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PubMed1999

Longitudinal changes of bone density and bone resorption in hyperthyroid girls during treatment.

Low bone mineral density (BMD) and increased bone turnover are common features of untreated hyperthyroidism in adult patients. The effect of treatment on BMD is still controversial. BMD and bone metabolism in hyperthyroid children have not been thoroughly investigated. In the present study, we measured spinal and whole body BMD by dual-energy X-ray absorptiometry in a group of 13 girls (aged 5.0-14.9 years) at diagnosis of hyperthyroidism. The bone resorption rate was assessed by urine measurement of N-terminal telopeptide of type I collagen (NTX). Hyperthyroid patients have been studied longitudinally during treatment. BMD values and NTX urine concentrations have been also determined in 155 healthy Caucasian girls (aged 2.4-24.2 years). Spinal and whole body bone density measurements were significantly lower compared with healthy controls in untreated hyperthyroid girls, after correction for differences in age and anthropometric measurements (p </= 0.033). Bone density measurements obtained after 12 and 24 months of treatment were no longer different from those of healthy girls. NTX urine levels at diagnosis of thyrotoxicosis were significantly higher than those found in healthy controls (p < 0.0001); 6 months after treatment, the urine levels did not show significant differences, and they remained stable after 12 and 24 months of therapy. Inverse correlations at diagnosis were found between serum-free thyroxine (FT4) serum levels and spinal (r = -0.42) and whole body bone density (r = -0.41); FT4 and free triiodothyronine serum levels directly correlated with the NTX concentration (r = 0. 77, and r = 0.71, respectively). In conclusion, the results of the present study demonstrate that low bone density values and high bone resorption rates are found in hyperthyroid children and adolescents at diagnosis of the disease. Our data also demonstrate that antithyroid treatment is able to reduce dramatically the bone resorption and to increase significantly both spinal and total body BMD, granting physiologic conditions for the achievement of the best obtainable peak bone mass.

Adolescent↗

PubMed1991

Bone mass and comparative rates of bone resorption and formation of fibular autografts: comparison of vascular and nonvascular grafts in dogs.

The metabolic fate of whole grafts that were either vascularized or nonvascularized were compared. This study was designed to quantify and correlate changes in bone resorption, formation, and mass in orthotopic, stably fixed, weight-bearing autografts. The grafts were 8-cm segments of the fibula that were internally fixed. Fibula segments subjected to sham operations, nonvascularized autografts, and vascularized autografts were studied in 16 dogs at three months after surgery. Three months prior to surgery the dogs were labeled repeatedly over two months with 3H-tetracycline and 3H-proline. Metabolic turnover of whole grafts was evaluated by quantifying loss of 3H-tetracycline for measuring postoperative resorption of bone mineral and loss of 3H-collagen for resorption of bone collagen. Net changes in bone dry weight, calcium, and collagen per whole grafts were obtained to determine differential changes in the mineral and matrix mass. The difference in change between bone resorption and bone mass was used to determine the amount of new bone formation that had replaced the resorbed bone. Vascularized autografts lost more mass (12%), and had more bone resorption (40%) and more bone formation (28%) than sham operated and unoperated fibulas. Nonvascularized grafts lost much more bone mass (48%) because resorption was large (61%) and formation was relatively small (13%). More new bone was formed in vascularized autografts than in nonvascularized autografts. During the incorporation of bone grafts, resorption is an early and rapid process, whereas formation is a late and slow process.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1985

Morphological evidence of reduced bone resorption in the osteosclerotic (oc) mouse.

