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PubMed1988

Use of minoxidil to demonstrate that prostacyclin is not the mediator of bone resorption stimulated by growth factors in mouse calvariae.

Growth factors, such as human transforming growth factor-alpha (hTGF alpha) and epidermal growth factor, as well as human tumor necrosis factor (hTNF) stimulate the resorption of bone in neonatal mouse calvariae in organ culture via a prostaglandin (PG)-mediated pathway. In response to such factors mouse calvariae produce substantial quantities of prostaglandin E2 (PGE2) and prostacyclin (PGI2). We have selectively inhibited the production of PGI2, but not PGE2, using the drug minoxidil and have measured the effects on stimulated bone resportion and arachidonic acid metabolism. The increased production of 6-keto-PGF1 alpha (6k-PGF1 alpha), the hydrolytic product of PGI2, stimulated by recombinant hTGF alpha and hTNF as well as murine epidermal growth factor was inhibited by minoxidil. There was no inhibition by minoxidil of PGE2 production. Despite essentially complete inhibition of stimulated 6k-PGF1 alpha formation, there was no inhibition of bone resorption. The possibility was investigated that growth factors and TNF enhanced enzymatic conversion of PGI2 to 6k-PGE1, which stimulates bone resorption in mouse calvariae with a potency about one fourth that of PGE2. Enzymatic conversion of PGI2 to 6k-PGE1 is inhibited by rutin. Rutin did not inhibit bone resorption stimulated by hTGF alpha or hTNF. We conclude, on the basis of these new results and previously published data, that the cyclooxygenase product that acts as the mediator of bone resorption enhanced by growth factors and TNF in mouse calvariae is probably PGE2.

6-Ketoprostaglandin F1 alpha↗

PubMed1992

Haptoglobin-stimulated bone resorption in neonatal mouse calvarial bones in vitro.

OBJECTIVE: To study the in vitro effects of human haptoglobin (Hp) on bone resorption and prostanoid formation. METHODS: Parietal bones were dissected out from neonatal mice that had been injected with 45Ca, and were cultured in chemically defined medium with or without test substances. Bone resorption was assessed by analysis of 45Ca release. Prostanoid formation was quantified by analysis of the amount of prostaglandin E2 (PGE2) in culture medium. RESULTS: Hp phenotype 2-1, in quantities greater than or equal to 0.17 mg/ml, stimulated the release of 45Ca and the biosynthesis of PGE2, in a time- and dose-dependent manner. Hp-induced PGE2 formation was abolished by indomethacin and flurbiprofen, whereas the stimulation of 45Ca release was only partially reduced. CONCLUSION: These observations suggest that the acute-phase reactant Hp may contribute, by a humoral mechanism, to the bone resorption seen in chronic inflammatory processes.

Animals↗

PubMed2002

IL-1beta regulates cellular proliferation, prostaglandin E2 synthesis, plasminogen activator activity, osteocalcin production, and bone resorptive activity of the mouse calvarial bone cells.

Interleukin-1beta (IL-1beta) regulates several activities of the osteoblast cells derived from mouse calvarial bone explants in vitro. IL-1beta stimulated cellular proliferation and the synthesis of prostaglandin E2 in the cultured cells in a dose-dependent manner. Furthermore, plasminogen activator activity of the mouse osteoblast was positively affected by IL-1beta in a dose-dependent manner over the dosage range of 0.01 ng-2 ng/mL with a maximal effect being observed at 2 ng/mL. However, the induction of osteocalcin synthesis and alkaline phosphatase activity in response to vitamin D, two characteristics of the osteoblast phenotype, were significantly antagonized by IL-1beta over a similar dose range. Treatment of mouse calvarial bone cells with IL-1beta resulted in a dose dependent stimulation of bone resorption and the bone resorption induced by IL-1beta was strongly inhibited by calcitonin treatment, indicating osteoclast-mediated bone resorption, suggesting that the bone resorption induced by IL-1beta appears to be osteoclast-mediated. This study supports the role of IL-1beta in the pathological modulation of bone cell metabolism, with regard to implication of the pathogenesis of osteoporosis by IL-1beta.

