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PubMedDate not supplied

Cellular mechanisms of bone resorption induced by metabolic acidosis.

Metabolic acidosis increases urine calcium excretion without an increase in intestinal calcium absorption, resulting in a net loss of bone mineral. In vitro metabolic acidosis induces bone calcium efflux initially by physicochemical dissolution and subsequently by cell-mediated mechanisms involving inhibition of osteoblasts and stimulation of osteoclasts. In bone, prostaglandins (PGs) are important mediators of bone resorption and we have recently determined that acid-induced bone resorption is mediated by PGs. Utilizing neonatal mouse calvariae in culture, we found that decreasing pH by a reduction in bicarbonate concentration, a model of metabolic acidosis, induced an increase in net calcium efflux and in medium prostaglandin E2 (PGE2) levels, both of which were inhibited in the presence of indomethacin. There was a direct correlation between calcium flux and medium PGE2. If pH is lowered to a comparable degree by an increase in pCO2 to model respiratory acidosis, there was no significant stimulation of net calcium efflux from the calvariae and no stimulation of PGE2 production. We have also shown that metabolic acidosis alters osteoblastic expression of a specific osteoclastogenic factor, RANKL, and this response is also PG dependent. Incubation of calvariae in acid medium stimulated expression of RANKL RNA in parallel with the increased calcium flux. Both responses were inhibited in the presence of indomethacin. Thus metabolic, but not respiratory, acidosis induces production of bone PGE2, which mediates acid-induced bone resorption.

Acidosis↗
PubMed1995

Immunolocalization of bone-resorptive cytokines in rat pulp and periapical lesions following surgical pulp exposure.

The bone-resorptive cytokines interleukin 1 (IL-1) and tumor necrosis factor (TNF) have been implicated in the pathogenesis of many chronic inflammatory diseases, including pulpitis and apical periodontitis.To further elucidate their role in these disorders, we have identified cells that express IL-1 alpha and TNF alpha in infected pulps and in developing rat periapical lesions after surgical pulp exposure. As detected by immunohistochemistry, IL-1 alpha- and TNF alpha-positive cells were present as early as 2 days after pulp exposure in both the pulp and periapical region. The numbers of cytokine-expressing cells increased up to day 4 in the pulp and up to day 30 in the periapex. In contrast, cells expressing IL-1 beta and TNF beta, the homologous forms of these mediators, were not found in pulp or periapical lesions during this period. Cells expressing IL-1 alpha and TNF alpha were identified primarily as macrophages and fibroblasts, with occasional staining of polymorphonuclear leukocytes. Osteoblasts and osteoclasts were also positive, whereas lymphocytes were negative. In general, cytokine-expressing cells were located proximal to abscesses and the root apex. These findings demonstrate that cells that express bone-resorptive cytokines IL-1 alpha and TNF alpha are present immediately after pulp exposure in this model, which supports the hypothesis that these mediators play a key role in pulpal and periapical pathogenesis, including the concomitant bone destruction. They also indicate that both resident connective tissue cells as well as infiltrating cells express bone-resorptive cytokines in response to infection in these lesions.

Alveolar Bone Loss↗
PubMed1979

Inflammatory lesions and bone resorption induced in the rat periodontium by lipoteichoic acid of Streptococcus mutans.

Severe inflammatory lesions were induced in the periodontal tissues of the rat following the intragingival injection of lipoteichoic acid (LTA) from Streptococcus mutans. There was no difference in the severity and distribution of the lesions between nonimmunized rats and animals immunized against LTA after antigenic challenge. The lesions are characterized by the occurrence of granulation tissue, massive infiltration of PMNs, abscess formation, bone resorption, and new bone formation. Deacylated LTA and saline caused relatively mild inflammation, and no significant bone resorption or new bone formation was evident. The peak response was reached after 3 intragingival infections. The mechanisms by which LTA caused the pathological alterations in the rat periodontium and the possible relations of this experimental model to periodontal disease in the human are discussed.

