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PubMed1989

[Radiographic study of bone resorption at the proximal end of the femur after total hip replacements].

Radiography following cemented total hip replacement (THR) often revealed progressive bone resorption at the proximal end of the femur. The purpose of this study is to clarify the relation between this bone resorption and loosening of the acetabular component. The radiographic analysis was done using radiographs of two hundred and ninety-nine Müller type THR for osteoarthritis with minimum five years follow-up at regular intervals. The bone resorption at the proximal end of the femur appeared frequently in cases of loosened acetabular component. As acetabular loosening progressed, the bone resorption increased accordingly. Further study revealed that incidences of loosened acetabular component were statistically higher in cases of progressive bone resorption than in cases of non-progressive, 5.2 years after operation. This study indicates that progressive bone resorption might be a histological reaction caused by debris of pulverized bone cement generated by loosening acetabular component. The degree to which bone resorption progresses, therefore, directly reflects the amount of loosening of the acetabular component and should be a indicator for surgery to reconstruct loosened acetabular component.

Acetabulum↗

PubMed1990

Prosthesis-associated pseudomembrane-induced bone resorption.

A pseudomembranous structure invariably develops at the cement-bone interface of implanted prostheses in association with aseptic loosening. The tissue has histological characteristics of a foreign body reaction presumably initiated by repetitive microtrauma-associated release of methacrylate cement and polyethylene wear debris. Explant cultures of pseudomembrane and synovial tissue derived from osteoarthritic patients undergoing revision for cemented hip implant failure have been shown to produce interleukin-1, tumour necrosis factor and prostaglandin E2, recognized mediators of bone resorption. Further, the conditioned media obtained from pseudomembrane cultures could directly effect bone resorption by inducing 45Ca release from prelabelled limb bone rudiments. Results implicate the prosthesis-associated pseudomembrane in the pathogenesis of the bone resorptive process responsible for prosthesis failure.

Adult↗

PubMed2006

[Current topics in drug therapy aiming at bone resorption].

The majority of current therapeutics for osteoporosis is targeting bone resorption by osteoclasts. Bisphosphonates, potent and specific inhibitors of bone resorption, are widely used for postmenopausal osteoporosis on the basis of large scale clinical trials which proved their ability to reduce fracture risk. Estrogen, which had been widely used in the US, lost its position of standard drug therapy for osteoporosis because of the recent evidence of increasing adverse events. On the other hand, the market share of selective estrogen-receptor modulators (SERMs), which utilize valuable functions of estrogen and have less adverse effects, has been climbing. Other novel therapeutic agents which aim at signal transduction of osteoclast differentiation and activation are promising as specific inhibitors of bone resorption.

Animals↗

PubMed1996

Vitamin K2 inhibits osteoclastic bone resorption by inducing osteoclast apoptosis.

In contrast to vitamin K1(VK1), vitamin K2(VK2) inhibited osteoclastic bone resorption by unfractionated bone cells and isolated osteoclasts. To investigate the mechanism of inhibition of osteoclastic bone resorption by VK2, we examined the effect of this vitamin on osteoclast apoptosis using a DNA-binding fluorescent dye, Hoechst 33258. In unfractionated bone cells and isolated osteoclasts on dentin slices, we first demonstrated that VK2 induced osteoclast apoptosis, but VK1 did not. Moreover, cycloheximide inhibited VK2-induced osteoclast apoptosis. These results suggest the possibility that VK2 inhibits osteoclastic bone resorption by targeting osteoclasts to undergo apoptosis, which leads to cell death.

Animals↗

PubMed1997

Pituitary adenylyl cyclase-activating polypeptides and vasoactive intestinal peptide inhibit bone resorption by isolated rabbit osteoclasts.