Animals↗

PubMed1984

Bone resorption in osteogenic sarcoma--II. Resorption of the bone collagenous matrix by tumor cells, normal fibroblasts and macrophages.

Three osteogenic sarcoma cell lines of human and canine origin were compared to normal fibroblastic cells and peptone-induced murine peritoneal macrophages in terms of bone collagenous matrix (BCM) resorption capacity. The dissolution of the BCM was measured in an in vitro system consisting of the tested cells and live or killed [3H]-proline-labeled fetal mouse long bones. Experiments with osteogenic sarcoma cells revealed a paradoxical phenomenon indicating an inverse relationship between the number of tumor cells and the rate of collagen resorption from live bones. On the other hand, collagen matrix of devitalized bones, particularly those denatured by exposure to heat, is strongly resorbed by osteogenic sarcoma cells even in the presence of serum. Contrary to osteogenic sarcoma cells, normal fibroblasts do not resorb collagen from either live or killed bones, regardless of the devitalization method and culture conditions utilized. Macrophages resorb collagenous matrix from live bones, but their collagen resorption activity from devitalized bones depends greatly on choice of the incubation condition. Results have shown that osteogenic sarcoma tumor cells, when acting alone, may not have the capacity to destroy healthy bone. We suggest, therefore, that bone destruction seen in osteogenic sarcoma patients depends on the metabolic condition of the affected bone, and the interaction between the tumor and normal host cells and tissues.

Animals↗

PubMed1992

Endothelin inhibits osteoclastic bone resorption by a direct effect on cell motility: implications for the vascular control of bone resorption.

The abundance of endothelin (ET)-producing endothelial cells in bone marrow and the proximity of these cells to bone-resorbing osteoclasts prompted us to evaluate the action of ET-1 on osteoclast function. Osteoclasts disaggregated from neonatal rat long bones were settled onto devitalized cortical bone substrate, and resorption was quantified by morphometry. The supernatant tartrate-resistant acid phosphatase activity was determined by a spectrophotometric method using paranitrophenol phosphate as substrate. Cell motility was quantified by time lapse video- and computer-assisted image processing using an empirical procedure for morphometric analysis. Cytosolic free calcium levels ([Ca2+]i) were measured in single cells by an indo 1-based microspectrofluorimetric method. Using the area of bone resorbed per slice as response, we found that ET-1 caused a significant (P = 0.011) concentration-dependent inhibition of osteoclastic bone resorption (EC50 = 2.5 nM) without inhibiting acid phosphatase secretion. Exposure of isolated osteoclasts to ET-1 also led to a marked concentration-dependent inhibition of osteoclast motility (EC50 = 7.9 nM; P = 0.013; t1/2 = 18 min) without significant effects on cell spread area. These effects of ET-1 were reversible after removing the peptide, and the cells remained viable during the experiments. In addition, ET-1 did not elevate [Ca2+]i at the concentrations tested. The results suggest that ET-1 specifically interacts with an osteoclast receptor to inhibit osteoclastic bone resorption and cell motility. As the concentration of ET-1 required for osteoclast inhibition was similar to that reported for smooth muscle contraction, it is possible that ET-1, produced locally from the bone marrow endothelial cell, might play a primary role in osteoclast regulation.

Acid Phosphatase↗

PubMed1991

Pertussis toxin inhibits hormonal stimulation of bone resorption in fetal rat limb bones.