Animals↗
PubMed1996

Dietary xylitol, sorbitol and D-mannitol but not erythritol retard bone resorption in rats.

The aim of the present study was to compare the ability of four dietary polyols to reduce bone resorption. Urinary excretion of 3H radioactivity from [3H]tetracycline-prelabeled rats was used as a marker of bone resorption. After prelabeling, the rats were divided randomly into five groups of 10, and fed for 1 mo a nonpurified diet that was supplemented in four groups with either xylitol, sorbitol, D-mannitol or erythritol, respectively, to give a polyol concentration of 1 mol/kg. Xylitol (42%), sorbitol (44%) and to a lesser degree D-mannitol (23%) decreased the excretion of 3H relative to the basal diet. The erythritol group, however, did not differ from the controls. Sorbitol caused continuous diarrhea, whereas in the other groups, intestinal adaptation took place during the 1st wk of polyol feeding. In conclusion, dietary xylitol, sorbitol and to a lesser degree D-mannitol supplementations in rats retard bone resorption, whereas dietary erythritol has no effect.

Animals↗
PubMed1993

Urinary hydroxypyridinium crosslinks of collagen as markers of bone resorption and estrogen efficacy in postmenopausal osteoporosis.

Estrogen deficiency-induced bone loss has been associated with accelerated bone turnover. Levels of some biochemical markers, such as serum osteocalcin (BGP), tartrate-resistant acid phosphatase (TRAP), and urinary hydroxyproline (OHP), have been shown to be related to the rate of bone turnover. They may therefore be useful in identifying the individual at risk for osteoporosis and monitoring the efficacy of the treatment. Two recently discovered markers, urinary pyridinoline (PYD) and deoxypyridinoline (DPD), are apparently directly related to bone matrix degradation and may be more accurate markers of bone resorption than OHP or TRAP. To evaluate the effects of menopause, osteoporosis, and estrogen replacement on the excretion of these new markers, we measured the levels of PYD and DPD and other biochemical markers of bone turnover in four groups of women, premenopausal healthy (PRE), postmenopausal healthy (POST), postmenopausal osteoporotic (UTO), and postmenopausal osteoporotic with estrogen treatment (ETO). Significant increases in PYD, DPD, BGP, TRAP, and OHP were found in POST and UTO groups compared with PRE. These increases were blunted by estrogen treatment when the levels of each of the markers returned to PRE levels. When comparing POST and UTO groups, significant increases were observed in UTO only for PYD, DPD, and urinary calcium but not for OHP, BGP, or TRAP. With subgroups matched for age and years from menopause, only DPD discriminated between POST and UTO. Indices of bone formation covaried with markers of bone resorption in the total population.(ABSTRACT TRUNCATED AT 250 WORDS)

Acid Phosphatase↗
PubMed2000

Risk assessment for osteoporosis. II. Biochemical markers of bone turnover: bone resorption indices.

This article describes the biochemical background and functional properties of molecular markers derived from osteoblasts, the collagenous, or noncollagenous bone matrix. Clinical applications and the selection, timing, and monitoring of antiosteoporotic treatment are critically discussed. Special emphasis has been put on reviewing the value of bone resorption markers in the prediction of future bone loss and the risk assessment for osteoporotic fractures. The potential of these indices as independent risk factors for future fractures alone or in combination with bone mineral density measurements has recently been demonstrated in large cohort studies. More data are needed, however, to establish biochemical markers of bone resorption as useful tools in the assessment of individual fracture risk.

Biomarkers↗
PubMed1985

Stimulation of bone resorption in vitro by synthetic transforming growth factor-alpha.

Experiments were conducted to test the hypothesis that tumor-derived transforming growth factor-alpha (TGF-alpha) is responsible for the increased bone resorption and hypercalcemia seen in some malignant diseases. Homogeneous synthetic TGF-alpha prepared by the solid-phase synthesis method stimulated bone resorption directly in vitro in a concentration-dependent manner. Incubation times of 72 hours or more were required to stimulate resorption, which is similar to the time course of bone resorption by epidermal growth factor.

