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PubMed2005

BSP and RANKL induce osteoclastogenesis and bone resorption synergistically.

UNLABELLED: RANKL and BSP are upregulated in several bone resorptive disorders. However, the mechanisms by which these two factors might induce osteoclastogenesis and bone resorption synergistically under pathological conditions remain largely unknown. INTRODUCTION: RANKL and bone sialoprotein II (BSP) have been shown to be upregulated in the serum of individuals with abnormally high osteoclastogenic and bone resorptive activities. Here we provide experimental evidence that RANKL and BSP induce osteoclastogenesis and bone resorption synergistically but mediate opposite effects in osteoclast survival and apoptosis. MATERIALS AND METHODS: RAW264.7 cells and mouse bone marrow-derived monocytes/macrophages were treated with human recombinant BSP in the presence and absence of RANKL. TRACP stainings, bone resorption assays, Western blotting, immunoprecipitation analyses, and semiquantitative RT-PCR were used to evaluate the effects of BSP in osteoclast differentiation and bone resorption. Survival, DNA condensation, and caspase activity assays were used to determine the putative effects of BSP in osteoclast survival and apoptosis. RESULTS AND CONCLUSIONS: RANKL induced osteoclast differentiation and bone resorption at a higher extent in the presence than in the absence of BSP in RAW264.7 cells and bone marrow-derived monocytes/macrophages. c-Src-dependent c-Cbl phosphorylation was 8-fold higher in RAW264.7 cells treated with BSP and RANKL than in those treated with RANKL alone. Furthermore, BSP and RANKL activated the master regulator of osteoclastogenesis nuclear factor of activated T cells (NFAT)-2 and increased the mRNA expression of other differentiation markers such as cathepsin K or TRACP. Inhibition of c-Src activity or chelating intracellular calcium inhibited the synergistic effects in bone resorption and the phosphorylation of the c-Src substrate c-Cbl. Inhibition of calcineurin or intracellular calcium elevation inhibited the synergistic effects in osteoclastogenesis and decreased NFAT-2 nuclear levels. On the other hand, BSP and RANKL mediated opposite effects in osteoclast survival and apoptosis. Thus, BSP increased survival and decreased apoptosis markers in differentiated RANKL-treated RAW267.5 cells and RANKL/macrophage-colony stimulating factor (M-CSF)-treated bone marrow-derived monocytes/macrophages. In addition, RAW267.5 cells treated with BSP and RANKL exhibited decreased activation of the proapoptotic Jun N-terminal kinase pathway and increased activation of anti-apoptotic AKT pathway than cells treated with RANKL or BSP alone. Taken together, our findings suggest that BSP contributes to RANKL-mediated bone resorption by inducing osteoclastogenesis and osteoclast survival and decreasing osteoclast apoptosis.

Animals↗
PubMed1997

Effects of an inhibitor of cathepsin L on bone resorption in thyroparathyroidectomized and ovariectomized rats.

The process of bone resorption by osteoclasts involves the dissolution of mineral salts and enzymatic degradation of the mainly collagenous extracellular matrix. Cysteine proteinases, which can efficiently degrade collagen at acidic pH, have been suggested to play an important role in the bone resorptive process. The cysteine proteinase cathepsin L is secreted by osteoclasts, and inhibitors of this enzyme can prevent bone resorption in vitro. The activity of acetyl-leu-leu-norleucinol (ALLN), a selective inhibitor of cathepsin L, was investigated in two models of bone resorption in vivo. In the first study, the ability of ALLN to inhibit bone resorption was investigated in Ro-13-6298 (arotinoid)-treated thyroparathyroidectomized (TPTX) rats. ALLN [100 mg/kg, intraperitoneally (i.p.)] inhibited hypercalcemia by 62.8% acutely (p < 0.001), compared to 94.9% (p < 0.001) inhibition by salmon calcitonin (sCT) (10 IU/kg, subcutaneously). In rats treated for 3 days with ALLN, arotinoid-induced reduction in cortical bone mineral density measured by peripheral quantitative computed tomography (pQCT) was inhibited by 86.4% (p < 0.05) in rats treated with ALLN 100 mg/kg, i.p., and by 82% in rats treated with 50 mg/kg, i.p. (p < 0.05). In a second study, the efficacy of ALLN was tested in a longitudinal study in ovariectomized (ovx) rats. Bone loss, measured by pQCT, was unaffected by treatment with ALLN. The bisphosphonate alendronate, however, inhibited bone loss in this model. These data demonstrate the ability of a cathepsin L inhibitor to inhibit bone resorption in arotinoid-treated TPTX rats, a process which may be dependent on the activity of cathepsin L-like cysteine proteinases. In contrast to its effects in TPTX rats, ALLN had no inhibitory activity on bone resorption in ovx rats. It is possible that in chronic bone resorption in ovx rats, the activity of other enzymes such as cathepsins OC-2 or K allows the process of resorption to continue even when cathepsin L is inhibited by ALLN. Further studies are required to determine why the activity of ALLN varies between different animal models. These data indicate that there may be variations in the effects of drugs in different animal models of bone resorption which should be considered when investigating novel antiresorptive therapies.