The cellular basis for hormonal control of bone resorption is poorly understood. As the identifiable receptors for bone resorbing agents such as parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] are located on osteoblasts rather than osteoclasts, the nature of cellular signaling is obscure. Here it is reported that exposure of fetal rat limb bones to pertussis toxin, a bacterial protein that inhibits certain GTP binding proteins (G-proteins) involved in signal transduction, markedly inhibits bone resorption elicited by PTH, 1,25(OH)2D3 and prostaglandin E2. Pertussis toxin does not block the inhibition of alkaline phosphatase activity by PTH or 1,25(OH)2D3, and it potentiates the cyclic AMP response to PTH. These data support the existence of a pertussis toxin-sensitive G-protein that participates in regulation of bone resorption. The putative G-protein is apparently not involved in the initial transduction of hormonal signals, but it may be part of a final common pathway through which the osteoclast is activated by agents with widely divergent initial actions.

Animals↗

PubMed2006

Development and characterization of biphenylsulfonamides as novel inhibitors of bone resorption.

Increased osteoclastic bone resorption plays a central role in the pathogenesis of many bone diseases, and osteoclast inhibitors are the most widely used treatments for these diseases. We have identified and characterized a series of novel biphenylsulfonamide derivatives that have potent inhibitory effects on osteoclastic bone resorption in vitro and that prevent ovariectomy-induced bone loss in vivo. A number of aromatic substituted derivatives were prepared and a QSAR model was generated, which allowed accurate prediction of compound potency. Using this model, we have prepared compounds able to inhibit osteoclast formation and bone resorption in vitro at concentrations in the nanomolar range. One such compound, 55 (ABD295) (Greig, I. R.; Mohamed, A. I.; Ralston, S. H.; van't Hof, R. J. Alkyl Aryl Sulfonamides as Therapeutic Agents for the Treatment of Bone Conditions. GB Patent WO2005118528, 2005), fully reversed ovariectomy-induced bone loss in mice at a dose of 5 (mg/kg)/day. In conclusion, biphenylsulfonamides like 55 form a new class of potent antiresorptive agents with possible therapeutic use in diseases characterized by increased bone resorption.

Animals↗

PubMed2004

Amylin inhibits bone resorption while the calcitonin receptor controls bone formation in vivo.

Amylin is a member of the calcitonin family of hormones cosecreted with insulin by pancreatic beta cells. Cell culture assays suggest that amylin could affect bone formation and bone resorption, this latter function after its binding to the calcitonin receptor (CALCR). Here we show that Amylin inactivation leads to a low bone mass due to an increase in bone resorption, whereas bone formation is unaffected. In vitro, amylin inhibits fusion of mononucleated osteoclast precursors into multinucleated osteoclasts in an ERK1/2-dependent manner. Although Amylin +/- mice like Amylin-deficient mice display a low bone mass phenotype and increased bone resorption, Calcr +/- mice display a high bone mass due to an increase in bone formation. Moreover, compound heterozygote mice for Calcr and Amylin inactivation displayed bone abnormalities observed in both Calcr +/- and Amylin +/- mice, thereby ruling out that amylin uses CALCR to inhibit osteoclastogenesis in vivo. Thus, amylin is a physiological regulator of bone resorption that acts through an unidentified receptor.

Amyloid↗

PubMed1997

Osteoclasts, macrophages, and the molecular mechanisms of bone resorption.

The osteoclast is a physiological polykaryon and the major if not exclusive resorptive cell of bone. It participates in bone remodeling, repair, and growth and mobilization of mineral to meet homeostatic demands. Most importantly, osteoporosis, a disease endemic in Western society and Asia, is always a reflection of enhanced osteoclastic activity relative to bone formation by osteoblasts. In fact, all forms of anti-osteoporosis therapy proven successful involve inhibition of osteoclastic bone resorption. Bone resorption is regulated either by altering recruitment of osteoclast precursors into fully differentiated resorptive polykaryons or modulating the rate at which mature osteoclasts degrade bone. With this in mind, our laboratory has focused on the molecular mechanisms of osteoclast differentiation and the means by which the cell degrades bone matrix.

Animals↗

PubMed2002

The clinical use of bone resorption markers in patients with malignant bone disease.