Animals↗
PubMed1995

Osteoblasts from the toothless (osteopetrotic) mutation in the rat are unable to direct bone resorption by normal osteoclasts in response to 1,25-dihydroxyvitamin D.

Osteopetrosis describes a diversified group of metabolic bone disorders characterized by a generalized, skeletal sclerosis resulting from reduced osteoclast-mediated bone resorption. The toothless (tl) osteopetrotic mutation in the rat is characterized by few osteoclasts and the inability to be cured by transplants of hemopoietic stem cells. This implies that the defect(s) responsible for reduced osteoclast activity in tl rats is within the skeletal microenvironment (cells or matrices). Osteoblasts and their products are known to play a role in regulating bone resorption and abnormalities in the osteoblast population in tl rats have been reported. The purpose of this study was to determine whether osteoblasts isolated from tl mutant rats, when cultured with normal osteoclasts, could increase bone resorption (pit formation) in response to stimulation by 1,25 dihydroxyvitamin D (1,25(OH)2D). The addition of 1,25(OH)2D produced a highly significant response in normal osteoblast cocultures but no response in mutant cultures. A dose response study with 1,25(OH)2D (10(-6) to 10(-9)M) revealed that mutant osteoblasts are unable to increase osteoclast activity. These data indicate that the vitamin D receptor-signal transduction pathway in tl rats needs to be examined.

Animals↗
PubMed1997

Assessment of different markers of bone resorption in postmenopausal osteoporotic women treated with pamidronate.

The aim of this study was to evaluate the different bone resorption markers, total pyridinoline (Pyr) and total deoxypyridinoline (Dpyr), assessed by a HPLC method, free Dpyr, assessed by a new immunoassay, and urinary excretion of hydroxyproline (OH-proline), in postmenopausal osteoporotic women during long-term treatment with pamidronate. A total of 60 postmenopausal women with previous distal forearm fracture were included in this 12-month placebo-controlled and double-blind study, where intermittent oral pamidronate, 75 or 150 mg, or placebo were given daily for 4 weeks, every 16 weeks. After 1 week a significant reduction in urinary excretion of total Dpyr was observed in the group treated with 150 mg pamidronate compared to the placebo (p < 0.01) and to the 75-mg group (p < 0.001). A maximal 50.4% decrease in total Dpyr, (p < 0.0001 compared to the placebo group, p < 0.01 compared to the 75-mg group), was observed after 3 weeks of treatment with 150 mg pamidronate, and this decrease persisted to week 52. After 4 weeks of treatment with 150 mg pamidronate the maximal decrease in free Dpyr was only 26.5%, which persisted during 12 months of treatment. Decreases in urinary excretion of total Pyr and OH-proline were less than the decreases in total Dpyr. The correlation between total Dpyr (HPLC method) and free Dpyr (Pyrilinks-D assay) at baseline was r = 0.91. Total Dpyr assessed by the HPLC method reflects the pamidronate-induced decrease in bone resorption, and the changes in this resorption marker were more pronounced than changes in free Dpyr, total Pyr and OH-proline. In this study free Dpyr analysis was less suitable for reflecting bone resorption during bisphosphonate therapy.

Aged↗
PubMed1994

The carboxy-terminal pyridinoline cross-linked telopeptide of type I collagen in serum as a marker of bone resorption: the effect of nandrolone decanoate and hormone replacement therapy.