Nerve fibres present in the periosteum, cortical bone and bone marrow are proposed to be involved in the regulation of bone metabolism by the release of neuropeptides acting locally on bone cells. The present study describes the effects of vasoactive intestinal polypeptide (VIP), shown to be present in the vicinity of bone, and the two related neuropeptides pituitary adenylyl cyclase-activating polypeptide(1-38) (PACAP-38) and PACAP-27 on bone resorption in vitro induced by osteoclasts isolated from 10-day-old rabbits. Bone resorption was measured as the number and total area of pits formed by tartrate-resistant acid phosphatase-positive multinucleated cells (TRAP + MNCs) cultured for 3 days on devitalized slices of bovine cortical bone. All three neuropeptides had significant inhibitory effects on both the number and area of pits formed. At a high concentration (10(-7) M) the mean +/- S.E.M. reductions in the total area resorbed compared with controls were 70.3 +/- 8.2, 45.2 +/- 7.3 and 63.4 +/- 7.2% for PACAP-38, PACAP-27 and VIP, respectively. The corresponding values for the apparent dissociation constants were 0.93 +/- 0.30, 3.2 +/- 1.6 and 0.35 +/- 0.14 nM, respectively. The number of TRAP + MNCs was unaffected by application of neuropeptides. Autoradiography showed the presence of 125I-VIP binding sites on some stromal cells, whereas osteoclasts had no binding sites for 125I-VIP. A high number of 125I-calcitonin binding sites was demonstrated on osteoclasts in the same preparation. The signal transduction pathway remains to be fully elucidated but seems to be partly dependent on changes in intracellular calcium concentrations, since a number of stromal cells responded to application of 10(-8) M PACAP-38 or VIP, and at least partly independent of cAMP accumulation. Trifluoperazine and mellitin, two selective calmodulin inhibitors, failed to block the VIP-induced inhibition of bone resorption. Our results demonstrate a non-toxic and probably stromal cell-derived effect of PACAP-38, PACAP-27 and VIP on isolated rabbit osteoclasts, resulting in a potent inhibition of bone resorption in vitro. The signal transduction pathway for inhibition induced by PACAP-38, PACAP-27 and VIP may be mediated partly by changes in intracellular Ca2+ in stromal cells.

Acid Phosphatase↗

PubMed2000

Breast cancer cell line MDA-231 stimulates osteoclastogenesis and bone resorption in human osteoclasts.

Breast cancers commonly cause osteolytic metastases in bone, a process that is dependent upon osteoclast-mediated bone resorption, but the mechanism responsible for tumor-mediated osteoclast activation has not yet been clarified. In the present study we utilized a well-known human breast cancer cell line (MDA-231) in order to assess its capability to influence osteoclastogenesis in human bone marrow cultures and bone resorption in fully differentiated osteoclasts. We demonstrated that conditioned medium (CM) harvested from MDA-231 increased the formation of multinucleated TRAP-positive cells in bone marrow cultures. Bone resorption activity of fully differentiated human osteoclasts and of osteoclast-like cell lines, from giant cell tumors of bone (GCT), was highly increased by the presence of MDA-231 CM. Moreover, while MDA-231 by themselves did not produce IL-6 tumor cell, CM increased the secretion of IL-6 by primary human osteoclasts and GCT cell lines compared to untreated controls. These data suggest that MDA-231 produce osteoclastic activating factor(s) that increase both osteoclast formation in bone marrow culture and bone resorption activity by mature cells. Moreover, breast cancer cells stimulate IL-6 secretion by osteoclasts that is one of the factors known to supports osteoclastogenesis.

Acid Phosphatase↗

PubMed1988

The role of collagenase in bone resorption. An overview.

Since its discovery, vertebrate collagenase is postulated to be the key enzyme for collagen degradation, but the evidence for its participation in bone resorption was, until recently, very weak. The osteoclast, which is the major bone resorbing cell, does apparently not produce collagenase but lysosomal acid proteinases, including collagenolytic cysteine proteinases, whose involvement in bone resorption is supported by many observations. Recent reports indicating 1) that osteoblasts produce and secrete collagenase in response to bone resorbing hormones and 2) that bone resorption is inhibited by a specific collagenase inhibitor, have reintroduced collagenase as a plausible participant in the mechanisms of bone resorption. Moreover bone resorbing agents do not act directly on osteoclasts, but on osteoblasts which, by an unknown mechanism, induce the osteoclasts to excavate bone matrix. Collagenase could participate in the control of bone resorption by degrading the unmineralized collagen which seems to shield the underlying bone from osteoclastic attack. In addition, collagenase, stored as a latent proenzyme in the mineralized matrix, might cooperate with the lysosomal cysteine proteinases in the subosteoclastic lysis of demineralized collagen.

