PubMed Health⌕ Search

Biomedical subjects

G C Nicholson

Publications and source records attributed to G C Nicholson.

At least 55 records · Page 3Linked to original sources
PubMed1996

Osteoblast-mediated effects of zinc on isolated rat osteoclasts: inhibition of bone resorption and enhancement of osteoclast number.

Zinc is an important element in biology yet little is understood of its role in bone cell metabolism and function. This study examined the effects of zinc on osteoclast (OC) function in cultures derived from neonatal rats and in cocultures of OC and UMR 106-01 osteoblast-like cells (UMR/OC cocultures). Treatment with zinc (10(-12)-10(-4) mol/L) had no effect on either bone resorption or the number of multinucleate cells positive for tartrate-resistant acid phosphatase (TRACP + ve MNC) in OC cultured for 24 h on bone slices. However, in UMR/OC cocultures, 10(-4) mol/L zinc (but not lower concentrations) decreased resorption pit formation by approximately 50% and increased TRACP + ve MNC number by approximately 40%. When osteoblast-like cells were pretreated with zinc prior to, but not during, coculture with OC, effects on TRACP + ve MNC and pit number persisted, although the effect was reduced. Zinc treatment also inhibited resorption and stimulated TRACP and calcitonin receptor (CTR) + ve MNC numbers in long-term (96-120 h) UMR/OC cocultures. Our results indicate that zinc increases TRACP + ve CTR + ve MNC numbers yet inhibits bone-resorbing activity, and that these effects are dependent on the presence of osteoblastic cells. Zinc is abundant in bone and may act as a local regulator of bone cells.

Acid Phosphatase↗
PubMed1996

Biochemical and radiologic improvement in Paget's disease of bone treated with alendronate: a randomized, placebo-controlled trial.

PURPOSE: The potent bisphosphonates offer great promise in the management of Paget's disease of bone, but are currently available only as parenteral preparations in most countries. There is a need for a well-tolerated, oral therapy. Furthermore, none of the currently available therapies have been rigorously demonstrated to heal the lytic bone lesions characteristic of this condition. Alendronate is a potent new oral aminobisphosphonate that has shown promising effects on Paget's disease in preliminary studies. METHODS: We report a double-blind, randomized comparison of oral alendronate 40 mg/day and placebo over 6 months in 55 patients with Paget's disease. Efficacy was determined from measurements of biochemical indices of bone turnover (serum alkaline phosphatase and urine N-telopeptide) and blinded radiologic assessment of lytic bone lesions. RESULTS: N-telopeptide excretion declined by 86% and serum alkaline phosphatase by 73% in patients receiving alendronate, but remained stable in patients receiving placebo (P < 0.001 between groups for both indices). Responses were similar whether or not patients had previously received bisphosphonate treatment. Alendronate treatment normalized alkaline phosphatase in 48% of patients. Forty-eight percent of alendronate-treated patients showed radiologic improvement in osteolysis whereas in the placebo group only 4% improved (P = 0.02 for between-groups comparison). No patient in either group showed worsening of osteolysis. Bone histomorphometry indicated that alendronate tended to normalize turnover indices. There was no evidence of abnormal mineralization in bone biopsies taken from 12 alendronate-treated subjects. The treatment was well tolerated. CONCLUSION: Oral alendronate appears to be a safe and effective therapy for Paget's disease and results in healing of lytic bone lesions.

Administration, Oral↗
PubMed1996

Clinical, biochemical, hematologic, and radiographic responses in Paget's disease following intravenous pamidronate disodium: a 2-year study.