Osteopetrosis, a metabolic bone disease characterized by a generalized sclerosis of the skeleton, is inherited as an autosomal recessive in a number of mammalian species. The pathogenesis of congenital osteopetrosis is mediated by a reduction in bone resorption as a result of decreased osteoclast function. This hypothesis is based on both functional and structural evidence of reduced bone resorption in all mutations examined to date. The present study examined the histology of cartilage and bone, the ultrastructure of osteoclasts, and the morphology of mineralized bone surfaces in a lethal osteopetrotic mutation, the osteosclerotic (oc) mouse. Histologically, epiphyseal cartilage growth plates, especially the hypertrophic zone, are markedly thickened in oc mice and metaphyses contain excessive osteoid, features characteristic of rickets. Transmission electron microscopy revealed that less than one-quarter of osteoclasts in oc mice demonstrated evidence of ruffled border formation compared with three-quarters of the osteoclasts in normal littermates. In mutants, ruffled borders were less elaborate and cytoplasmic processes penetrated into bone surfaces, suggesting that bone may be removed by mechanical rather than by enzymatic means. There was little morphological evidence of cartilage degradation and broad laminae limitantes persisted in mutants. Mineralized surfaces that undergo resorption in normal mice showed no evidence of bone resorption by scanning EM in mutants. The presence of a rachitic condition, the observations of reduced bone resorption, and the possible contribution of undermineralized matrices to decreased bone resorption are characteristics of the osteosclerotic mutation which suggest that it is a unique osteopetrotic mutant in which to study both the development and regulation of skeletal metabolism.

Animals↗

PubMed1995

Bone resorption induced by a metastatic human melanoma cell line.

Bone resorption resulting from the metastatic human melanoma cell line (A375) was investigated morphologically using an experimental model of bone metastases in nude mice. An injection of A375 (1 x 10(5)) in the left ventricle produced multiple osteolytic lesions. Many TRAPase-positive multinucleated cells, identified by EM as osteoclasts, were observed on the bone surface at the site of metastases. The findings suggest that bone resorption was caused by osteoclasts developed in the presence of tumor cells. Even where tumor cells were juxtaposed to bone surface, small and flat TRAPase-positive cells were shown to exist on the bone surface. Thus, bone resorption was mainly associated with the occurrence of osteoclasts. A large number of osteoclast progenitor cells were also observed adjacent to tumor cells and/or stromal cells located apart from bone, indicating possible participation of tumor cells and/or stromal cells in the differentiation of osteoclasts. Ultrastructurally, stromal cells and/or extracellular matrices were present between tumor cells and osteoclast progenitor cells. Immunohistochemical observation clarified the localization of heparan sulfate proteoglycan (HSPG) and fibronectin (FN) around osteoclast progenitor cells. These findings suggest that they play an important role in providing a microenvironment favorable for osteoclast differentiation and activation. The immunohistochemical localization of IL-6, PGE2, and TGF-alpha also indicates that they are involved in osteoclast differentiation and activation. In conclusion, bone resorption at the metastatic sites of A375 is mediated via osteoclasts and A375 cells may be involved in the differentiation and activation of osteoclasts in association with stromal cells, extracellular matrices (HSPG, FN) and osteotropic cytokines (IL-6, PGE2, TGF-alpha).

Acid Phosphatase↗

PubMed1986

Purification and partial characterization of a Mr 52,000 glycoprotein from human cancer ascites fluid which stimulates bone resorption in vitro.

A glycoprotein which stimulates bone resorption in vitro has been purified at least 375-fold from human cancer ascites fluid. Purification was accomplished utilizing fractionation with ammonium sulfate, anion exchange chromatography, high-performance size exclusion chromatography, adsorptive chromatography on hydroxylapatite, and high-performance anion exchange chromatography. The homogeneous bone-resorptive protein possesses an apparent molecular weight of 52,000 as calculated from electrophoresis in sodium dodecyl sulfate:polyacrylamide gels. On polyacrylamide gels at pH 8.9 in the absence of sodium dodecyl sulfate, the bone-resorptive protein migrates with the mobility of an alpha 2-globulin. The amino acid composition of this protein is marked by the absence of methionine and by a relatively high content of nonpolar amino acids. The protein possesses a single amino- and a single carboxyl-terminal amino acid, alanine, and leucine, respectively. The carbohydrate moiety, comprising 20% of the total weight, consists of neutral hexoses, galactosamine and glucosamine, and sialic acids. With respect to its biological activity, the ascites glycoprotein is one-fourth as potent as parathyroid hormone, on a molar basis, in its ability to stimulate calcium release from bone explants in vitro. Calcium release is significantly decreased on heating at 60 degrees C but is not inhibited by indomethacin.