BACKGROUND: Advanced tumors often metastasize to bone, resulting in a variety of skeletal complications. Bisphosphonates are potent inhibitors of osteoclast-mediated bone resorption that reduce the incidence and delay the onset of skeletal complications and reduce the need for radiation and surgery. Biochemical markers of bone resorption have been identified that can augment the imaging techniques used to diagnose bone metastases and assess response to bisphosphonate therapy. METHODS: In the current study, the available literature regarding bone resorption markers is reviewed and the clinical relevance of these data with respect to the treatment of bone metastases discussed. RESULTS: Urinary calcium and hydroxyproline have been widely used to assess bone metabolism, but do not appear to be well correlated with clinical outcome in patients with bone metastases. Several unique breakdown products of Type I collagen (including pyridinium crosslinks, pyridinoline, and deoxypyridinoline) and peptide-bound crosslinks (N-telopeptide and C-telopeptide) are more specific and sensitive markers of bone resorption. N-telopeptide and C-telopeptide have been identified as the most sensitive biochemical markers currently available for detecting bone metastases and for assessing response to therapy or disease progression. CONCLUSIONS: To the author's knowledge markers of bone resorption have not yet been recommended for routine clinical use. However, further research is needed to define their potential role in the diagnosis of bone metastases, the assessment of disease progression and response to bisphosphonate therapy, and predict the rate of bone loss and the potential for fracture. Suppression of bone resorption markers in response to bisphosphonate therapy appears to correlate with clinical outcome in patients with both osteolytic and blastic bone lesions; therefore, the goal of bisphosphonate therapy should be to suppress markers of bone resorption.

Biomarkers↗

PubMed1985

The effect of calcium-regulating hormones and prostaglandins on bone resorption by osteoclasts disaggregated from neonatal rabbit bones.

It has previously only been possible to assess osteoclastic bone resorption in intact bone, where other cell types may modify or mediate osteoclastic responses to environmental agents. We have recently developed techniques which enable us to measure bone resorption by osteoclasts extracted from bone and have used these techniques to assess the effects of prostaglandins (PGs) and calcium-regulating hormones on bone resorption by these cells. Osteoclasts were mechanically disaggregated from neonatal rabbit long bones and cultured on slices of devitalized cortical bone for 8 or 24 h. After this time, osteoclasts were associated with the appearance in the scanning electron microscope of characteristic resorption pits, the volume of which was calculated by computer-assisted morphometric and stereophotogrammetric techniques after removal of cells. Salmon calcitonin inhibited osteoclastic bone resorption at concentrations of 1 pg/ml and above, while PTH and 1,25-dihydroxyvitamin D3 were without significant effect. This suggests that the latter hormones do not increase bone resorption in intact bone through a direct effect on osteoclasts. PGI2, PGE1, and PGE2, all of which are known to stimulate resorption when added to intact bone, paradoxically reduced resorption in our cultures. It appears likely that PGs act as direct inhibitors of osteoclastic bone resorption but have an additional effect on other cells in bone, which are induced by PGs to cause osteoclastic stimulation.

Alprostadil↗

PubMed1985

[Effects of 1,25-dihydroxyvitamin D3 on bone resorption and 45Ca2+ efflux in bone cells].

1,25-dihydroxyvitamin D3[1,25(OH)2D3] effects on bone resorption in organ culture and on 45Ca2+ efflux rates in bone cells were measured in presence of a calcium channel inhibitor, diltiazem. Though, diltiazem reduced the 45Ca release from mice calvaria it did not act at the same Ca compartment as 1,25(OH)2D3 to alter Ca2+ flux parameters. It therefore seems difficult to hypothesize a simple relationship between bone resorption and Ca2+ movements in bone cells.

Animals↗

PubMed1991

Indomethacin inhibition of middle ear bone resorption.