Animals↗
PubMed1998

Osteoclast differentiation factor mediates an essential signal for bone resorption induced by 1 alpha,25-dihydroxyvitamin D3, prostaglandin E2, or parathyroid hormone in the microenvironment of bone.

Osteoclast differentiation factor (ODF), a ligand for osteoprotegerin (OPG)/osteoclastogenesis-inhibitory factor (OCIF), induces osteoclast-like cell formation in vitro. To elucidate the role of ODF in the microenvironment of bone, we examined effects of ODF, OPG/OCIF, and anti-ODF polyclonal antibody on bone resorption using a fetal mouse long bone culture system. A genetically engineered soluble-form ODF (sODF) elicited bone resorption in a concentration-dependent manner and OPG/OCIF blocked the bone resorption. Anti-ODF polyclonal antibody, which neutralizes ODF activity, negated bone resorption induced by 1 alpha,25-dihydroxyvitamin D3, parathyroid hormone, or prostaglandin E2. OPG/OCIF also abolished bone-resorbing activity elicited by these bone-resorbing agents. Interleukin 1 alpha-stimulated bone resorption was also significantly suppressed by anti-ODF polyclonal antibody and OPG/OCIF. Thus, we conclude that ODF plays a critical role in bone resorption in the microenvironment of bone.

Animals↗
PubMed1987

Hypercalcemia induced with an arotinoid in thyroparathyroidectomized rats. New model to study bone resorption in vivo.

A model of stimulated bone resorption was developed using a synthetic retinoid in thyroparathyroidectomized rats. The retinoid induced an increase in bone resorption and in the number of vertebral subperiosteal osteoclasts. The resulting increase in plasma Ca could be used as an easily measured index of bone resorption. Three bisphosphonates produced a dose-related prevention and reversal of retinoid-induced hypercalcemia. Their potencies were similar to those previously obtained by histomorphometry. Irradiation (600 rad) of the rats prevented hypercalcemia but failed to reverse it, showing that proliferation of osteoclast precursor cells was important in inducing, but not in maintaining, bone resorption. Calcitonin produced similar effects on calcemia and prevented the increase in osteoclast number but failed to reverse the increase, suggesting that it inhibited precursor proliferation. This model represents a new tool to study mechanisms of bone resorption and the action of inhibitors in vivo.

Animals↗
PubMed2006

Bisphosphonate modulates morphological and mechanical properties in distraction osteogenesis through inhibition of bone resorption.