Adult↗

PubMed1983

Inhibition of bone resorption in tissue culture by H1-receptor antagonists.

Mouse bone culture studies show that several representative H1-receptor antagonists, promethazine hydrochloride, pyrilamine maleate, tripelennamine hydrochloride, and diphenhydramine hydrochloride, inhibit parathyroid extract-stimulated bone resorption. The H2-receptor antagonists, metiamide and cimetidine, are ineffective. In view of the finding that histamine and histamine agonists did not stimulate bone resorption, it is unlikely that histamine receptors are involved in mediating parathyroid extract-stimulated bone resorption. Because H1-receptor antagonists bind to phospholipids and have been shown to influence membrane structure and function, it is suggested that they inhibit bone resorption by a mechanism that depends on their membrane-stabilizing effect.

Animals↗

PubMed1996

Mechanisms of cytokine induced bone resorption: role of nitric oxide, cyclic guanosine monophosphate, and prostaglandins.

We have examined the role of prostaglandins, nitric oxide (NO), and the NO induced effector molecule cyclic-guanosine monophosphate (cGMP) as mediators of cytokine effects on bone resorption in murine calvarial organ cultures. The combination of interleukin-1 beta (IL-1) and tumor necrosis factor alpha (TNF) stimulated NO production, PGE2 production, and bone resorption. The increase in bone resorption was inhibited by the NO synthase inhibitor L-NG-monomethyl arginine (LMMA) and by the cyclo-oxygenase inhibitor indomethacin, indicating that both factors act as mediators of bone resorption induced by IL-1 and TNF. In contrast, interferon gamma (IFN) inhibited bone resorption induced by IL-1, markedly stimulated NO production, but had no effect on IL-1 induced PGE2 production. The suppressive effect of IFN on bone resorption was reversed by LMMA, but enhanced by indomethacin confirming that the inhibitory effect of IFN on cytokine induced resorption is entirely attributable to high levels of NO production. While cytokine induced NO production was accompanied by increased production of cyclic guanosine monophosphate (cGMP), the cGMP agonist 8-bromo-cGMP had no significant effect on bone resorption, suggesting the effects of NO in bone resorption are mediated by other pathways. We conclude that the effect of cytokines on bone resorption are determined by a balance between levels of NO and PGE2; high NO concentrations inhibit bone resorption and antagonize the effects of PGE2, whereas lower concentrations act together with prostaglandins to enhance bone resorption. These observations may be of relevance to the pathogenesis of bone loss in inflammatory diseases such as rheumatoid arthritis (RA) where, IL-1 and TNF production are increased but IFN production is diminished, resulting in modest increases in NO and large increase in PGE production that are pro-resorptive.

Animals↗

PubMed1994

Blockade of osteoclast-mediated bone resorption through occupancy of the integrin receptor: a potential approach to the therapy of osteoporosis.

Bone resorption requires the tight attachment of the bone-resorbing cells, the osteoclasts, to the bone mineralized matrix. Integrins, a class of cell surface adhesion glycoproteins, play a key role in the attachment process. Most integrins bind to their ligands via the arginyl-glycyl-aspartyl (R-G-D) tripeptide present within the ligand sequence. The interaction between integrins and ligands results in bidirectional transfer of signals across the plasma membrane. Tyrosine phosphorylation occurs within cells as a result of integrin binding to ligands and probably plays a role in the formation of the osteoclast clear zone, a specialized region of the osteoclast membrane maintained by cytoskeletal structure and involved in bone resorption. Human osteoclasts express alpha 2 beta 1 and alpha v beta 3 integrins on their surface. Such signaling may also lead to "inside-out" effects, like increased expression of integrin receptors on the cell surface, or increased affinity of the integrin to its ligand. The alpha v beta 3 integrin, a vitronectin receptor, plays an essential role in bone resorption. Antibodies to this integrin and short synthetic RGD-containing peptides are able to block bone resorption in vitro. Echistatin, an RGD-containing protein from a snake venom, binds to the alpha v beta 3 integrin and blocks bone resorption both in vitro and in vivo. Peptides containing the RGD motif are potential competitive "antagonists" of the osteoclast integrins and may have utility in the blockade of bone resorption. Agonists may be identified by stimulation of intracellular signaling.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗

PubMed1985

Effects of the calcium antagonist, diltiazem on in vitro and in vivo/in vitro bone resorption.