Localized osteoclastic bone resorption is responsible for the pathological changes within the middle and inner ear, which result in hearing loss and vertigo in chronic otitis media and otosclerosis. The local control of osteoclastic bone resorption is incompletely understood. Various small, locally active molecules, cytokines, have been shown to affect resorptive processes. Additionally, prostaglandins and their inhibitors have been shown to modulate the resorptive process in a number of in vitro studies. In this study, indomethacin, a cyclooxygenase inhibitor, was tested in a model of localized bone resorption, the pressurized gerbil bulla. After the experimental period, indomethacin was found to inhibit the number of osteoclasts and the resorptive area on the inner surface of the bulla. Therefore, it is likely that endogenous cyclooxygenase metabolites are intermediates in the sequence of cellular events, which results in localized bone resorption as in some systemic models.

Animals↗

PubMed1989

Forskolin sensitizes parathyroid hormone-induced cyclic AMP response, but not the bone resorptive effect, in mouse calvarial bones.

The effect of forskolin on parathyroid hormone (PTH) stimulated bone resorption, as assessed in vitro by the release of 45Ca from prelabelled neonatal mouse calvarial bones, and cyclic AMP formation in mouse calvarial bones and osteoblast-like cells was investigated. Much higher concentrations (100-300-times) of PTH were required to stimulate cyclic AMP accumulation than to stimulate mineral mobilization in murine calvarial bones. PTH, in the absence of phosphodiesterase inhibitor, stimulated cyclic AMP formation in mouse calvarial bones at and above concentrations of 3-10 nmol/l with EC50 at 10-15 nmol/l. In the presence of forskolin (1 or 10 mumol/l) the minimal concentration required to obtain a cyclic AMP response to PTH was decreased by a factor of 30-100 and the EC50 value was decreased to 1-2 nmol/l. Similar results were seen in osteoblast-enriched cells. In addition, the magnitude of the PTH-induced cyclic AMP response was substantially potentiated by forskolin, both in calvarial bones and in isolated osteoblasts. Forskolin, in the absence of PTH, stimulated cyclic AMP levels in mouse calvaria at and above 1 mumol/l. In the presence of PTH, the response to forskolin was potentiated over the whole dose-response curve with apparent EC50 value at 1-2 mumol/l of forskolin. Forskolin (1 mumol/l) did not affect the magnitude of the 45Ca release response to PTH in 24 or 48 h cultures. In 96 h cultures, forskolin, in an additive manner, potentiated the effect of PTH on calcium mobilization. These results show that forskolin, in mouse calvarial bones and in isolated osteoblasts, in addition to directly stimulating cyclic AMP, can enhance receptor-mediated activation of adenylate cyclase. The finding that forskolin did not synergistically potentiate PTH-induced bone resorption suggests that there is no simple relationship between PTH-induced cyclic AMP formation and stimulation of bone resorption.

Animals↗

PubMed1998

Gutta-percha-stimulated mouse macrophages release factors that activate the bone resorptive system of mouse calvarial bone.

This study investigated the capacity of macrophages exposed to gutta-percha particles to produce factors affecting bone metabolism. Peritoneal mouse macrophages were isolated and incubated with and without gutta-percha particles, and the supernatants were assessed for bone resorbing activity by adding macrophage-conditioned media to cultures of neonatal mouse calvarial bones. Bone resorption was measured by mineral mobilization (45Ca release) and matrix degradation (3H from [3H]proline labelled bones). The results showed that supernatant from gutta-percha-stimulated macrophages enhanced bone resorption. This effect was related to the amount of gutta-percha, and the concentration and time of exposure to the conditioned media. Stimulated macrophages released enhanced amounts of prostaglandins E2 and I2; however, indomethacin, which inhibits the prostanoid response, had no effect on bone resorbing activity. The stimulatory effect on bone resorption was inhibited by calcitonin, interleukin-1 receptor antagonistic protein, and by antiserum neutralizing mouse interleukin-1alpha(IL-1alpha), but not by anti-IL-1beta. Filtration experiments revealed that the molecules involved in the resorption activity had an apparent molecular weight between 3000 and 30,000 Da. These experiments show that mouse peritoneal macrophages, when exposed to gutta-percha particles, release factors which have a bone resorbing activity that is primarily due to enhanced production of IL-1alpha.