An intravenous dosage schedule using pamidronate disodium, based on biochemical severity, was used to treat 71 patients with Paget's disease who had no previous bisphosphonate treatment. Disease severity was stratified by fasting hydroxyproline excretion (HypE): Group (Gp) I (mild disease; HypE < 5.0 mumol/LGF) received a total dose of 120 mg; Gp II (moderate; HypE 5.00-9.99) received 180 mg; and Gp III (severe; HypE > or = 10) received 240 mg. Within each group patients were randomly allocated to receive daily 30 mg or 60 mg infusions. Observations for 2 years included pain scores, indices of bone turnover, and radiology of lytic lesions. There was no difference in biochemical responses, or in the percentage of patients with early fever, between the 30 mg and 60 mg daily subgroups; for convenience, 60 mg infusions are recommended. Neutrophils and total white cell counts were both significantly below baseline 4 days after the first infusion; lymphocytes were significantly reduced by day 2; and all three measures had returned to within the reference range by day 6. Remission was assessed at 6 months, when both plasma alkaline phosphatase (ALP) and HypE had reached stable nadirs. Increasing severity was associated with increasing resistance to suppression of HypE at 6 months to within the reference range: Gp I, 87%; Gp II, 44%; and Gp III, 0% (p < 0.0001 by chi-square test). Biochemical relapse at 2 years (defined as ALP 50% above the 6 month level) was also dependent on initial disease severity (Gp I, 6%; GpII, 39%; Gp III, 62%; p < 0.0005 by chi-square test). There was no association between time to relapse and either initial dose or log dose. Radiologic lytic lesions (in 22 patients) were all in remission at 3 months; however, relapse rates at 2 years appeared to be severity-dependent: Gp I, 13%; Gp II, 43%; and Gp III, 57% (n.s. by chi-square test). Remission rates based on a fall to < 50% of pretreatment of either HypE or ALP were more in accord with lytic lesion remission rates than were rates based on HypE falling to within the reference range. Pamidronate produced a significant reduction from baseline in Pagetic bone, Pagetic joint, and unrelated musculoskeletal pain in the first 6 months (p < 0.0001). From 0 months to 2 years the maintenance of improvement in bone pain (p < 0.005) and joint pain (p < 0.05) was significantly better than in unrelated pain. Pamidronate is a safe, welltolerated, and effective treatment for Paget's disease. In spite of larger dosage in severe disease, increasing severity was associated with resistance to normalization of biochemistry and a higher incidence of biochemical and radiological relapse at 2 years. Our current dosage recommendation would be for two 60 mg infusions for mild disease (Gp I); and four 60 mg infusions for moderate disease (Gp II). Severe disease (Gp III) remains a challenge; regardless of dosage, the majority of patients will be in relapse 2 years after a single course of treatment.

Aged↗
PubMed1996

Body fat distribution and non-insulin-dependent diabetes: comparison of a fiber-rich, high-carbohydrate, low-fat (23%) diet and a 35% fat diet high in monounsaturated fat.

The effects of a fiber-rich, high-carbohydrate, low-fat (HCLF) diet and a modified-fat (MF) diet high in monounsaturated fat on body fat distribution were examined by dual-energy X-ray absorptiometry (DXA) in 16 subjects with non-insulin-dependent diabetes (NIDDM) during a randomized crossover study. Subjects lost similar amounts of body fat consuming the HCLF and MF diets (-0.83 +/- 0.37 and -0.87 +/- 0.40 kg, respectively) despite a marked difference in total fat consumption. With the MF diet, the ratio of upper- to lower-body fat (UF:LF) remained unchanged because fat was lost proportionately from the upper and lower body. In contrast, with the HCLF diet, a disproportionate loss of lower-body fat caused the UF:LF to increase. The effects of diet on regional body fat loss were significant (P < 0.05, two-factor repeated-measures ANOVA).

Absorptiometry, Photon↗
PubMed1995

Dietary composition, body weight, and NIDDM. Comparison of high-fiber, high-carbohydrate, and modified-fat diets.

OBJECTIVE: To examine the effects of a high-carbohydrate low-fat (HCLF) and a modified-fat (MF) diet on body weight and metabolic control in subjects with non-insulin-dependent diabetes mellitus (NIDDM) living at home. RESEARCH DESIGN AND METHODS: Twenty-four NIDDM patients followed HCLF and MF diets alternately and in random order for a 3-month period while at home, with a 1-month baseline and washout between diets. Before and after each diet, fasting glucose and lipids, HbA1c, blood pressure, and body weight were measured. Dietary preferences were assessed by questionnaire. RESULTS: Subjects consumed 50% of energy as carbohydrate and 23% as fat on the HCLF diet and 40% of energy as carbohydrate and 36% as fat (over half of which was monounsaturated fat) on the MF diet. Subjects lost weight on both HCLF and MF diets (mean loss 0.7 and 1.3 kg, respectively). Although the MF diet resulted in a small decrease in fasting glucose levels, there was no significant change in HbA1c. Similarly, there was no significant difference between the diets in changes in blood pressure or fasting blood lipids. Most subjects (65%) preferred the MF diet. CONCLUSIONS: Although the MF diet is not a low-fat diet, it did not appear to facilitate weight gain in subjects with NIDDM living at home. The MF diet provides an alternative for individuals unable to comply with HCLF diets.

