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PubMed1998

A proposal for standardizing urine collections for bone resorption markers measurement.

Diurnal variations in the excretion of bone resorption markers were assessed in order to identify the type of urine collection which provides the most information on bone resorption rate and its relation to measuring bone dynamics in a postmenopausal population. Sixty women, ages 43-67 and without disease or treatment known to affect bone mineral density, were divided into two groups on the basis of femoral mineral density T-score: <1.5 (Group I), >1.5 (Group II). Bone formation was assessed by measuring bone alkaline phosphatase activity and osteocalcin concentration, bone resorption by urinary hydroxyproline, pyridinoline and deoxypiridinoline, N-telopeptide, galactosyl hydroxylysine, and CrossLaps. To identify the more appropriate collection times, urine samples were collected from 7 am to 3 pm; from 3 pm to 11 pm; from 11 pm to 7 am. Twenty-four hour urine collection and first morning void urine samples were also measured. The findings suggest that nocturnal collection and first morning void samples provide the most reliable data on the rate of bone degradation, possibly showing bone loss not only in osteopenic patients but also in women with a low T-score. Nocturnal and first morning samples should therefore be recommended in order to standardize sample collection, as they enable an accurate assessment of bone resorption markers and improved comparability to results from different studies, as well as a less cumbersome collection modality.

Adult↗
PubMed2001

The effect of calcium intake on bone composition and bone resorption in the young growing rat.

A low Ca intake by both rats and man increases bone resorption, decreases bone mass and increases the risk of osteoporosis. The skeletal effect of high Ca intakes is less clear, particularly during periods of bone mineral accrual. Twenty-four female 5-week-old rats, Wistar strain, were randomized by weight into three groups of eight rats each and fed ad libitum a semi-purified diet containing 2 (Ca-restricted), 5 (normal) or 20 (Ca-supplemented) g Ca/kg for 3 weeks. When compared with the normal Ca diet, urinary Ca excretion was unaffected by the dietary restriction of Ca for 3 weeks, but was greater (P<0.001) in Ca-supplemented rats. Urinary pyridinoline (Pyr) and deoxypyridinoline (Dpyr) levels were significantly greater during weeks 2 (Pyr P<0.05, Dpyr P<0.001) and 3 (Pyr P<0.01, Dpyr, P<0.001) of dietary Ca restriction, but were unaffected by Ca supplementation. Femoral dry weight and the concentration of Mg and P in femora were unaffected by dietary Ca concentration. Femoral Ca concentration was reduced (P<0.05) in the Ca-restricted group compared with the other two groups. In conclusion, these results suggest that increasing dietary Ca intake, well above the recommended level, had no effect on bone mineral composition or bone resorption (as assessed with urinary pyridinium crosslinks) in young growing female rats. In addition, these results confirm the findings of previous studies which have shown that bone Ca content in young growing rats was reduced by dietary Ca restriction and that this reduction results, at least in part, from an increased rate of bone resorption.

Amino Acids↗
PubMed2005

The role of subchondral bone resorption pits in osteoarthritis: MMP production by cells derived from bone marrow.

OBJECTIVE: The vascular invasion of bone marrow tissue into the subchondral plate is often observed in articular cartilage and we named it the subchondral bone absorption pit; however, its implication in the pathogenesis of osteoarthritis (OA) has been poorly understood. The purpose of this study was to evaluate its characteristics and roles in osteoarthritic conditions. METHODS: Articular cartilage specimens from 11 patients with medial type knee OA and 7 non-arthritic cadavers were analyzed with HE staining. OA sections were stained with safranin-O, TRAP (tartrate resistant acid phosphatase) and immunostained with anti-MMP-1, MMP-3, MMP-13, vitronectin receptor (VNR)-alpha chain, vimentin and bone morphogenic protein (BMP) 2/4 antibodies. RESULTS: Subchondral bone resorption pits were classified according to the extent of invasion: pits with bone marrow tissue were located within uncalcified cartilage below the tidemark in grade I and invaded beyond the tidemark in grade II, while no invasion was seen in grade 0. Grade II pits were dominant in OA compared to non-arthritic joints, especially medial condyles. Proteoglycan detected with safranin-O staining was lost around the tip of grade II pits and the density of pits was related to the modified Mankin Score. Cells in pits expressed vimentin, MMP-1, MMP-3 and MMP-13. Some polynuclear cells co-expressed VNR-alpha chain and MMP-13, whereas pits showed reparative features expressing BMP. CONCLUSION: These results suggest that subchondral bone resorption pits contribute to cartilage degradation by expressing matrix metalloproteinases in OA.