Despite the general clinical acceptance of distraction osteogenesis and much attention to bone formation in this method, little is recognized about activated bone resorption in the regenerated bone. The purpose of this study was to demonstrate the simultaneously activated bone resorption with activated bone formation and to investigate the role and efficacy of bisphosphonate in distraction osteogenesis. Left tibiae of 54 immature rabbits were lengthened for 3 weeks at a rate of 0.7 mm/day after a 1-week lag. Regenerated bone was quantitatively investigated by radiographic bone density, bone histomorphometry, and three-point bending testing. Animals received either vehicle or nitrogen-containing bisphosphonate (N-BP), YM529/ONO5920 at doses of 0.4 mg/kg/w or 0.004 mg/kg/w for 6 weeks. Regenerated bone of the vehicle group showed a radiologically characteristic zone structure containing the osteopenic zones adjacent to the sclerotic zones. The regenerated bone of the 0.4-mg/kg/w group showed no osteopenic zones during the course and eventually became homogeneously radiodense. The bone volume corresponding to the osteopenic zone of this group was 5.6-fold greater compared with that of the vehicle group. The lengthened bone strength of this group was 3.3-fold greater in ultimate force than that of the vehicle group and equivalent to the contralateral tibia. The 0.004-mg/kg/w group had no substantial differences compared with the vehicle group, despite radiological enhancement of the mineralized front as well as somewhat delayed bone resorption. These results demonstrate that not only bone formation but also bone resorption is highly activated in the regenerated bone, implying high bone turnover. Sufficient N-BP caused a notable modulation in morphological properties of the regenerated bone through inhibition of highly activated bone resorption and eventually increased mechanical properties.

Absorptiometry, Photon↗
PubMed1980

Diphosphonates inhibit bone resorption by macrophages in vitro.

The diphosphonates are a group of synthetic compounds which are adsorbed onto hydroxyapatite crystal surfaces and inhibit both the growth and dissolution of these crystals. They also inhibit mineralisation and resorption of bone in vivo. The effects of diphosphonates were tested on the attachment of macrophages to bone and on the dissolution of bone mineral by macrophages. Attachment was unaffected but resorption was inhibited. Diphosphonates were found to be cytotoxic at much lower concentrations when bone mineral was present, and the most likely explanation for the effects of diphosphonate on bone resorption is that the drug is adsorbed onto the mineral surface where it reaches cytotoxic concentrations.

Animals↗
PubMed1988

A local pathophysiologic mechanism of the resorption of residual ridges: prostaglandin as a mediator of bone resorption.

The role of PG as a bone resorption mediator in RRR was investigated in the rat model and the following may be concluded from the data. 1. PG is suggested to be a mediator of the RRR. 2. The continuous and localized bone resorption in RRR may be caused by continuous synthesis of local PG. 3. PG producing cells and specific stimuli responsible for RRR are still unknown.

Alveolar Process↗
PubMed2004

The role of interleukin-1 in bone resorption in rheumatoid arthritis.

Bone loss in RA includes juxta-articular osteopenia, erosions and systemic osteoporosis. In each case, synthesis of new bone matrix is unable to balance osteoclast-mediated bone resorption, resulting in net bone loss. IL-1, TNF and other proinflammatory cytokines stimulate osteoclast differentiation and activation, resulting in bone loss. In addition, these proinflammatory cytokines stimulate synovial fibroblasts and chondrocytes to produce proteinases that degrade cartilage. In animal arthritis models, blocking IL-1 significantly reduces bone erosions and cartilage degradation, whereas blocking TNF decreases synovitis. In patients with active RA, treatment with the TNF blockers etanercept and infliximab, as well as with anakinra, a recombinant human IL-1 receptor antagonist, significantly reduced erosions and joint space narrowing. It remains to be determined, however, whether slowing radiographic progression with these biological therapies will significantly improve long-term outcomes in RA.

Antibodies, Monoclonal↗
PubMed1991

Ibuprofen inhibits localized bone resorption in the middle ear.

Localized osteoclastic bone resorption plays a significant role in the pathogenesis of several diseases of the middle ear as well as orthodontic tooth movement and long bone remodeling. The mechanisms of control of localized bone loss and systemic bone resorption may be different but both may be mediated by a final common pathway which includes prostaglandins. Prostaglandins seem to have a predominantly stimulatory effect on bone resorption, although the exact mechanism is poorly understood. Ibuprofen, a nonsteroidal antiinflammatory drug, is known to inhibit the synthesis of prostaglandins. It is likely that ibuprofen, through its inhibition of prostaglandin synthesis, would decrease the localized osteoclastic bone resorption in a previously described animal model system. Mongolian gerbils were divided into three groups: low dose ibuprofen (10 mg/kg per day), high dose ibuprofen (30 mg/kg per day), and a control group. Following surgical implantation of catheters to the right bullae of each gerbil, pressure was applied for 8 days, stimulating osteoclastic bone resorption. After killing the animals and histomorphometric analysis of the bullae from each, comparisons were made between each group using osteoclast surface (percentage of bone area covered by osteoclasts), osteoclast number (number of osteoclasts/mm bone length), and osteoclast profile area (in microns2). Significantly lower osteoclast surface (Oc.S/BS) was found in pressurized bullae from both treatment groups when compared with pressurized bullae from controls (P less than 0.05) and significantly lower osteoclast number (N.Oc/T.L) in pressurized bullae from both treatment groups when compared with pressurized bullae from controls (P less than 0.05). These differences were found to be dose-dependent.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1981