Blood Glucose↗
PubMed1994

Carboxyl-terminal parathyroid hormone-related protein inhibits bone resorption by isolated chicken osteoclasts.

Carboxyl-terminal peptides from parathyroid hormone-related protein (PTHrP) have been studied for their effect on bone resorption by osteoclasts isolated from 15 day embryonic chickens. Basal bone resorption by chicken osteoclasts was directly inhibited by chicken and human PTHrP-(107-139) and the pentapeptide PTHrP-(107-111). The chicken and human analogs were equipotent. Both the number of resorption pits and the total area resorbed per bone slice were reduced by PTHrP-(107-139), but it did not alter the size of individual resorption pits. Resorption stimulated by hPTH-(1-34) in cocultures of chicken osteoclasts with osteoblasts was also inhibited by cPTHrP-(107-139) but required a concentration three orders of magnitude greater than that required to inhibit basal resorption in cocultures or cultures of isolated osteoclasts. The finding of resorption inhibitory activity by PTHrP-(107-139) in avian as well as mammalian species strengthens the hypothesis that carboxyl-terminal PTHrP may act as a paracrine regulator of bone cell activity.

Animals↗
PubMed1994

Tartrate resistant acid phosphatase activity in rat cultured osteoclasts is inhibited by a carboxyl terminal peptide (osteostatin) from parathyroid hormone-related protein.

A carboxyl-terminal peptide sequence ("osteostatin") from parathyroid hormone related protein has been shown to have an inhibitory effect on osteoclastic bone resorption--an action opposite to its amino-terminal sequence. In this study, we proposed that inhibition of osteoclastic bone resorption by osteostatin was associated with reduction of tartrate resistant acid phosphatase (TRAcP) activity in osteoclasts. Our results have indicated that osteostatin reduced TRAcP activity in a dose dependent manner. This effect of osteostatin was both sensitive (half maximal effect approximately 5 x 10(-13) M) and potent (maximum inhibition approximately 50% of control). In the first 90 min of treatment, however, reduction of TRAcP activity was erratic but became persistent and progressive when the time course was extended. Moreover, throughout the experimental period the levels of TRAcP activity in the culture medium had fallen significantly. It appears that osteostatin has a biphasic effect on TRAcP activity, inhibiting its secretion and either suppressing its synthesis or increasing its degradation. In addition, osteostatin induced rapid cellular retraction of both human and rat cultured osteoclasts, which was morphologically distinct from that produced by calcitonin.

Acid Phosphatase↗
PubMed1994

Osteoblasts mediate thyroid hormone stimulation of osteoclastic bone resorption.

Thyroid hormones increase bone turnover in vivo and stimulate bone resorption in vitro. Clinical states associated with excess circulating thyroid hormone levels are known to produce osteoporosis. To determine the effect of T3 on bone resorption, we used an isolated rat osteoclast bone resorption assay in the absence or presence of added osteoblasts. This makes it possible to distinguish between direct and indirect effects of thyroid hormones on osteoclasts. In short settlement osteoclast cultures, which contain relatively few osteoblasts, 24-h treatment with T3 (10(-10)-10(-8) M) produced no stimulation of bone resorption. However, after 48-h incubation in the presence of T3, an increase in resorption was observed (2.3-fold at 10(-9) M). In cocultures of osteoclasts and osteoblasts (UMR 106-01 osteoblast-like cells or long settlement cultures), T3 stimulated resorption at 24 h. Furthermore, stimulation of resorption occurred when osteoblasts (UMR 106-01 or rat calvarial cells) were pretreated with T3 and the subsequent osteoblast-osteoclast cocultures conducted for 24 h in the absence of T3. Thus, direct exposure of osteoclasts to T3 was not required for the stimulatory effect. Treatment for 48 h with T3 (10(-9) M) or PTH (10(-8) M) had no effect on bone resorption in osteoblast-free cultures derived from human osteoclastoma tumours. T4 was 100-fold less potent than T3 as a stimulator of osteoclast activity, and rT3 had no effect. T3-induced stimulation was inhibited by salmon calcitonin (10(-10) M). These findings indicate that thyroid hormone can act on osteoblasts to indirectly stimulate osteoclastic bone resorption.