Animals↗

PubMed1981

The effect of dental plaque grown in the presence of xylitol or sucrose on bone resorption in vitro.

Bone culture was used as an experimental model in studying the ability of dental plaque grown in the presence of xylitol or sucrose to induce bone resorption. Plaque samples were collected in young adults after six or ten days with no oral hygiene and with frequent use of xylitol- or sucrose-sweetened chewing gum. The rate of resorption was assayed by measuring the release of both acid phosphatase and 45Ca from bones into culture media during a three-day incubation period. Sucrose-induced plaque collected after ten days increased both of these indicators of bone resorption, while xylitol plaque decreased or had no effect under identical conditions. Xylitol consumption induced a marked increase in acid phosphatase activity of dental plaque - a phenomenon which would appear to be unrelated to bone resorption. The results suggest that the inflammatory potential of dental plaque may be reduced during xylitol consumption as compared to sucrose consumption.

Acid Phosphatase↗

PubMed1978

Isolation of a bone-resorptive factor from human cancer ascites fluid.

A protein fraction that induces the resorption of bone explants in organ culture was isolated from the ascitic fluid of patients with advanced cancer metastatic to the peritoneal cavity. Partial purification was achieved by means of gel filtration, affinity chromatography, and ion-exchange chromatography. The isolated fraction, the components of which have an apparent molecular weight of 60,000, was found to be heterogeneous by disc gel electrophoresis and to be composed primarily of proteins with relatively acidic electrophoretic properties. The specific bone-resorptive activity of this protein fraction was greatly increased over that of the unfractionated starting material, and the activity could be completely destroyed upon incubation with pronase and on heating. As determined by immunoassay and extraction procedures with various solvents, the bone-resorptive action of the isolated fraction was not attributable to the presence of parathyroid hormone, prostaglandin E2 or vitamin D-like sterols. In parallel experiments the supernatants of phytohemagglutinin-stimulated normal human peripheral leukocytes were subjected to identical chromatographic techniques, and a proten fraction with a molecular weight of 60,000, which resembled the resorptive fraction isolated from cancer ascites fluid and which contained significant bone-resorptive activity, was also partially purified.

Adult↗

PubMed2001

Comparison of the effects of intravenous pamidronate and oral clodronate on symptoms and bone resorption in patients with metastatic bone disease.

BACKGROUND: There is considerable debate as to the optimum schedule of bisphosphonate treatment in advanced malignancy. Short term studies using symptomatic response and biochemical markers of bone resorption may provide useful insight into differences between agents. PATIENTS AND METHODS: Fifty-one patients with metastatic bone disease were randomly allocated to either oral clodronate 1,600 mg daily (group 1), intravenous clodronate followed by the same schedule of oral clodronate (group 2). or intravenous pamidronate 90 mg monthly (group 3). No radiotherapy was delivered or other systemic anticancer treatments were allowed except for long term endocrine therapy. Bone resorption was assessed by measurement of urinary collagen crosslinks. At each visit a pain score was recorded. RESULTS: Symptomatic response was more frequent in the pamidronate group than in patients receiving clodronate. Nine of sixteen patients experienced a sustained improvement in pain score in the pamidronate-treated group, in contrast to only 4 of 16 and 2 of 11 patients in groups 1 and 2, respectively. There was a significant improvement in pain scores in the pamidronate arm compared with the clodronate treated patients after both three months of treatment (P <0.01) and at the last measurement (P <0.05). Biochemical changes correlated with changes in the pain score (P = 0.01). CONCLUSION: Intravenous pamidronate appears to be more effective than oral clodronate in both controlling symptoms and suppressing bone resorption.

Administration, Oral↗