The effect of the calcium antagonist diltiazem on bone resorption in organ culture has been investigated. It was found that diltiazem was ineffective alone but that in concentrations above 5 mumol/l it reduced mineral and organic resorption induced in vitro by 1.25 dihydroxycholecalciferol (1.25 (OH)2D3). No additivity with calcitonin effects was observed. Diltiazem did not significantly affect bone resorbing activity stimulated by 24,25(OH)2D3. Bone resorption was measured by an in vivo/in vitro technique using 45Ca prelabelled mice. Compared with 1.25(OH)2D3 alone treated group (0.480 pmol/g), it was found that diltiazem (100 nmol/g) reduced bone resorption without effect on calcium and phosphorus plasmatic concentrations at death. These data suggest that such a calcium antagonist is able to inhibit 1.25-(OH)2D3-increased-bone resorption either in vitro or in vivo/in vitro.

Animals↗

PubMed2002

Interferon-gamma production changes in parallel with bacterial lipopolysaccharide induced bone resorption in mice: an immunohistometrical study.

It has been reported that bacterial lipopolysaccharide (LPS) induces alveolar bone resorption and that the host immune system, especially activated T cells, plays a crucial role in osteoclastogenesis. On the other hand, interferon-gamma (IFN-g), which is produced by activated T cells, suppresses bone resorption both in vitro and in vivo. Thus, the question arises as to whether or not IFN-g production increases with increasing bone resorption. We previously demonstrated that repeated injections of Escherichia coli LPS into mouse gingiva causes osteoclast formation in alveolar bone. In the present study we observed changes in the IFN-g production of infiltrating cells in concurrence with bone resorption. Mice were repeatedly injected with 5 mg LPS 26 times every 48 hours. After the 16th injection, when the alveolar bone resorption reached a plateau, the concentration of LPS was altered (25 mg LPS or PBS alone). The level of bone resorption became significantly elevated, and the number of IFN-g- and interleukin-1 beta (IL-1b)-bearing cells also increased significantly in relation to bone resorption within the 25 mg LPS-injected group. On the other hand, few tartrate-resistant acid phosphatase positive cells, or IFN-g- and IL-1b-bearing cells, were seen in the PBS-injected group. These results suggest that alteration in IFN-g-bearing cells might play a role in counterbalancing LPS-induced bone resorption resulting from osteoclast activating cytokines such as IL-1b.

Animals↗

PubMed2000

The effect of particle phagocytosis and metallic wear particles on osteoclast formation and bone resorption in vitro.

Osteoclasts are multinucleated bone-resorbing cells that are formed from precursors that circulate in the monocyte fraction. This study has determined the effect of phagocytosis of metal particles on osteoclast formation and bone resorption in vitro. Human peripheral blood monocytes were cocultured for 21 days with osteoblast-like UMR 106 cells, in the presence of 1,25-dihydroxyvitamin D3, dexamethasone, and human macophage colony-stimulating factor. Cobalt-chrome alloy (CoCr), stainless steel (316L-SS), titanium alloy (TiAlV), and commercially pure titanium (cpTi) particles (size range, 0.5-3.0 microm) and 1.0-microm latex particles were added to the cocultures as a single dose at the beginning of each experiment. All 5 types of particles were readily phagocytosed by the monocytes. After 4 days' exposure to high concentrations of all the metal particles, some cell death was found in the cocultures. After 14 days, a reduction in the number of CD14+ cells was seen in cocultures exposed to high concentrations of metal particles, particularly CoCr and 316L-SS particles. Phagocytosis of latex particles by osteoclast precursors did not affect the ability of these cells to undergo osteoclast differentiation. In contrast, exposure to metal wear particle preparations caused a dose-dependent reduction in the number of vitronectin receptor-positive osteoclastic cells formed and a dose-dependent reduction in the bone resorption produced by these cells. This decrease in resorption was greater after exposure to CoCr and 316L-SS particles compared with TiAlV and cpTi particles. This in vitro cell culture system may provide a useful model to compare the effect of different prosthetic materials on human osteoclast formation and bone resorption.