Animals↗
PubMed1993

Rapid, divergent changes in spinal and forearm bone density following short-term intravenous treatment of Paget's disease with pamidronate disodium.

Intravenous disodium 3-amino-1-hydroxypropylidene-1,1-bisphosphonate pentahydrate (pamidronate disodium) was used to treat 39 patients (22 males and 17 females, age range 48-85 years) with symptomatic Paget's disease. Patients were stratified into three groups based on the biochemical severity of the disease as assessed by fasting urinary hydroxyproline excretion (HypE, mumol/liter GF, glomerular filtrate): group I (n = 23), HypE < 5.0, treated with 120 mg total dose over 2 or 4 days; group II (n = 6), 5.0 < or = HypE < or = 10.0, 180 mg over 3 or 6 days; and group III (n = 10), HypE > 10.0, 240 mg over 4 or 8 days. Bone mineral density (BMD) was measured before and 3 and 6 months following treatment in the spine (L1-4) using dual-energy x-ray absorptiometry and in the forearm at an ultradistal and a shaft site using single-photon absorptiometry. When groups I-III were combined, nonpagetic and pagetic lumbar spinal BMD had both risen significantly at 3 months compared with the pretreatment values (p < 0.001). In each group, lumbar spinal BMD in pagetic vertebrae rose markedly by 3 months, with no further significant change at 6 months. The percentage rises in the three groups were not different from each other at 3 or 6 months. Nonpagetic lumbar spinal BMD followed a similar and significant trend but with a significantly smaller rise than for pagetic bone. (For the combined groups, nonpagetic BMD rose 5.1 +/- 1.1% SEM, above pretreatment at 6 months; pagetic BMD rose 17.8 +/- 1.6%: significance of comparison = p < 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

Absorptiometry, Photon↗
PubMed1993

Long-term culture of disaggregated rat osteoclasts: inhibition of bone resorption and reduction of osteoclast-like cell number by calcitonin and PTHrP[107-139].

The isolated osteoclast bone resorption assay has proved to be a useful means of examining the response of mammalian and avian osteoclasts to a variety of stimuli. The assay has traditionally been performed over a period of 24 hours. By extending the duration of the osteoclast bone resorption assay, we have been able to assess the long-term effects of carboxyl-terminal parathyroid hormone-related protein (hPTHrP[107-139]), salmon calcitonin (sCT) and hPTH[1-34] on bone resorption and TRACP-positive osteoclast-like cell number. We found that, in control cultures over a period of up to 144 hours, the osteoclast-like cells not only remained viable but their numbers also increased. The number of mononucleated and multinucleated osteoclast-like cells doubled in the first 48 hours before stabilizing over the remainder of the incubation period. Osteoblasts also proliferated, resulting in a resorption response to hPTH[1-34] being evident from 48 hours onward. hPTHrP]107-139] persistently inhibited basal and PTH-stimulated bone resorption for at least 96-144 hours, whereas "escape" from the inhibitory effect of sCT was seen after 48-72 hours. Decreased numbers of both mononucleated and multinucleated TRACP-positive osteoclast-like cells were seen by 48 hours in cultures treated with sCT. In contrast, hPTHrP[107-139] reduced the number of mononuclear TRACP-positive cells with only a late effect on multinucleated cells. Furthermore, the increased number of osteoclast-like cells seen in response to hPTH[1-34] was inhibited by carboxyl-terminal PTHrP. In summary, this study indicates that the extended bone resorption assay system is a complex one where both osteoclastic resorption and osteoclast maturation are evident. Using this system, we have shown that hPTHrP[107-139] acts as a potent long-term inhibitor of osteoclastic bone resorption, without evidence of escape from its effect. Its action to reduce the number of mononucleated osteoclast-like cells suggests that it affects several aspects of osteoclast activity.

Acid Phosphatase↗
PubMed1993

Fluoride treatment of osteoporosis: cyclical non-blinded or continuous blinded studies?