Aged↗
PubMed2000

Divergent effects of protein kinase C (PKC) inhibitors staurosporine and bisindolylmaleimide I (GF109203X) on bone resorption.

Activation of protein kinase C (PKC) has been suggested to play a role in bone resorption. However, phorbol esters, which activate PKC, have been reported to have both stimulatory and inhibitory effects on bone resorption. To study the role of PKC in bone resorption further, we have measured calcium release elicited by bone-resorbing hormones from isolated bones incubated with the PKC inhibitors staurosporine (ST) and the more PKC-selective ST analog bisindolylmaleimide I (GF109203X; GF). In fetal rat limb bone organ cultures, ST (1 microM) or GF (1 microM) significantly reduced the bone resorption induced by maximal concentrations of parathyroid hormone (PTH). However, when submaximal concentrations of PTH were used, lower concentrations of the two antagonists had divergent effects. GF (20-300 nM) acted solely as an antagonist, whereas ST (10-100 nM) significantly enhanced resorptive responses to PTH. ST also enhanced the bone resorption elicited by alpha-thrombin, tumor necrosis factor-alpha (TNF-alpha), and thyroxin (T4). ST alone had small stimulatory effects in some experiments. GF prevented the stimulatory effects of ST alone as well as the enhancing effect of ST on PTH-stimulated resorption. The divergent effects of ST and GF on the responses of bone to low concentrations of PTH and the ability of GF to antagonize the stimulatory effects of ST suggest that PKC isozymes have complex and even antagonistic effects on bone resorption.

Animals↗
PubMed2003

Differential effects of calmodulin and protein kinase C antagonists on bone resorption and acid transport activity.

Tamoxifen inhibits bone resorption by disrupting calmodulin-dependent processes. Since tamoxifen inhibits protein kinase C in other cells, we compared the effects of tamoxifen and the PKC inhibitor, bis indolylmaleimide II (bIM), on bone resorption and acid transport activity in isolated membrane vesicles. Bis indolylmaleimide inhibited bone resorption 50% with an IC50 approximately 3 microM, as well as acid transport activity in a concentration -dependent manner with an IC50 of approximately 0.4 IM. The IC50 of bIM for inhibiting acid transport activity was similar to that of calmodulin antagonists. The potassium ionophore, valinomycin, failed to restore bIM or tamoxifen-dependent inhibition of acid transport, suggesting that bIM and tamoxifen both inhibit H(+)-ATPase activity. Half maximal inhibitory concentrations of tamoxifen and bIM were not additive in acid transport assays, suggesting different sites of action. Furthermore, exogenous calmodulin blocked tamoxifen, but not bIM, -dependent inhibition of acid transport. We also compared the effects of tamoxifen and bIM on phosphorylation of proteins in isolated membrane fractions as determined by 32P incorporation and autoradiography. Tamoxifen had no effect on protein phosphorylation in contrast to bIM, which inhibited phosphorylation of eight proteins with different apparent kinetics. The data suggest that, while tamoxifen and bIM both affect H(+)-ATPase activity, the mechanisms of action are different.

Acridine Orange↗
PubMed1982

Unidirectional migration of osteosarcoma cells with osteoblast characteristics in response to products of bone resorption.

To investigate the mechanisms by which bone-forming cells are attracted to areas of bone resorption during bone remodeling, we have used in vitro methods to look for signals released by resorbing bone, which may be chemotactic for cultured bone cells. We have found that cultured rat osteosarcoma cells, which have characteristics associated with the osteoblastic phenotype, migrate in a unidirectional manner in response to a signal released by resorbing bones. These cells also migrated unidirectionally in response to Type I collagen, which comprises 95% of the bone matrix. This phenomenon of chemotaxis of bone-forming cells to sites of previous resorption may be an important component of the process of bone remodeling and the coupling of bone formation to bone resorption.