Carboxy-terminal pyridinoline cross-linked telopeptide of type I collagen (ICTP) in serum has recently been proposed as a new biochemical marker of bone resorption. In the present study we compared serum ICTP with radiopharmaceutical and histomorphometric measurements of bone turnover in postmenopausal women with mild osteoporosis, and assessed the effect of hormone replacement therapy (HRT) (2 mg 17 beta-estradiol plus 1 mg norethisterone daily) and anabolic steroid therapy (50 mg nandrolone decanoate (ND) i.m. every 3 weeks) on serum ICTP in two double-blind placebo-controlled studies with 55 to 75-year-old women. Serum ICTP measured by radioimmunoassay (RIA) correlated significantly with the 24-hour whole body retention of 99m-technetium diphosphonate (Rho = 0.47, P < 0.001, n = 66), but not with histomorphometric measurements of bone turnover in iliac crest biopsies. One year of HRT (n = 16) versus placebo (n = 15) did not produce significant changes in serum ICTP. Compared with placebo (n = 17), 1 year of ND (n = 19) produced an increase in serum ICTP of 90 +/- 16% (P < 0.0001); 6 months after discontinuation of the treatment, serum ICTP had returned to pretreatment values. We conclude that serum ICTP does reflect bone metabolism in postmenopausal osteoporosis, but it is not a sensitive marker of the changes in bone resorption induced by hormone replacement therapy, and it does not correspond with other measures of bone resorption during anabolic steroid therapy.

Aged↗
PubMed1999

Mechanical compression of a fibrous membrane surrounding bone causes bone resorption.

Early micromovement and migration of a prosthesis of a hip or knee predicts late clinical loosening of the prosthesis. Such migration is likely to be associated with mechanical compression of the fibrous membrane interpositioned between bone and prosthesis during movement. Compression of the fibrous membrane by loading may lead to locally high fluid pressures reaching the underlying bone tissue. It has been established that high fluid pressures can lead to bone resorption. This resorption may eventually lead to clinical loosening of the prosthesis. We developed an experimental model to study the effects of compression of a soft tissue layer located between a titanium implant and cortical bone. In twelve rabbits, this device was implanted in the proximal tibia and allowed to osseointegrate. Next, a layer of soft tissue was allowed to form between titanium and bone. Subsequently, in six rabbits a cyclic load of 60 times in 2 min per day during 2 weeks was applied, leading to compression of the interpositioned soft tissue layer only. In the other six rabbits no load was applied. In all six loaded specimens, osteocyte death and bone resorption was observed underneath the area where compression of the fibrous membrane was exerted to a depth exceeding the amplitude of the loading device. Furthermore, formation of fibrocartilage was observed in the loaded areas. Formation of fibrocartilage, osteocyte death or bone resorption did not occur in the controls. Our results indicate that compression of a fibrous membrane surrounding bone can lead to resorption of the underlying bone primarily because of osteocyte death and subsequent resorption of dead bone tissue. This may explain the observation that early migration of a hip or knee prosthesis is predictive of clinical loosening of the prosthesis.

Animals↗
PubMed1993

Inhibition of prostanoid synthesis depresses alveolar bone resorption but enhances root resorption in the rat.

Tooth drift requires the deformation of the root socket and the adjustment of the other components of the attachment apparatus, namely, the periodontal ligament (PDL) and the cementum. Indomethacin (7.5 mg/kg/d), an inhibitor of prostanoid synthesis, provoked in rats a depression in the bone resorption effecting the deformation of the socket (Lasfargues and Saffar, Anat. Rec., 234:310-316, 1992). In the present paper we examined the consequence of this treatment both on the PDL and the root surface. After 3 days of treatment, when osteoclastic resorption was not yet disturbed, the root had been markedly resorbed (P < 0.05) opposite the resorbing bone surface; at that time the PDL width remained in the normal range. After 7 days, i.e., when the bone resorption was depressed, the PDL was widened as the result of the ongoing root resorption. Despite the extensive root resorption, the anchorage of the PDL fibers appeared to remain effective, suggesting that it was rapidly restored. On day 14 at the time of the bone resorption recovery, cementum was deposited in the root resorption lacunae and the PDL width had returned to its control value. As early as day 3 the daily rate of dentine formation increased in the pulp area subjacent to the root resorption lacunae (P < 0.01). These data demonstrate that i) the responses of the different components of the periodontal apparatus are coordinated to allow for the maintainance of the PDL width so that when bone resorption is disturbed, root resorption compensates for it, and ii) the odontoclasts can differentiate and resorb under prostanoid inhibition whilst osteoclastic resorption of the bone socket is inhibited.