The future of sodium fluoride (NaF), the most potent osteoblast stimulator known to man, is in the balance. Of three recent randomized trials of continuous NaF only one found a significant in vertebral fractures in the NaF group. When data from the first year were excluded, two of the studies (those with the largest numbers) showed a significantly reduced risk of vertebral fracture on NaF. The effect of NaF on cortical bone is poorly documented. Two studies have shown reduced forearm cortical bone density with continuous NaF. A further two (histomorphometric) studies have shown the development of increased cortical porosity on continuous NaF treatment. In one, this was selectively at the external cortex and was linearly correlated with cancellous volume increase. Our pilot study using NaF administered cyclically has shown an encouraging (though non-significant) reduction in vertebral fracture rates (excluding year 1) and no fall in forearm cortical density. Another (US) cyclical study has shown no increase in cortical porosity. A current W. Australian randomized study of 50 patients is described where NaF dosage is varied proportional to the osteoblast response, and duration is dependent on densitometric and radiographic response. The future of NaF should involve cyclical administration, in cautious initial dosage (50-60 mg/day) of enteric-coated NaF, in conjunction with a potent inhibitor of resorption such as hormone replacement, bisphosphonates or calcitonin.

Aged↗
PubMed1992

Evidence that protein kinase-A, calcium-calmodulin kinase and cytoskeletal proteins are involved in osteoclast retraction induced by calcitonin.

Calcitonin is a direct inhibitor of osteoclastic activity. Osteoclast retraction is readily induced by calcitonin and it is possible that calcitonin-induced inhibition of bone resorption is in part due to this effect. However, little is known of the mechanisms of this action. In these studies, we have investigated the intracellular signalling pathway of calcitonin-induced osteoclast retraction using cultures of freshly isolated rat osteoclasts. The spread area occupied by single Giemsa-stained rat osteoclasts was measured in vitro by a computer imaging analysis system and used as a quantitative parameter for calculating the degree of osteoclast retraction in response to various agents. Our results show that cAMP may be an important second messenger in the reaction of osteoclasts to calcitonin. Moreover, both protein kinase-A and calcium/calmodulin-dependent protein kinase are involved in the osteoclast retraction induced by this hormone, while cytoskeletal proteins are required for the process to occur.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1991

Biphasic effect of calcitonin on tartrate-resistant acid phosphatase activity in isolated rat osteoclasts.

Tartrate-resistant acid phosphatase (TRAP) has been implicated as being involved in osteoclastic bone resorption, and calcitonin (CT) is known to inhibit the resorptive process. This study investigates the kinetics of CT action on TRAP activity in isolated rat osteoclasts using both biochemical and quantitative cytochemical methods. The latter technique has been developed to detect very small changes in intracellular TRAP activity at the single-cell level. The biochemical study showed that 10(-9) M salmon CT (sCT) decreased TRAP activity in medium throughout the experimental period; TRAP activity in the cells was increased during the first 2 h but subsequently declined and was decreased to a significant level at 6 h. TRAP activity in sCT-treated osteoclasts measured by the cytochemical method showed significant increases within the first hour. This response was dose dependent between 10(-16) and 10(-11) M sCT with EC50 at 8 X 10(-14) M. After 1 h, the initial increase in intracellular TRAP activity in CT-treated osteoclasts was followed by a decline to below control levels, reaching statistical significance at 9 h. Treatment with forskolin (10(-5) M) showed a similar trend, suggesting that this response is mediated by cyclic AMP-regulated phosphorylation events. From these results, we conclude that CT has two actions on TRAP in isolated rat osteoclasts: the first to inhibit its release, the second to inhibit its synthesis and/or increase its degradation.

Acid Phosphatase↗
PubMed1991

A quantitative cytochemical investigation of osteoclasts and multinucleate giant cells.