Animals↗
PubMed2003

Effects of cyclosporine on osteoclast activity: inhibition of calcineurin activity with minimal effects on bone resorption and acid transport activity.

Cyclosporine results in rapid and profound bone loss in transplant patients, an effect ascribed to osteoclasts. Cyclosporine, complexed with the appropriate immunophilin, inhibits calcineurin (the calcium/calmodulin dependent serine/threonine phosphatase) activity. We tested the hypothesis that cyclosporine inhibits calcineurin activity in osteoclasts, resulting in stimulation of osteoclast activity. We compared the effects of cyclosporine A and the calmodulin antagonist, tamoxifen, on bone resorption by avian osteoclasts. Tamoxifen inhibits bone resorption approximately 60%, whereas cyclosporine A only inhibited bone resorption 12%. One-hour treatment with 100 nM cyclosporine inhibited osteoclast calcineurin activity 70% in whole cell lysates, whereas 10 microM tamoxifen only inhibited calcineurin activity 25%. We compared the effects of cyclosporine A and tamoxifen on acid transport activity in isolated membrane vesicles and in isolated membrane vesicles obtained from osteoclasts treated with cyclosporine A or tamoxifen under conditions that inhibit calcineurin activity. Direct addition of cyclosporine A in the acid transport assay, or pretreatment of cells with cyclosporine A followed by membrane isolation, had no effect on acid transport activity in membrane vesicles. In contrast, direct addition of tamoxifen to membranes inhibits acid transport activity, an effect that can be prevented by addition of exogenous calmodulin. Furthermore, acid transport activity was also inhibited in membrane vesicles isolated from cells treated with tamoxifen. In conclusion, cyclosporine A inhibits osteoclast calcineurin activity; however, calcineurin inhibition does not correspond to a significant effect on acid transport activity in isolated membrane vesicles or bone resorption by osteoclasts.

Acids↗
PubMed1986

The effect of ipriflavone (TC-80) on bone resorption in tissue culture.

The fetal long bone culture system developed by Raisz for the assessment of bone resorption was modified to improve the sensitivity, by using radii and ulnae separately, based on the observation of the consistently higher release of 45Ca from the radii than ulnae. Effects of ipriflavone (TC-80), an isoflavonoid derivative currently under clinical trial for its effect on osteoporosis, on bone resorption were examined in this new system. Ipriflavone and its metabolites (5 out of 6) at 10 micrograms/ml or more inhibited basal 45Ca release from bones. The inhibitory effects were still demonstrated in the presence of submaximal concentration of parathyroid hormone (12.5 ng/ml). The effect of ipriflavone on bone resorption was apparently not due to its toxicity on bone cells, since the inhibition was reversible.

Animals↗
PubMed2005

Immune response: the key to bone resorption in periodontal disease.