Adaptation, Physiological↗
PubMed1992

Human parathyroid hormone-related peptide-(107-111) does not inhibit bone resorption in neonatal mouse calvariae.

Recent analysis of the structure-function relationship of human PTH-related peptide (hPTHrP) has led to the discovery that its direct inhibitory activity on osteoclastic bone resorption resides fully in the 107-111 sequence of the peptide, as assessed by a bone resorption assay using isolated rat osteoclasts. Here we report that hPTHrP-(107-111) is inactive in neonatal mouse calvariae in culture. hPTHrP-(107-111), at doses of 10(-12)-10(-6) M and incubation periods up to 96 h, did not affect either basal or agonist-stimulated 45Ca release from prelabeled neonatal mouse calvariae, while salmon calcitonin was a potent and powerful inhibitor of both basal and stimulated 45Ca release from bone. Moreover, salmon calcitonin, but not hPTHrP-(107-111), inhibited the increase in osteoclast number in hPTHrP-(1-34)-treated bones. Furthermore, hPTHrP-(107-139) also failed to inhibit 45Ca release and the hPTHrP-(1-34)-induced increase in osteoclast number in this organ culture model when tested under conditions identical to those for hPTHrP-(107-111). The addition of indomethacin to hPTHrP-(107-111)- or hPTHrP-(107-139)-treated bones was without effect, excluding the possibility that the direct inhibitory activity of these peptides on osteoclasts is ablated by a prostaglandin-mediated mechanism. Although the mechanism underlying the apparent inability of the carboxyl-terminal PTHrP fragments to inhibit osteoclastic bone resorption in neonatal mouse calvariae is unknown, it may involve the complex microenvironment of osteoclasts in intact bone, which contains a large variety of cell types other than osteoclasts.

Animals↗
PubMed1995

The role of 1,25-dihydroxycholecalciferol and prostaglandin E2 in the regulation of human osteoclastic bone resorption in vitro.

Prostaglandins increase human osteoclast generation in vivo whereas they have been shown to exert the opposite effect in vitro: the latter results are based on enumeration of osteoclast-like cells, whose nature is controversial. We have generated human osteoclasts in vitro as assessed by bone resorption, a function unique to the osteoclast, and analysed the role of prostaglandin E2 (PGE2) in osteoclast activity. Human bone marrow cells were cultured to form a mature stroma and then sedimented onto bone slices with or without a recharge of non-adherent bone marrow cells. Bone resorption was increased by 1,25-dihydroxycholecalciferol (1,25(OH)2D3) and PGE2 and inhibited by indomethacin: this inhibition was reversed by addition of PGE2. Our work supports the observation that PGE2 increases bone resorption in vivo and demonstrates the value of assessing osteoclast generation and activity in vitro using bone resorption.

Bone Marrow Cells↗
PubMed1990

Buserelin-mediated osteoporosis: effects of restoring estrogen on bone resorption and whole body calcium content in the rat.

In the rat, prolonged administration of the luteinizing, hormone-releasing hormone agonist buserelin (25 micrograms/kg body wt/day s.c.) lowers blood estradiol, raises bone resorption, and induces osteopenia. The present study was undertaken to determine whether withdrawal of buserelin normalizes blood estradiol, slows bone resorption, and corrects buserelin-mediated osteopenia. Four groups of female rats with 45Ca-labeled bones were studied: group 1A received 0.2 ml saline s.c. daily for 4 weeks; group 2A received 0.2 ml buserelin s.c. daily for 4 weeks; group 1B received 0.2 ml saline s.c. daily for 8 weeks; group 2B received 0.2 ml buserelin s.c. daily for 4 weeks followed by 0.2 ml saline s.c. daily for 4 weeks. Bone resorption was monitored by measuring urinary 45Ca and hydroxyproline. The rats in groups 1A and 2A were killed after 4 weeks and those in groups 1B and 2B after 8 weeks. The mineral contents of the femoral bones and the whole skeletons were measured. Buserelin lowered blood estradiol, elevated urinary 45Ca and urinary hydroxyproline, and lowered femur and total body calcium and 45Ca in group 2A vs. 1A (P less than 0.05). By contrast all these measurements became similar in groups 2B and 1B. Thus, osteopenia generated by a 4-week period of buserelin-mediated hypo-estrogenism is reversible by withdrawing buserelin for 4 weeks. Consequently, buserelin administration and withdrawal may be used to study effects of inducing and reversing estrogen-deficiency bone loss in the rat.