Alloys↗

PubMed1989

Renal cell carcinoma in tissue culture secretes nondialyzable product that stimulates bone resorption in organ-cultured mouse calvaria.

The bone-resorbing capacity of human renal cell carcinomas in vitro has been examined. Bone resorption in cultures of mouse calvarial bones was assessed by the release of 45Ca from bones prelabeled in vivo and the mobilization of stable calcium and inorganic phosphate from nonlabeled bones. In addition, bone organic matrix degradation was determined either by the release of 3H from [3H]proline-labeled bones or by the loss of hydroxyproline from bone explants during culture. Tumor tissue-conditioned media (TCM) from 13 of 13 renal cell carcinomas stimulated bone resorption in a dose-dependent manner. From 5 of 13 kidneys with renal cell carcinoma, normal kidney cortex tissue was cultured and 4 of these 5 also produced bone-resorbing activity, but the amount was much less compared with the tumor tissue. The stimulatory effect of TCM on 45Ca release could be observed first after 12-24 h of culture. The effect could be inhibited by calcitonin but not by inhibitors of prostaglandin synthesis. The production of bone-resorbing activity by tumor cells could be inhibited by indomethacin and meclofenamic acid. In some tumors, the inhibition by indomethacin was total, whereas in other tumors only partial inhibition could be obtained. In 3 of 4, TCM bone-resorbing activity could be found in the retentate after dialysis. The results show that fresh human renal cell carcinoma tissue can elaborate prostanoid as well as nonprostanoid products that can stimulate bone resorption.

Animals↗

PubMed2000

The role of prostaglandin E receptor subtypes (EP1, EP2, EP3, and EP4) in bone resorption: an analysis using specific agonists for the respective EPs.

PGE2 functions as a potent stimulator of bone resorption. The action of PGE2 is thought to be mediated by some PGE receptor subtypes present in osteoblastic cells. In this study, we examined the involvement of PGE receptor subtypes, EP1, EP2, EP3, and EP4, in PGE2-induced bone resorption using specific agonists for the respective EPs. In mouse calvaria cultures, EP4 agonist markedly stimulated bone resorption, but its maximal stimulation was less than that induced by PGE2. EP2 agonist also stimulated bone resorption, but only slightly. EP1 and EP3 agonists did not stimulate it at all. RT-PCR showed that osteoblastic cells isolated from newborn mouse calvaria expressed all of the EPs messenger RNA (mRNA). Both EP2 agonist and EP4 agonist induced cAMP production and the expression of osteoclast differentiation factor (ODF) mRNA in osteoblastic cells. Simultaneous addition of EP2 and EP4 agonists cooperatively induced cAMP production and ODF mRNA expression. In mouse bone marrow cultures, EP2 and EP4 agonists moderately induced osteoclast formation, but the simultaneous addition of the two agonists cooperatively induced it, similar to that by PGE2. In calvaria culture from EP4 knockout mice, a marked reduction in bone resorption to PGE2 was found. In EP4 knockout mice, EP4 agonist failed to induce bone resorption, but EP2 agonist slightly, but significantly, induced bone resorption. These findings suggest that PGE2 stimulates bone resorption by a mechanism involving cAMP and ODF, which is mediated mainly by EP4 and partially by EP2.

Animals↗

PubMed2003

Osteoprotegerin regulates bone formation through a coupling mechanism with bone resorption.