Immunoreactive collagenase and bone resorption.

1. Active mouse bone collagenase is excluded from its inhibitory antibody by preincubation of that antibody with various forms of inactive enzyme, e.g. 'procollagenase', some collagenase-inhibitor complexes or partially denatured or degraded collagenase. This property allows the detection of several enzymatically inactive forms of collagenase. 2. The accumulation of immunoreactive collagenase in the culture fluid of mouse bones occurred only in the presence of heparin and was not correlated with bone resorption induced by parathyroid hormone. These experiments provide further (see Lenaers-Claeys, G. and Vaes, G., Biochim. Biophys. Acta (1979) 584, 375-388), more conclusive evidence that the critical role in the resorption of the organic matrix of these explants may be due to another enzyme system than collagenase.

Animals↗
PubMed1994

Effects of plasminogen and interleukin-1 beta on bone resorption in vitro.

Inflammatory bone resorption, a characteristic feature of periodontal disease and rheumatoid arthritis, appears to be mediated by interleukin-1 beta (IL-1 beta). IL-1 beta has been shown to stimulate a wide range of proteolytic enzymes, including collagenases and plasminogen activators, in particular chondrocytes, synovial cells, and isolated osteoblasts. In this study, we have examined the hypothesis that IL-1 beta may stimulate bone loss by inducing the activity of plasminogen activators (PAs) in bone cultures. The latter would convert plasminogen to plasmin, which in turn can activate precursor procollagenase to collagenase. Active collagenase would then break down the bone collagen matrix. In the present study, release of 45Ca from fetal rat long bones in culture was studied in the presence of plasminogen and IL-1 beta. Plasminogen and IL-1 beta separately enhance resorption of fetal rat long bones in vitro. When plasminogen and IL-1 beta are added together at suboptimal levels, mainly additive effects are observed. The presence of heat-inactivated serum does not alter these results. These data tend to indicate that IL-1 beta is stimulating bone resorption through both PA-dependent and PA-independent pathways.

Animals↗
PubMedDate not supplied

Urinary bone resorption markers in patients with metabolic bone disorders.

Recently, urinary pyridinoline and deoxypyridinoline have been commonly employed as bone resorption markers. We studied these markers in 17 patients with hyperthyroidism, 15 undergoing long-term anticonvulsant drug therapy, and 28 with postmenopausal osteoporosis. Both markers had significantly higher levels than those in age-matched control groups. Values of urinary pyridinoline and deoxypyridinoline correlated well with urinary hydroxyproline levels in patients with hyperthyroidism (r = 0.856, p < 0.001 for pyridinoline and hydroxyproline; r = 0.919, p < 0.001 for deoxypyridinoline and hydroxyproline); however, poor correlations were observed, especially between urinary deoxypyridinoline and urinary hydroxyproline (r = 0.357, NS) in patients with postmenopausal osteoporosis. To compare the discriminatory ability of urinary pyridinoline and deoxypyridinoline, receiver operating characteristic (ROC) curves were generated for each of these patient groups using data from age-matched healthy females as the control group. The areas under the curves for both markers were 100.0% in hyperthyroidism. The areas under the curves for pyridinoline in patients undergoing long-term anticonvulsant drug therapy (mean +/- SE; 98.1 +/- 2.8%) and postmenopausal osteoporosis (77.9 +/- 5.7%) were significantly higher than those for deoxypyridinoline in anticonvulsant drug therapy (92.4 +/- 3.3%) and in osteoporosis (64.9 +/- 4.3%). Using data from premenopausal healthy females as the control group, areas under ROC curves for urinary pyridinoline (100.0%) and deoxypyridinoline (94.8 +/- 5.9%) were significantly higher than those for urinary hydroxyproline (73.8 +/- 9.4%) in patients undergoing long-term anticonvulsant drug therapy. In patients with postmenopausal osteoporosis, those for urinary pyridinoline (97.0 +/- 2.8%) were also significantly higher than those for urinary hydroxyproline (74.0 +/- 6.4%).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1986