Animals↗

PubMed1995

Stimulative effects of lead on bone resorption in organ culture.

To clarify whether hypercalcemia after injection of Pb to rats is due to biological bone resorption or physicochemical mineral dissolution, the effect of lead (Pb) on release of previously incorporated 45Ca in organ culture was investigated. Pb at 50 microM and above stimulated the release of 45Ca and hydroxyproline (Hyp). Pb did not stimulate 45Ca release from the bones inactivated by freezing and thawing. Eel calcitonin (ECT), bafilomycin A1 and scopadulcic acid B (SDB) inhibited Pb-stimulated 45Ca release. These results indicate that Pb-induced 45Ca release is due to osteoclastic bone resorption. Pb-stimulated bone resorption was inhibited by indomethacin and flurbiprofen. Pb stimulated the release of prostaglandin E2 (PGE2) from the bones into the media. There was significantly high correlation between 45Ca and PGE2 release. Pb-induced bone resorption was inferred to be mediated by PGE2. From these results, it was suggested that hypercalcemia after Pb injection might be caused by biological bone resorption.

Animals↗

PubMed2005

MCP-1-induced human osteoclast-like cells are tartrate-resistant acid phosphatase, NFATc1, and calcitonin receptor-positive but require receptor activator of NFkappaB ligand for bone resorption.

MCP-1 (monocyte chemotactic protein-1) is a CC chemokine that is induced by receptor activator of NFkappaB ligand (RANKL) in human osteoclasts. In the absence of RANKL, treatment of human peripheral blood mononuclear cells with macrophage colony-stimulating factor and MCP-1 resulted in tartrate-resistant acid phosphatase (TRAP)-positive multinuclear cells that are positive for calcitonin receptor (CTR) and a number of other osteoclast markers, including nuclear factor of activated t cells, cytoplasmic, calcineurin-dependent 1 (NFATc1). Although NFATc1 was strongly induced by MCP-1 and was observed in the nucleus, MCP-1 did not permit the formation of bone-resorbing osteoclasts, although these cells had the typical TRAP(+)/CTR(+) multinuclear phenotype of osteoclasts. Despite a similar appearance to osteoclasts, RANKL treatment was required in order for TRAP(+)/CTR(+) multinuclear cells to develop bone resorption activity. The lack of bone resorption was correlated with a deficiency in expression of certain genes related to bone resorption, such as cathepsin K and MMP9. Furthermore, calcitonin blocked the MCP-1-induced formation of TRAP(+)/CTR(+) multinuclear cells as well as blocking osteoclast bone resorption activity, indicating that calcitonin acts at two stages of osteoclast differentiation. Ablation of NFATc1 in mature osteoclasts did not prevent bone resorption activity, suggesting NFATc1 is involved in cell fusion events and not bone resorption. We propose that the MCP-1-induced TRAP(+)/CTR(+) multinuclear cells represent an arrested stage in osteoclast differentiation, after NFATc1 induction and cellular fusion but prior to the development of bone resorption activity.

Acid Phosphatase↗

PubMed1998

Suppression of bone resorption in early postmenopausal women by intranasal salmon calcitonin in relation to dosage and basal bone turnover.

In the present study, we assessed the ability of increasing doses of intranasal calcitonin to suppress urinary deoxypyridinoline cross-link (DPD), a specific biochemical marker of bone resorption, in early postmenopausal women. Subjects consisted of 30 healthy Thai women within 5 years of postmenopause, randomly assigned to 50, 100, or 200 IU of intranasal calcitonin 5 days/week for 3 months. Calcium supplementation by calcium carbonate capsules at 750 mg of elemental calcium per day was given to all subjects. Twenty four-hour urine for DPD and creatinine assays was collected at baseline, 1 month, and 3 months after treatment. All DPD values were corrected with urinary creatinine before analyses. Data were expressed as mean +/- SEM. DPD decreased significantly 1 month after intranasal calcitonin treatment (P < 0.01). However, at 3 months, DPD increased when compared with the values at 1 month (P < 0.01), suggesting that there may be a reduction in the suppression of bone resorption after prolonged calcitonin therapy. Using a stepwise multiple regression model to address whether dosage and DPD at baseline influence the response to intranasal calcitonin, it was found that DPD suppression after intranasal calcitonin was not related to dosage but was strongly associated with baseline DPD (P < 0.0001). Suppression of bone resorption in early postmenopausal women by intranasal calcitonin is determined more by the state of bone turnover at baseline than the dosage of calcitonin.