Periodontal disease infection with oral biofilm microorganisms initiates host immune response and signs of periodontitis, including bone resorption. This review delineates some mechanisms underlying the host immune response in periodontal infection and alveolar bone resorption. Activated T lymphocytes have been historically implicated in experimental periodontal bone resorption. An experimental rat adoptive transfer/gingival challenge periodontal disease model has been demonstrated to require antigen-specific T lymphocytes and gingival instillation of antigen and LPS for bone resorption. Interference with costimulatory interactions between T cells and antigen-presenting cells abrogated bone resorption, further emphasizing the significance of immune response in periodontal disease. Receptor activator of nuclear factor kappaB ligand (RANKL), a critical osteoclast differentiation factor, is expressed on T lymphocytes in human periodontal disease as determined by immunohistochemical and confocal microscopic analyses. Interference with RANKL by systemic administration of osteoprotegerin (OPG), the decoy receptor for (and inhibitor of) RANKL, resulted in abrogation of periodontal bone resorption in the rat model. This finding indicated that T cell-mediated bone resorption is RANKL-dependent. In additional experiments, treatment of T cell-transferred rats with kaliotoxin (a scorpion venom potassium channel inhibitor) resulted in decreases in T-cell RANKL expression, diminished induction of RANKL-dependent osteoclastogenesis, and abrogation of bone resorption, implicating an important role of immune response/RANKL expression in osteoclastogenesis/bone resorption. In other experiments, adoptive transfer of antigen-specific, RANKL-expressing B cells, and infection with the antigen-bearing Actinobaccillus actinomycetemcomitans gave rise to periodontal bone resorption, indicating that B cells also have the capacity to mediate bone resorption, probably via RANKL expression. In humans, prominent T lymphocytes have been identified in periodontal disease, and diseased tissues showed elevated RANKL mRNA expression, as well as decreased OPG mRNA expression. Mononuclear cells from periodontal lesions involving T cells and B cells of patients induced osteoclastogenesis in vitro. In summary, a biofilm interface initiates immune cell infiltration, stimulating osteoclastogenesis/bone resorption in periodontal disease. This resorption can be ameliorated by inhibition of RANKL activity or by diminishing immune cell stimulation. These two procedures, if localized, have the potential to lead to the prevention or therapeutic management of periodontal disease and therefore require further study.

Aggregatibacter actinomycetemcomitans↗
PubMed1999

Autocrine regulation of osteoclast formation and bone resorption by IL-1 alpha and TNF alpha.

Bone resorption is regulated by the cytokines within marrow cells that mediate osteoclast formation and activation. IL-1 and TNF induce bone resorption by stimulating the production of osteoclast-like multinucleated cells and by increasing the bone-resorbing activity of formed osteoclasts. This study was designed to detect IL-1 and TNF in osteoclasts in vitro and to determine whether these cytokines up-regulate osteoclast differentiation and bone resorption. The production of IL-1 alpha, -beta, and TNF alpha, beta in osteoclasts was examined immunohistochemically and by in situ hybridization. In the co-culture of C57BL/6N mouse bone marrow and MC3T3-G2/PA6 cells, a colony of osteoclasts formed, and IL-1 alpha and TNF alpha were detected. However, IL-1 beta and TNF beta were not detected. To investigate the role of IL-1 alpha and TNF alpha from osteoclasts, we enumerated TRAP-positive cells and measured the resorption pit areas in the presence of antibodies against IL-1 alpha and TNF alpha. The addition of antibodies against IL-1 alpha and TNF alpha to the co-culture system decreased the number of TRAP-positive colonies at seven days after incubation (anti-IL-1 alpha, 25.0 +/- 2.3%; anti-TNF alpha, 41.7 +/- 3.7%; anti-IL-1 alpha + anti-TNF alpha, 40.5 +/- 1.3%; and control, 100%), and the ratio of mononuclear to multinuclear cells had changed (anti-IL-1 alpha, 90:10; anti-TNF alpha, 75:25; anti-IL-1 alpha+ anti-TNF alpha, 88:12; and control, 60:40). The total pit areas per dentin slice also decreased with the addition of antibodies (anti-IL-1 alpha, 28,828; anti-TNF alpha, 49,249; anti-IL-1 alpha + anti-TNF alpha, 30,685; and control, 303,139 mm2). These results suggest that local production of IL-1 alpha and TNF alpha by osteoclasts is an important mechanism for regulating the osteoclast differentiation and bone resorptive process.

Acid Phosphatase↗
PubMed1995

The effect of bisphosphonate on alveolar bone resorption following mucoperiosteal flap surgery in the mandible of rats.