Deficiency of osteoprotegerin (OPG), a soluble decoy receptor for receptor activator of nuclear factor-kappaB ligand (RANKL), in mice induces osteoporosis caused by enhanced bone resorption, but also accelerates bone formation. We examined whether bone formation is coupled with bone resorption in OPG-deficient (OPG-/-) mice using risedronate, an inhibitor of bone resorption. Histomorphometric analysis showed that bone formation-related parameters (e.g. mineral apposition rate and osteoblast surface/bone surface) in OPG-/- mice sharply decreased with suppression of bone resorption by daily injection of risedronate for 30 d. OPG-/- mice exhibited high serum alkaline phosphatase activity and osteocalcin concentration, both of which were decreased to the levels in wild-type mice by the risedronate injection. Serum levels of RANKL were markedly elevated in OPG-/- mice, but were unaffected by risedronate. The ectopic bone formation induced by bone morphogenetic protein-2 implantation into OPG-/- mice was not accelerated even with a high turnover rate of bone, but attenuation of mineral density from the ectopic bone was more pronounced than that in wild-type mice. These results suggest that bone formation is coupled with bone resorption at local sites in OPG-/- mice, and that serum RANKL levels do not reflect this coupling.

Animals↗

PubMed1992

Parathyroid hormone sensitizes long bones to the stimulation of bone resorption by 1,25-dihydroxyvitamin D3.

In response to hypocalcemia the serum PTH level increases rapidly followed by a PTH-induced rise in 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] production. Therefore, bone is first exposed to increased PTH levels before increased 1,25-(OH)2D3 levels. In the present study the effect of pretreatment with PTH on 1,25-(OH)2D3-induced bone resorption was examined. Bone resorption was measured as release of prelabeled 45Ca during culture from 17-day-old fetal mice radii/ulnae and metatarsals. Radii/ulnae and metatarsals are characterized by differences in development. In radii/ulnae mature osteoclasts are present, whereas in metatarsals only different stages of preosteoclasts can be found. Preincubation for 24 h but not 4 h with PTH increases the stimulation of bone resorption by 1,25-(OH)2D3 in fetal radii/ulnae but not in metatarsals. Coincubation of PTH and 1,25-(OH)2D3 did not result in a significant change in bone resorption compared to 1,25-(OH)2D3 alone. The observed difference in the effect of pretreatment with PTH between radii/ulnae and metatarsals indicates that PTH does not stimulate the development of early osteoclast precursors but that a certain level of differentiation of the osteoclast precursor is required. Pretreatment with prostaglandin E2 resulted in an effect similar to that of PTH. Inhibition of prostaglandin synthesis by indomethacin prevented the potentiation of 1,25-(OH)2D3-induced bone resorption by pretreatment with PTH. Thus, the present study demonstrates that PTH sensitizes responses to 1,25-(OH)2D3. PTH must be present before 1,25-(OH)2D3 to observe a potentiation of 1,25-(OH)2D3-induced bone resorption.(ABSTRACT TRUNCATED AT 250 WORDS)

Acid Phosphatase↗

PubMed1998

Inhibitory effect of genistein on bone resorption in tissue culture.

The effect of genistein on bone resorption in vitro was investigated. Femoral-metaphyseal tissues obtained from elderly female rats were cultured for 48 hr in Dulbecco's modified Eagle's medium (high glucose, 4.5%) supplemented with antibiotics and bovine serum albumin. The experimental cultures contained 10(-7) to 10(-3) M genistein. The bone-resorbing factors parathyroid hormone (1-34) (PTH; 10(-7) M), prostaglandin E2 (PGE2; 10(-5) M), and lipopolysaccharide ( 10 microg/mL) caused a significant decrease in bone calcium content. The decrease in bone calcium content induced by bone-resorbing factors was inhibited completely by genistein (10(-7) to 10(-5) M). In addition, this isoflavonoid (10(-5) M) completely inhibited the PTH (10(-7) M)- or PGE2 (10(-5) M)-induced increase in medium glucose consumption and lactic acid production by bone tissues. Moreover, genistein (10(-5) M) blocked both PTH (10(-7) M)-increased acid phosphatase and -decreased alkaline phosphatase activities of bone tissues. The inhibitory effect of genistein (10(-5) M) on PTH (10(-7) M)-stimulated bone resorption was clearly prevented by the presence of 10(-6) M tamoxifen, an anti-estrogen reagent. Genistein (10(-5) M) did not further enhance the inhibitory effect of estrogen (10(-9) M) on PTH-stimulated bone resorption. These findings indicate that genistein has a direct inhibitory effect on bone resorption in tissue culture in vitro.