Administration, Intranasal↗

PubMed2002

Increased bone resorption in the critically ill: association with sepsis and increased nitric oxide production.

OBJECTIVE: Cytokines stimulate nitric oxide production in bone, and high concentrations of cytokine-induced nitric oxide inhibit bone resorption in vitro. This has led to the suggestion that nitric oxide may protect against bone loss in inflammatory and infectious diseases. In this study, we sought to determine whether nitric oxide generated as the result of sepsis was associated with suppression of bone resorption in vivo. DESIGN: Observational study. SETTING: Adult intensive care unit of a university hospital. PATIENTS: We studied 20 consecutive patients who had been admitted to the intensive care unit because of sepsis and three who had been admitted because of trauma. Controls were 29 patients with noninflammatory musculoskeletal conditions. INTERVENTIONS: Standard clinical care. MEASUREMENTS AND MAIN RESULTS: Bone resorption was assessed by measurement of urinary pyridinoline and deoxypyridinoline as a ratio to urinary creatinine. Nitric oxide production was assessed by measuring the ratio of the nitric oxide breakdown products nitrate and nitrite to urinary creatinine. Urinary nitrate and nitrite/creatinine values were significantly higher in intensive care patients with sepsis (mean +/- sem, 0.164 +/- 0.053 micromol/mmol) than in intensive care patients with trauma (0.066 +/- 0.008) and controls (0.079 +/- 0.007; p =.007 between groups). Urinary pyridinoline/creatinine values were increased in intensive care patients with sepsis (553.8 +/- 193 nmol/mmol) and trauma (238 +/- 32) compared with controls (44.7 +/- 2.6; p =.001 between groups), and similar differences between the groups were observed for deoxypyridinoline/creatinine values: intensive care patients with sepsis, 86.4 +/- 24.0; intensive care patients with trauma, 46 +/- 4.2; and controls, 10.3 +/- 0.7 (p =.001). CONCLUSIONS: Critically ill patients with sepsis have increased nitric oxide production and increased bone resorption, whereas trauma patients have increased bone resorption in the presence of normal nitric oxide production. High concentrations of nitric oxide generated during the course of infection do not afford significant protection against accelerated bone resorption.

Adult↗

PubMed1987

Bone resorption and turnover in health and disease.

Excessive bone loss is a common cause of disability and presents a major public health problem in western societies. The most common cause is age-related bone loss and osteoporosis, but other common diseases associated with increased bone resorption include malignant disease, primary hyperparathyroidism, and Paget's disease. Despite the frequency of these disorders and the suffering they cause, their pathophysiology still remains obscure. However, recent advances in techniques in bone cell biology are now providing new insights into the pathogenesis and treatment of diseases associated with increased bone resorption. These advances have been paralleled by improvements in techniques for non-invasive assessment of bone status in patients with the common metabolic bone diseases.

Bone Neoplasms↗

PubMed1988

The anti-bone-resorptive agent calcitonin also acts in vitro to directly increase bone formation and bone cell proliferation.