[Age-related changes and sex differences in bone resorption in the mouse femur: a light and scanning electron microscopic study].

Bone resorption surfaces can be identified as rough areas by scanning electron microscopy. In this study, for understanding the principle of bone resorption and influences of gonads on the bone resorption in long bones, osteoclasts and bone resorption surfaces in the femur were qualitatively and quantitatively examined by light and scanning electron microscopy in 250 dd-mice of both sexes at 4, 7, and 14 weeks of age; some of the animals were gonadectomized at 4 weeks and examined at 7 and 14 weeks. The numbers of osteoclasts and bone resorption surfaces on the distal trabecular bones in the femur were large at 4 and 7 weeks and became smaller at 14 weeks. The area-proportion of the bone resorption surfaces in the distal trabecular bone region was large at 4 weeks and decreased with age. The number of osteoclasts and the number and area-proportion of the bone resorption surfaces were greater in females than males at 7 and 14 weeks. The sex-differences after puberty were large at 14 weeks than 7 weeks. After gonadectomy, the above values were not changed in females but significantly increased in males. In gonadectomized mice, the values were greater in males than females at 14 weeks. The results suggest that bone resorption activities change corresponding to the growth rate of the femur and receive inhibitory influences by male gonadal products, possibly androgenic hormones.

Aging↗
PubMed1998

A useful method to evaluate bone resorption inhibitors, using osteoclast-like multinucleated cells.

Since excessive bone resorption in postmenopausal osteoporosis is a pathological manifestation of the disease, it is important to control bone resorption activity of osteoclasts as a means of controlling the disease. To screen bone resorption inhibitors, a simple and quantitative method to assay bone resorption is needed. However, it has been difficult to prepare a lot of osteoclasts required for the screening of many compounds in vitro. We used the method for the preparation of mouse osteoclast-like multinucleated cells in vitro and developed a useful method in which osteoclast-like multinucleated cells were placed on dentin slices and the calcium released from dentin into the culture medium was measured. Under the optimal conditions, the increase of the calcium concentration caused by bone resorption activity of the osteoclast-like cells was significant and inhibited by calcitonin in a dose-dependent manner. We also examined the inhibitory effect of calcitonin on the pit area caused by bone resorption and found that the decrease of the calcium released from dentin was correlated with that of the pit area. Furthermore, several known bone resorption inhibitors such as bisphosphonate, bafilomycin A1, and herbimycin A showed inhibitory effects on the calcium release from dentin slices. Thus, this simple method provides us a useful screening system to find bone resorption inhibitors with novel mechanisms.

Animals↗
PubMed2002

Gender differences in serum markers of bone resorption in healthy subjects and patients with disorders affecting bone.

To assess how two different serum markers of bone resorption may reflect changes in bone turnover, we compared age- and sex-related changes in serum C-terminal telopeptide of type I collagen (betaCTx) and tartrate-resistant acid phosphatase activity (TRAP) in 136 healthy men and 184 normal women. Serum levels of the two markers were also assessed in several groups of patients of both sexes presenting with the most common metabolic and endocrine bone diseases: established osteoporosis (n = 77), primary hyperparathyroidism (n = 44), glucocorticoid excess (n = 17), chronic renal failure (n = 39), active Paget's disease of bone (n = 5), humoral hypercalcemia of malignancy (n = 3), osteomalacia (n = 3), hyperthyroidism (n = 10), post-surgical hypoparathyroidism (n = 10), acromegaly (active disease, n = 8) and Cushing's syndrome (n = 10). In men the regression of betaCTx with age showed an initial decrease in bone resorption followed by an increase thereafter, starting from the sixth decade of life. No age-related change in serum TRAP activity was observed. In women, by contrast, a slight but significant linear correlation of both serum betaCTx and TRAP with age (r = 0.223, p<0.003 and r = 0.333, p<0.0001, respectively) was found, the two markers being positively correlated (r = 0.238, p<0.002). In each class of patients the mean Z-scores of betaCTx were significantly higher than those of TRAP activity. Moreover, compared with normal subjects, serum betaCTx seems to be characterized by a superior sensitivity relative to TRAP measurement, at least in the disorders studied.