Quantitative cytochemical, immunocytochemical, autoradiographic and electron cytochemical investigations have been used to compare osteoclasts with multinucleate giant cells that had been freshly obtained from the same animal. The levels of beta-acid galactosidase activity, the DNA in individual nuclei and the cellular protein content were similar in both cell types. However, osteoclasts generally possessed greater acid phosphatase and NADH dehydrogenase activity but lower levels of fluoride-inhibited non-specific esterase activity than multinucleate giant cells. The acid phosphatase activity in multinucleate giant cells was completely inhibited by 100 mM tartrate, but in osteoclasts only a 20% reduction in activity was observed. Formation of multinucleate giant cells in a "bone microenvironment" (thin bone slices) did not increase their content of tartrate-resistant acid phosphatase activity. Moreover, in osteoclasts, endogenous peroxidase activity was undetectable but present in several granules within the cytoplasm of multinucleate giant cells. Osteoclasts and multinucleate giant cells displayed a similar microtubules distribution, but calcitonin, which induced rearrangement of microtubules and cellular contraction in osteoclasts, had no effect on multinucleate giant cells. Thus, these investigations reveal both similarities and differences between these two syncytia and support the hypothesis that osteoclasts and multinucleate giant cells are related. Possibly osteoclasts arise from monocyte progenitors before commitment to a macrophage lineage has occurred.

Acid Phosphatase↗
PubMed1991

RNA synthesis in isolated rat osteoclasts: inhibitory effect of calcitonin.

The metabolism of RNA has not been studied in the osteoclast (OC) because these bone-resorbing cells are only available in small numbers and cultures are always contaminated with other cells. Using two single-cell assay techniques, tritiated uridine (3H-UdR) autoradiography and gallocyanin quantitative cytophotometry, we have examined RNA synthesis in OCs isolated from neonatal rats. Oligo-nuclear OCs showed greater nuclear uptake of 3H-UdR than cells with many nuclei, and the variance of nuclear labeling within polykarya was greater in the latter, possibly because they contain nuclei of various ages. Salmon calcitonin (sCT) was a potent (ED50 approximately 5 x 10(-12) M) and rapid (40% reduction in 2 h, 75% reduction in 6 h) inhibitor of 3H-UdR uptake, and also reduced cytochemical total cellular RNA by 22% within 4 h. Forskolin (10(-5) M) inhibited nuclear uptake of 3H-UdR, suggesting that the sCT response may be mediated by cyclic AMP. Following a short (30 min) exposure to sCT, there was a progressive decline in labeling, followed by complete recovery by 4.5 h, a response possibly related to the phenomenon of calcitonin-induced persistent activation of adenylate cyclase. Inhibition of OC RNA synthesis may be an important component of its anti-resorptive action.

Animals↗
PubMed1991

What's new in osteoclast ontogeny?

The osteoclast (OC) is a multinuclear bone-resorbing cell which shares several characteristics with cells of the mononuclear phagocyte system. Unlike terminally differentiated macrophages, OCs possess specialized characteristics such as tartrate resistant acid phosphatase activity and the presence of calcitonin receptors. It appears that myeloid progenitor cells, probably granulocyte-macrophage colony-forming units, generate OC precursors which then differentiate and fuse into OCs under the regulation of osteotropic hormones, cytokines and other local factors. Parathyroid hormone and 1,25 dihydroxy Vitamin D3 induce both the formation and fusion of OC precursors, while calcitonin inhibits fusion. Osteoblasts also produce factor(s) which regulate OC precursor differentiation and therefore bone resorption; the nature of these factor(s), however, is unknown. In addition, the OC surface interacts specifically with a range of cellular and extracellular matrix-associated ligands which influence OC differentiation. The precise regulation of OC formation, however, is complex and awaits further investigation.

Animals↗
PubMed1991

Treatment of osteoporosis and Paget's disease.

Osteoporosis is a major public health problem. In women, the estimated lifetime risks of hip and vertebral fractures are 15% and 25%, respectively. The development of accurate and reproducible methods of assessing bone mineral density has enabled identification of persons at risk of fracture and assessment of response to treatment. Estrogen replacement therapy is effective in the prophylaxis of postmenopausal osteoporosis, and is the only therapy with well-proven antifracture efficacy. Fluoride can dramatically increase bone density, although a recent large, controlled study has demonstrated no effect on vertebral fractures. Bisphosphonates are emerging as a likely effective therapy for both idiopathic and glucocorticoid-induced osteoporosis. Calcium, vitamin D, calcitonin, and anabolic steroids may still have a role. Parathyroid hormone is a promising development that will need further study. Paget's disease is also common, affecting more than 3% of people over 40 years old. Calcitonin is an established therapy, although the bisphosphonates are a promising alternative.

Calcitonin↗