Following elevation of a full thickness flap a transient burst of regional remodeling occurs. This phenomenon is termed in orthopedic surgery as regional accelerated phenomenon (RAP), beginning with accelerated resorption activity followed by a slow process of bone regeneration. Recently we have demonstrated that a mucoperiosteal surgical flap of rat mandible is producing a typical RAP process. Bisphosphonates are synthetic compounds that are taken up preferentially by the skeleton and suppress osteoclast-mediated bone resorption by a mechanism that is not yet fully understood. Amino bisphosphonate has been shown to inhibit active bone resorption without interfering with bone formation. In this study we evaluated the effect of amino bisphosphonate on bone resorption associated with a mucoperiosteal flap used as a resorptive model. We compared the effect of amino bisphosphonate in rats using IV administration with topical application at 3 dose levels. The results show that topical application of all 3 doses (0.15, 0.75, and 1.5 mg/ml) had no inhibiting effect on bone resorption after surgery, while IV administration at 0.5 mg/kg body weight significantly reduced the bone resorption. Interestingly, in the non-operated side, amino bisphosphonate increased mineral density.

Administration, Topical↗
PubMed1985

Generalised increase in bone resorption in carcinoma of the prostate.

Several indirect biochemical indices of bone resorption are increased in patients with carcinoma of the prostate and skeletal metastases. We have examined histological indices of bone resorption in biopsies from affected patients. Bone-forming surfaces and active osteoblast numbers were increased in skeletal sites adjacent to tumour tissue and indices of bone resorption were significantly increased at sites adjacent to tumour. Contrary to expectation, indices of bone resorption were also increased in bone distant from skeletal metastases. These findings suggest that prostatic cancer induces generalised loss of trabecular bone which may minimise disturbances in plasma calcium homeostasis but could contribute to morbidity.

Bone Neoplasms↗
PubMed1994

Dimensional analysis of osteoclastic bone resorption and the measurement of biologically active calcitonin.

Calcitonin inhibits bone resorption through a direct action on the osteoclast. We report a quantitative analysis of bone resorption by disaggregated rat osteoclasts. We then used our findings to develop a formal bioassay for calcitonin. Osteoclasts were mechanically disaggregated from neonatal rat long bones and dispersed at low densities on slices of devitalized bovine cortical bone. The resulting areas of bone excavation were quantified to micrometric precision by scanning electron microscopy together with computer-assisted image analysis. These findings were correlated with the volumes of bone resorption in the same slices measured by confocal scanning microscopy for the first time. The total planar areas of bone resorption per slice correlated linearly (r = 0.78) with the confocal microscopic measurements of total volume resorbed, provided that volume was expressed to its two-thirds power. The latter transformation resulted in representations of the determined areas ([length]2) and volumes ([length]3) which were dimensionally consistent. These findings thus demonstrate that osteoclastic bone excavations show a consistent relationship between area and volume and that assessments of the area of excavations accordingly provide an empirical representation of the volume of bone resorbed. Furthermore, in view of the skewed nature of the distributions of area measurements, we assessed the effect of transforming the response variable to derive a metameter, (planar area of resorption)1/2. Such transformed data points, which expressed the data in the dimensions of [length], were more normally distributed than the raw data points and had more stable variances over a wider concentration range. We accordingly determined relative potencies using parallel line analyses on the transformed data. The latter offered a consistent correlation to the volume measurements when these were also converted to dimensions of [length] (r = 0.805). It was confirmed that the inhibition of bone resorption by calcitonins from various species, namely, pig, salmon and eel, was quantitatively dependent upon concentration of the respective peptides. The resulting assay was also found to be sufficiently sensitive to measure picomolar peptide concentrations with a precision, lambda (standard deviation/slope), ranging between 0.3 and 0.8. Finally, we identified factors affecting assay precision and sensitivity.

Animals↗
PubMed1991

The effect of sex hormones on bone resorption by rat osteoclasts.

