion in urine voids serially collected during a 24 h period from subjects living their normal daily routine (as opposed to a controlled hospital setting). This mimics the situation for walk‐in patients visiting a clinician and providing a spot urine. A total of 35 dentists (20 males, 15 females) collected all urine voids separately over a 24 h period. Urines were analyzed for creatinine and NTx. The effects of time of day on the excretion rates of these metabolites (in nmol/h) and on the cross‐link:creatinine ratio were assessed. A circadian rhythm was evident in the excretion rate of creatinine with a peak in the late afternoon (18% higher than the 24 h mean,p= 0.0004). The NTx excretion rate peaked in the morning (9% higher than the 24 h mean) but this latter rhythm was not statistically significant (p= 0.31). The NTx:creatinine ratio fell during the day from a high (122% of the 24 h mean) in the early morning to a low in the early evening. This rhythm in the NTx:creatinine ratio in untimed spot urines was statistically significant (p<0.0001). In conclusion, the NTx:creatinine ratio in spot urines from adult outpatient subjects showed a significant circadian rhythm. Variations in creatinine excretion were the primary cause. Time of day should, therefore, be taken into account when comparing test results of spot urines with normal ranges or with other samples from the same

ISSN:0884-0431    

DOI:10.1002/jbmr.5650101207

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

年代:1995

数据来源: WILEY

摘要:

AbstractGap junction intercellular communication (GJIC) may be related to coordinating the function of osteoblasts during bone mineralization. Since an alkaline pH supports mineral deposition while an acidic pH promotes mineral dissolution, it was investigated whether GJIC is altered by changes in extracellular pH (pHo) Functional GJIC was assessed by fluorescent dye transfer after microinjection, and connexin protein abundance was examined by immunoprecipitation and immunoblotting in MC3T3‐E1 cells, a model of osteoblast‐like cells. The percent of cells coupled by GJIC was found to be 40.7% (24 of 59 injected cells) at pH 6.9, 72.2% (26 of 36) at pH 7.2, and 92.8% (26 of 28) at pH 7.6. A decrease in GJIC was detectable by 30–60 minutes of exposure to a pHoof 6.9. Decreased gap junction communication was also found in cells after 3, 8, and 24 h of incubation in a bicarbonate‐CO2system at an ambient pH of 6.9. Connexin protein abundance experiments showed that at after exposure to a pH of 6.9 for 2.75 h, the specific band(s) at 41–43 kD were fainter compared with these same band(s) at pH 7.2 and 7.6. There was no significant difference in band densities at pH 7.2 and 7.6. Determination of intracellular pH (pHi) showed that it was similar to pHoafter 2.75 h of incubation at each ambient pH. When pHiwas clamped at 6.9 or 7.2, there was a time‐dependent decrease in the gap junction coupling frequency at a pHiof 6.9 when pHowas 7.2. Steady‐state mRNA levels were decreased at pHo6.9 but were unchanged at either pHo7.2 or 7.6. Our conclusions are that (1) longer incubations (≥2.75 h) at low pHodecrease GJIC which in part may be due to a decrease in connexin protein abundance perhaps as a result of a decrease in connexin steady‐state mRNA expression; (2) GJIC inhibition or augmentation found at low and high pHo, respectively, suggests that gating of the GJ channel by pH may also occur; (3) pHo‐induced alterations in GJIC in the MC3T3‐E1 osteoblastic model are related to conco

ISSN:0884-0431    

DOI:10.1002/jbmr.5650101208

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

年代:1995

数据来源: WILEY

摘要:

AbstractTo assess the influence on the risk of hip fractures in men of medical conditions associated with secondary osteoporosis or with an increased likelihood of falling, we conducted a population‐based nested case‐control study among the 232 Rochester, Minnesota, men with an initial hip fracture due to moderate trauma in 1965–1989 and an equal number of age‐matched control men from the general population. Information on selected medical and surgical conditions and certain behavioral risk factors prior to fracture (or comparable index date for controls) was obtained from inpatient and outpatient medical records in the community that averaged over 36 years in duration. After adjusting for age, obesity, and inactivity, disorders linked with secondary osteoporosis were associated with a 2‐fold increase in the risk of hip fracture in men (odds ratio [OR] 2.3; 95% confidence interval [CI]1.3–4.3), while conditions linked with an increased risk of falling were associated with almost a 7‐fold increase in risk (OR 6.9; 95% CI 3.3–14.8). These factors together appeared to account for about 72% of the hip fractures in men. Increased attention must be paid to these conditions which, in aggregate, are very common in elderly men and lead to a substantial increase in the risk of hip fracture with its devastating sequelae of death, disab

ISSN:0884-0431    

DOI:10.1002/jbmr.5650101209

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

年代:1995

数据来源: WILEY

摘要:

AbstractThe epidemiologic patterns of vertebral and femoral fractures are sufficiently different to suggest that they represent distinct disorders (type I versus type II osteoporosis) although osteopenia is common in both. To determine whether differences in femoral geometry, one of the main determinants of bone quality, might contribute to the heterogeneity in osteoporotic fractures, we obtained dual energy X‐ray absorptiometry scans on 210 women age 60 or older, including 105 type 1 fracture cases, 30 type II patients, and 75 controls. Hip axis length, measured on the scan printout, was significantly increased (p<0.01) in hip fracture patients compared with women with postmenopausal osteoporosis, whereas femoral neck density (BMD) was equal in both groups. The best discrimination between both fracture types was obtained by a logistic regression model based on age and axis length. Adding BMD to the model did not improve the discriminative power (p= 0.67). These data provide further evidence that geometric characteristics may be implicated in hip fracture risk. Furthermore, these findings suggest that an increase in hip axis length may predispose osteopenic subjects to a femoral localization of fragility fractures, consistent with the postulated heterogeneity in the pathogenesis of osteoporotic fracture

ISSN:0884-0431    

DOI:10.1002/jbmr.5650101210

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

年代:1995

数据来源: WILEY

摘要:

AbstractThe organic matrix of renal calculi has long been considered to influence the crystal growth that occurs in these pathological mineral deposits. Recent advances in characterizing individual organic moieties from mineralized tissues in general and the combined use of antibodies raised against these molecules with different immunocytochemical approaches have allowed their precise distribution to be visualized in a variety of normal and pathological mineralized tissues. The present ultrastructural study reports on the epithelial expression and extracellular localization of several noncollagenous proteins in rat and human kidney stones using high‐resolution colloidalgold immunocytochemistry. To this end, we have examined in an ethylene glycol‐induced calcium oxalate model of urolithiasis in the rat, and in human kidney stones, the distribution of certain noncollagenous and plasma proteins known to accumulate in bone and other mineralized tissues that include osteopontin, osteocalcin, bone sialoprotein, albumin, and α2HS‐glycoprotein. Of these proteins, osteopontin (uropontin) and osteocalcin (or osteocalcin‐related gene/protein) were prominent constituents of the calcium oxalate‐associated crystal “ghosts” found in the nuclei, lamellae, and striations of the organic matrix of lumenal renal calculi in the rat and of small crystal ghosts found within epithelial cells. Immunocytochemical labeling for both proteins of the content of secretory granules in tubular epithelial cells from treated rats, together with labeling of a similarly textured organic material in the tubular lumen, provides evidence for cosecretion of osteopontin and osteocalcin by epithelial cells, their transit through the urinary filtrate, and ultimately their incorporation into growing renal calculi. In normal rat kidney, osteopontin was localized to the Golgi apparatus of thin loop of Henle cells. In human calcium oxalate monohydrate stones, osteopontin was similarly detected in the lamellae and striations of the organic matrix. Based on these data, it is proposed that during urolithiasis, secretion of osteopontin (uropontin) and osteocalcin (or osteocalcin‐related gene/protein), and the subsequent incorporation of these proteins into kidney stone matrix, may influence the nucleation, growth processes, aggregation, and/or tubular adhesion of renal calculi in m

ISSN:0884-0431    

DOI:10.1002/jbmr.5650101211

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

年代:1995

数据来源: WILEY