Acid Phosphatase↗

PubMed1993

Bone resorption activity of particulate-stimulated macrophages.

Particulate wear debris from bone cement or prosthetic components can stimulate macrophages to cause bone resorption in a dose-dependent manner. This bone resorption activity of particulate-stimulated macrophages is associated with increased levels of both prostaglandin E2 (PGE2) and interleukin-1 (IL-1). In this study we compared the effect of particulate size, concentration, and composition on the secretion of IL-1 and PGE2 by peritoneal macrophages and on the bone-resorbing activity of conditioned medium (CM) harvested from particulate-challenged macrophages. Particulates (titanium, Ti; polymethylmethacrylate, PMMA; and polystyrene, PS) only with phagocytosable size stimulated peritoneal macrophages to secrete IL-1 and PGE2 in a dose- and time-dependent manner. Ti particles (1-3 microns) exhibited significantly enhanced bone-resorbing activity measured as 45Ca release. The maximum bone-resorbing response was observed at a concentration of 0.1% Ti (approximately 10-15 Ti particulates per cell), which also corresponded with the highest IL-1 levels measured in particulate-challenged CM. This was measured using either conditioned media from Ti-stimulated macrophages or in cocultures of calvarial bone and macrophages in the presence of Ti. Exogenous PGE2 and recombinant human IL-1 could significantly increase the 45Ca release; indomethacin (IM) significantly reduced both the spontaneous calcium efflux and active 45Ca release from in vivo labeled calvarial bones. However, IM and/or anti-IL-1 antibodies could suppress only partly the macrophage-mediated bone resorption, indicating that, in a macrophage-bone coculture system, factors other than PGE2 and IL-1 also may regulate particulate-induced bone resorption, probably involving multiple cell types.

Animals↗

PubMed1990

Simultaneous assessment of bone resorption and formation in cultures of 22-day fetal rat parietal bones: effects of parathyroid hormone and prostaglandin E2.

We have developed a method that allows us to measure bone resorption and formation simultaneously in the parietal bones from 22-day fetal rat calvaria. Parietal bones labeled with 45Ca, by injection of the mother, were cultured for 72 h with parathyroid hormone (PTH, bovine 1-34, 1.56 nM) or prostaglandin E2 (PGE2, 100 nM), in the presence or absence of indomethacin (Indo, 1 microM) or corticosterone (Cort, 1 microM). Two hours prior to the end of the culture, the bones were pulsed with [3H]-proline or [3H]-thymidine. Resorption was assessed as the percent of 45Ca released into the medium. Incorporation of [3H]-proline into collagenase digestible protein (CDP) and of [3H]-thymidine into DNA (TDR) were measured to assess collagen and DNA synthesis, respectively. Basal %45Ca release was 16 +/- 1% and was significantly decreased by Indo and Cort. Cort decreased TDR and CDP while Indo did not. PTH and PGE2 significantly increased %45Ca release, and this was not blocked by Indo. However, in the presence of Cort, only PTH increased %45Ca release while PGE2 did not. PGE2 increased TDR under all culture conditions while PTH increased TDR only in the presence of Cort. While PTH and PGE2 had the same effects on bone resorption, they had different effects on CDP. PGE2 increased CDP in the presence of Indo or Cort but PTH did not. Thus, this model allows us to study bone resorption, collagen synthesis, and DNA synthesis simultaneously. We have also shown that PTH and PGE2 differ in their sensitivity to inhibition of resorption by Cort and in their effects on bone formation.

Animals↗