The studies summarized in this report were intended to determine whether salmon calcitonin had direct effects on bone formation indices in vitro. The results of these investigations demonstrate acute effects of calcitonin on skeletal tissues derived from embryonic chickens to increase calvarial cell proliferation ([3H]thymidine incorporation into DNA) and bone matrix synthesis ([3H]proline incorporation into collagen, as [3H]hydroxyproline) in intact calvaria and tibiae. The effects of calcitonin on [3H]thymidine incorporation were significant at 1 mU/ml (0.08 nM; P less than 0.05), additive with respect to the action(s) of F (calcitonin increased the maximum effect of F, and F increased the effect of low dose calcitonin; P less than 0.01 for each), associated with an increase in total cell protein (r = 0.82; P less than 0.02), and inversely dependent on osteoblastic differentiation (r = -0.96; P less than 0.005). The effects of calcitonin to increase bone matrix synthesis ([3H]hydroxyproline incorporation, 139% and 155% of untreated control values for tibiae and calvaria, respectively; P less than 0.005 for each) were maximal at approximately 5 mU/ml (0.4 nM) and associated with a proportional increase in alkaline phosphatase activity in the bones (r = 0.71; P less than 0.05 for tibiae). These effects of calcitonin were not dependent on continuous exposure. [3H]Thymidine incorporation was increased in calvarial cells 16 h after a 4-h limited (inductive) exposure to calcitonin (at 3 mU/ml; P less than 0.01). [3H]Proline incorporation in embryonic chicken calvaria was also increased during 3 days of limited exposure (i.e. 4 h/day) to 10 mU/ml calcitonin (P less than 0.02). The proliferative action(s) of calcitonin was not unique to chicken osteoblastline cells. Salmon calcitonin also increased [3H]thymidine incorporation in the transformed murine calvarial cell lines MMB and MC-3T3-E1 and in primary cultures of cells prepared from newborn mouse calvaria (P less than 0.05 for each). Furthermore, these effects were observed at calcitonin doses (3-30 mU/ml) that also decreased murine bone resorption (i.e. 45Ca release from prelabeled neonatal mouse calvaria; P less than 0.01).

Alkaline Phosphatase↗

PubMed1993

Osteopontin mRNA expression during bone resorption: an in situ hybridization study of induced ectopic bone in the rat.

To study the relationship between the expression of osteopontin mRNA and ectopic bone formation and resorption, in situ hybridization using 35S-labeled RNA probes was performed on ectopic bone that was induced in an experimental rat model. The expression of type I collagen and osteocalcin in this ectopic bone was also examined. After 6-week-old male Wistar rats were injected intravenously with colchicine at a dose of 1 mg/kg, trabecular bone-like ectopic calcified tissue had formed in the medial bone marrow cavity of the tibia on day 4, and then continued to increase progressing forward to the distal cavity. On day 8 peak growth was attained, after which it was resorbed within 4 days as a result of osteoclast recruitment. Subsequent in situ hybridization of sections of the ectopic bone at 4, 6, 8, and 10 days after this colchicine treatment revealed that high levels of the type I collagen mRNA were expressed in the osteoblasts of the mineralized ectopic bone surface, not only during the formation period but also during bone resorption. Although osteocalcin showed no specific signals throughout the experiments, osteopontin mRNA was expressed temporarily at day 10 during the initial phases of ectopic bone resorption, primarily in both osteoblasts and osteocytes and further in some osteoclasts. These results suggest that de novo synthesis of osteopontin is closely associated with bone resorption and could possibly be required to initiate and mediate this biological process.

Animals↗

PubMed2004

Quercetin suppresses bone resorption by inhibiting the differentiation and activation of osteoclasts.

Although quercetin has suppressed bone resorption in several animal studies, its target cells and the mechanism of its action related to bone resorption has not been fully elucidated. We investigated the effect of quercetin on the differentiation and activation of osteoclasts. We used cocultures of mouse spleen cells and ST2 cells, and cultures of osteoclast progenitor cells [M-CSF-dependent (MD) cells from mouse bone marrow and murine monocytic RAW 264 (RAW) cells]. Quercetin dose-dependently inhibited osteoclast-like (OCL) cell formation at 2-5 microM concentration in both the coculture and MD cell culture. Quercetin inhibited the increase of tartrate-resistant acid phosphatase (TRAP) activity of mononuclear preosteoclasts (pOCs) induced by receptor activator of nuclear factor-kappaB (NF-kappaB) ligand (RANKL) in both MD and RAW cell cultures. Quercetin reversely induced the disruption of actin rings in OCLs. Quercetin also suppressed both pit formation induced by osteoclasts on dentine slices and PTH-stimulated (45)Ca release in mouse long bone cultures. These results suggest that osteoclast progenitors as well as mature osteoclasts, are quercetin's target cells in relation to bone resorption, and that quercetin's suppressive effect on bone resorption results from both its inhibitory effect on the differentiation of osteoclast progenitor cells into pOCs and from its disruptive effect on actin rings in mature osteoclasts.

Acid Phosphatase↗

PubMed1992

Inhibition of bone resorption in vitro by human enkephalinase (EC 3.4.24.11), a neutral metalloendopeptidase.