Although sex hormones are important in the attainment and maintenance of bone mass, the mechanism by which they exert their effect is unknown. We therefore tested the effects of estradiol-17 beta, dihydrotestosterone, and progesterone on osteoclasts, the cells that resorb bone. Osteoclasts were disaggregated from neonatal rat long bones, and incubated with or without the addition of osteoblastic cells or osteoblast-like cell lines. Bone resorption was assessed by scanning electron microscopy as the extent of excavation of the bone surface after incubation. We found dihydrotestosterone (1-100 nmol/l) and progesterone (10-1000 nmol/l) to have no significant effect on bone resorption. By contrast, E2 (1 nmol/l) reduced bone resorption in osteoclast cultures to which osteoblasts had been added, by approximately 25%, although consistent inhibition with other concentrations (0.01, 0.1, 10 nmol/l) was not observed. To our surprise, E2 was also associated with a delayed, dose-responsive, stimulation of bone resorption, in the range 0.1-10 nmol/l, in osteoclast cultures free from added osteoblastic cells. Tamoxifen, which itself had no effect on bone resorption, appeared to antagonise these E2 effects. Although the physiological significance of the stimulatory effect is unclear, we hypothesize that its presence prevented us, and previous workers, from observing dose-responsive inhibition of bone resorption by E2 in vitro.

Animals↗
PubMed1996

Effect of diacylglycerols on osteoclastic bone resorption.

We studied the effect of various synthetic diacylglycerols (DAGs) on bone resorption by rat and chick osteoclasts. 1-stearoyl-2-arachidonoyl-sn-glycerol (DAG IV), at a concentration of 100 microM, caused a significant reduction in resorption pit number in both species at 6 and 24 hours without any toxic effect. Over a 6-hour incubation period, a significant inhibition was seen at 10 and 100 microM in both species. 1,2-dioctanoyl-sn-glycerol (DAG I) and 1,2-dihexanoyl-sn-glycerol (DAG III) caused a marked inhibition of resorption by rat osteoclasts at 6 hours, but there was recovery of bone-resorptive ability over a 24-hour incubation period. DAGs with the -rac conformation failed to have any effect on bone resorption. In time-lapse video studies, osteoclast motility was not influenced by any of the DAGs at any of the concentrations used. Our results indicate that DAGs with the -sn conformation inhibit bone resorption, and DAGs with the -rac conformation do not. The finding that DAGs, the physiological activators of protein kinase C (PKC), inhibit bone resorption provides further evidence for an important role of the PKC pathway in the regulation of osteoclast activity.

Analysis of Variance↗
PubMed2002

Onion and a mixture of vegetables, salads, and herbs affect bone resorption in the rat by a mechanism independent of their base excess.

Prevention of low bone mass is important to reduce the incidence of osteoporotic fractures. In man, the consumption of fruits and vegetables is associated with greater bone mineral density (BMD), an effect that is claimed to be caused by their base excess buffering metabolic acid, thought to dissolve bone. We showed previously that in the rat the consumption of several vegetables, salads, and herbs inhibits bone resorption and that onion increases bone mass. In this study we show that, although the intake of onion is associated with a decrease in urinary noncarbonic acid excretion and a concomitant inhibition of bone resorption of similar magnitude, the two findings are not causally related. Onion retains its bone resorption inhibitory activity in the rat even when added to a vegetarian diet with typical base excess. Onion and a mixture of vegetables, salads, and herbs retain their inhibitory activity even when metabolic acid is buffered with potassium citrate. In addition, neither the pH nor the potassium content of individual ashed vegetables, salads, and herbs correlates with inhibition of bone resorption. The effect of vegetables, salads, and herbs, which inhibit bone resorption in the rat, therefore is not mediated by their base excess but possibly by a pharmacologically active compound(s).

Animals↗
PubMed1989

Cyclosporines: correlation of immunosuppressive activity and inhibition of bone resorption.

Cyclosporine A (CsA) is a potent immunosuppressive agent that inhibits stimulated bone resorption in vitro. To study the mechanism of this effect, we have compared CsA with several cyclosporine analogs that vary in immunosuppressive potency. CsA as well as another potent immunosuppressive analog, CsG, inhibited parathyroid hormone (PTH) and interleukin-1 (IL-1)-stimulated resorption of fetal rat limb bones. The nonimmuno-suppressive analogs CsH and CsF did not inhibit PTH or IL-1-stimulated bone resorption. Likewise, the weakly immunosuppressive analog CsD did not significantly inhibit PTH-stimulated bone resorption. Although other mechanisms cannot be excluded, our data are consistent with the concept that bone resorption may involve an immune cell-derived mediator.

Animals↗