Animals↗
PubMed2001

Serum beta2-microglobulin reflects increased bone resorption in immobilized stroke patients.

OBJECTIVE: The so-called bone-derived growth factor, beta2-microglobulin, has a regulatory function in bone metabolism by stimulating osteoclast activity. We undertook this study because osteoclast activity is known to be enhanced in patients with immobilized stroke, suggesting that their beta2-microglobulin concentrations may be increased. DESIGN: We studied 79 patients with acute stroke hemiplegia, including 36 men and 43 postmenopausal women ranging in age between 51 and 70 yr. RESULTS: The mean Barthel Index was 43 and 42 for men and women, respectively. The serum beta2-microglobulin concentration was increased in male and female patients, compared with the findings of 44 age-matched control subjects, and the serum concentration of pyridinoline cross-linked carboxyterminal telopeptide of type 1 collagen was also increased in male and female patients, compared with the findings of the control subjects. Serum concentrations of pyridinoline cross-linked carboxyterminal telopeptide of type 1 collagen correlated negatively with Barthel Index scores in both genders, indicating increased bone resorption caused by immobilization in these patients. Linear regression analysis revealed a positive correlation between beta2-microglobulin and pyridinoline cross-linked carboxyterminal telopeptide of type 1 collagen in both genders. CONCLUSIONS: These findings suggest that beta2-microglobulin reflects osteoclastic activity in response to stroke-induced immobilization in both genders. Beta2-microglobulin is a useful indicator of bone resorption in patients with immobilized stroke.

Aged↗
PubMed1982

Effect of tetracycline on gingival inflammation and alveolar bone resorption in beagles: an individual tooth by tooth analysis.

The effect of systemic tetracycline on gingival inflammation and alveolar bone resorption was studied in beagle dogs. Seventeen dogs were divided into three groups receiving either no treatment, 250 mg tetracycline HCl, or 500 mg tetracycline HCl daily. The severity of gingival inflammation and activity of alveolar bone resorption during a 6-month pretreatment period was compared to a 24-month treatment period for each individual tooth studied. In the first 12 months of treatment there was a significant decrease in the severity of gingival inflammation and the activity of alveolar bone loss in the tetracycline treated dogs. By 24 months of treatment increased gingival inflammation and rate of bone loss was evident in the treated dogs. In the untreated control dogs there was a statistically significant association between the severity of gingival inflammation and activity of alveolar bone resorption about the teeth studied. In the tetracycline treated dogs, no such association existed.

Alveolar Process↗
PubMed1993

Stimulation of a Gs-like G protein in the osteoclast inhibits bone resorption but enhances tartrate-resistant acid phosphatase secretion.

Previous studies have demonstrated that G-protein agonists induce quiescence (Q effect) or retraction (R effect) in isolated osteoclasts. We now report the functional effects of such agonists on osteoclastic bone resorption and enzyme release. Exposure of osteoclasts to tetrafluoro-aluminate anions (AlF4-), a universal G protein stimulator, resulted in a marked concentration-dependent inhibition of bone resorption. This was associated with a dramatic increase in the secretion of the osteoclast-specific enzyme, tartrate-resistant acid phosphatase (TRAP). Cholera toxin, a Gs stimulator and a selective Q effect agonist, similarly abolished bone resorption and enhanced TRAP secretion. In contrast, pertussis toxin, a Gi inhibitor and a selective R effect agonist, inhibited bone resorption significantly, but slightly reduced enzyme release. The results suggest an involvement of a Gs-like G protein in TRAP secretion from the osteoclast, possibly through a cyclic AMP-dependent mechanism.

Acid Phosphatase↗