Bone metabolism is regulated by a wide variety of both circulating and locally produced peptides. The activity of such agents must be regulated, and one potential regulating mechanism is the inactivation of these peptides by locally produced proteolytic enzymes. One candidate for such a class of enzymes is enkephalinase (EC 2.3.24.11), a membrane-bound neutral metalloendopeptidase that inhibits the activity of a range of biologically active peptides, including interleukin-1 (IL-1), a potent bone-resorbing agent. In this study, we examined the effects of human enkephalinase on bone resorption in cultures of fetal rat long bones. We found that partially purified and highly purified enkephalinase inhibited bone resorption stimulated by parathyroid hormone (PTH) and IL-1 alpha. The effects on PTH-stimulated resorption were reversible, but enkephalinase did not inhibit prestimulated resorption. Enkephalinase also inhibited resorption induced by the nonpeptide stimulators 1,25-(OH)2D3, retinoic acid, and prostaglandin E2 (PGE2). In addition, preliminary studies confirmed a previous report of the presence of an enkephalinase-like activity in osteoblast-like osteosarcoma cells. These data are consistent with the hypothesis that proteolytic enzymes, such as enkephalinase, may play a role in the local regulation of bone resorption.

Animals↗

PubMed2002

Polyethylene and methyl methacrylate particle-stimulated inflammatory tissue and macrophages up-regulate bone resorption in a murine neonatal calvaria in vitro organ system.

There is considerable evidence that orthopaedic wear debris plays a crucial role in the pathology of aseptic loosening of joint prostheses. This study examined the effect of inflammatory membranes stimulated with methyl methacrylate and polyethylene on bone resorption, using the murine air pouch model. The capacity of RAW 264.7 mouse macrophages exposed to polymer particles to produce factors affecting bone metabolism was also studied. Neonatal calvaria bones were co-cultured with either pouch membranes or conditioned media from activated macrophages. Bone resorption was measured by the release of calcium from cultured bones, and the activity of tartrate-resistant acid phosphatase in both bone sections and culture medium was also assayed. Results showed that inflammatory pouch membrane activated by methyl methacrylate and polyethylene enhanced osteoclastic bone resorption. Conditioned media from particles stimulated mouse macrophages also stimulated bone resorption, although this effect was weaker than resorption induced by inflammatory pouch membranes. The addition of the particles directly into the medium of cultured calvaria bones had little effect on bone resorption. Our observations indicate that both inflammatory tissue and macrophages provoked by particles can stimulate bone resorption in cultured mouse neonatal calvaria bones. This simple in vitro bone resorption system allows us to investigate the fundamental cellular and molecular mechanism of wear debris induced bone resorption and to screen potential therapeutic approaches for aseptic loosening.

Animals↗

PubMed1990

Effect of glucocorticoids on the biologic activities of myeloma cells: inhibition of interleukin-1 beta osteoclast activating factor-induced bone resorption.

Regulatory effects of glucocorticoids (dexamethasone) on myeloma cells as well as bone resorption in multiple myeloma were investigated. Glucocorticoids significantly inhibited proliferation of myeloma cells, and decreased the messenger RNA (mRNA) expressions of interleukin-6 (IL-6) and secretory type immunoglobulin G (IgG). The inhibitory effects of glucocorticoids on myeloma cell proliferation could be due to the decreased expression of IL-6 mRNA, decreased IL-6 production, and thus suppression of autocrine growth by IL-6, which is an autocrine growth factor for myeloma cells as reported previously (Nature 332:83, 1988). Glucocorticoids also inhibited M-protein secretion by decreasing the levels of secretory type Ig mRNA. On the other hand, because IL-1 beta rather than lymphotoxin is considered to be a major osteoclast activating factor (OAF) produced by myeloma cells, and glucocorticoids decreased the expression of IL-1 beta mRNA and markedly suppressed the bone resorbing activity induced by IL-1 beta OAF in 45Ca-release bone resorption assay, it is suggestive that glucocorticoids could inhibit bone resorption induced by IL-1 beta OAF in multiple myeloma. Therefore, from these data it is concluded that glucocorticoids could be more effective chemotherapeutic agents in multiple myeloma than we expected, especially with regards to the inhibitory effects on proliferation and M-protein secretion from myeloma cells, as well as bone resorption by myeloma cells.

Blotting, Northern↗