Acid Phosphatase↗
PubMed2005

Increased osteoblastogenesis and decreased bone resorption protect against ovariectomy-induced bone loss in thrombospondin-2-null mice.

Although bone is composed primarily of extracellular matrix (ECM), the dynamic role that the ECM plays in regulating bone remodeling secondary to estrogen loss is relatively unexplored. Previous studies have shown that mice deficient in the matricellular protein thrombospondin-2 (TSP2-null) form excess endocortical bone; thus, we postulated that enhanced bone formation in TSP2-null mice could protect against ovariectomy (OVX)-induced bone loss. Wild-type (WT) OVX mice showed a significant loss of both midfemoral endocortical and proximal tibial trabecular bone, but OVX did not significantly alter TSP2-null bone. TSP2-null mice showed an increase in bone formation, as indicated by a 70% increase in serum osteocalcin two weeks post OVX and a two-fold increase in bone formation rate (BFR) five weeks post OVX as measured by dynamic histomorphometry. WT animals showed only a 20% increase in serum osteocalcin at two weeks and no change in BFR at five weeks. This increase in bone formation in TSP2-null OVX mice was accompanied by a three-fold increase in osteoprogenitor number. Although these results provide a partial explanation for the maintenance of bone geometry post-OVX, TSP2-null mice five weeks post-OVX also showed a significantly lower level of bone resorption than OVX WT mice, as determined by serum levels of the amino-terminal telopeptide of type I collagen (NTx). We conclude that the absence of TSP2 protects against OVX-induced bone loss by two complementary processes: increased formation and decreased resorption.

Animals↗
PubMed2005

The effect of a simultaneous dietary administration of xylitol and ethanol on bone resorption.

Our previous studies have shown that dietary xylitol supplementation diminishes bone resorption in rats, as well as protects against ovariectomy-induced increase of bone resorption during experimental osteoporosis. Interestingly, ethanol, when given simultaneously with xylitol, is known to increase blood concentration of xylitol. On the other hand, ethanol, when given alone, has been shown to increase bone resorption. The aim of the present study was to evaluate the effects of a simultaneous dietary administration of 10% xylitol and 10% ethanol on bone resorption. Bone resorption was determined using measurement of urinary excretion of hydrogen 3 (3H) radioactivity in 3H-tetracycline prelabeled rats. Already 4 days after the beginning of dietary supplementations, excretion of 3H was about 15% lower in the xylitol group (diet supplemented with 10% xylitol) and about 25% lower in the xylitol-ethanol group (diet supplemented with 10% xylitol and 10% ethanol) as compared to the controls. The excretion of 3H in these groups remained smaller than that of the controls throughout the entire study period of 40 days. The excretion of 3 H in the xylitol-ethanol group remained also smaller than that of the xylitol group. Bone mineral density and bone mineral content were determined with a peripheral quantitative computed tomography (pQCT) system from the rat tibiae at the end of the experiment. Trabecular bone mineral density and trabecular bone mineral content were significantly greater in the xylitol group and in the xylitol-ethanol group compared to the controls. They were also greater in the xylitol-ethanol group as compared to the xylitol group. Cortical bone mineral density and cortical bone mineral content did not differ significantly between the groups. In conclusion, a simultaneous dietary supplementation with 10% xylitol and 10% ethanol seems to diminish bone resorption and to increase trabecular bone mineral density and trabecular bone mineral content in rats. These effects seem to be stronger than the effects induced by 10% xylitol supplementation alone.

Animals↗