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PubMedDate not supplied

A prospective longitudinal study of urinary excretion of a bone resorption marker in adolescents.

In growing subjects, the rates of bone resorption and bone deposition are substantially larger than in non-growing individuals. The purpose of this study was to measure the urinary excretion of a specific bone resorption marker in function of adolescent growth stages in a prospective longitudinal study. A cohort of 60 adolescents (28 male and 32 female) was followed for 3.4 years (range 1.7-4.6 years). Monthly measurements of height, weight and urinary excretion of a bone resorption marker, collagen type I N-telopeptides (NTx), were made. Changes in standing height were used to classify the adolescents into one or more of six adolescent growth stages: pre-pubertal growth (continuous moderate growth rate), ascending growth spurt (increasing growth rate), peak growth spurt (growth rate higher than 7 cm/year for at least 6 months), descending growth spurt (continuous decrease in growth rate), end of growth (growth rate between 0 and 2 cm/year), and no growth. An increase in NTx excretion from the pre-pubertal to peak growth spurt of about 33% was found (44% and 27% for females and males respectively). The decreasing growth rate after the pubertal growth spurt coincided with a clear decrease in NTx excretion. These differences were statistically significant, except between the prepubertal and ascending growth stage. Individual mean NTx excretion during each growth stage was correlated with the individual's growth rate during that time (r = 0.81). There was large inter-and intra individual variability. In non-growing adolescents (growth rate 0 cm/y) NTx excretion levels were 4-7 times greater than in adults. In all females, menarche was followed by a decrease in NTx excretion. In conclusion, the excretion of a specific bone resorption marker, NTx, was correlated with the changes in growth rate during adolescence, both for males and females. There were large inter and intra-individual differences in NTx excretion during the different growth stages. In adolescents who reached their adult height at the end of the pubertal growth spurt. bone resorption decreased dramatically but remained 4-7 fold higher than in adults.

Adolescent↗
PubMed1993

Cellular biology of bone resorption.

Past knowledge and the recent developments on the formation, activation and mode of action of osteoclasts, with particular reference to the regulation of each individual step, have been reviewed. The following conclusions of consensus have emerged. 1. The resorption of bone is the result of successive steps that can be regulated individually. 2. Osteoclast progenitors are formed in bone marrow. This is followed by their vascular dissemination and the generation of resting preosteoclasts and osteoclasts in bone. 3. The exact pathways of differentiation of the osteoclast progenators to mature osteoclasts are debatable, but there is clear evidence that stromal cells support osteoclast generation. 4. Osteoclasts are activated following contact with mineralized bone. This appears to be controlled by osteoblasts that expose mineral to osteoclasts and/or release a factor that activates these cells. 5. Activated osteoclasts dissolve the bone mineral and digest the organic matter of bone by the action of agents secreted in the segregated microcompartments underlying their ruffled borders. The mineral is solubilized by protons generated from CO2 by carbonic anhydrase and secreted by an ATP-driven vacuolar H(+)-K(+)-ATPase located at the ruffled border. The organic matrix of the bone is removed by acid proteinases, particularly cysteine-proteinases that are secreted together with other lysosomal enzymes in the acid environment of the resorption zone. 6. Osteoclastic bone resorption is directly regulated by a polypeptide hormone, calcitonin (CT), and locally, by ionized calcium (Ca2+) generated as a result of osteoclastic bone resorption. 7. There is new evidence that osteoclast activity may also be influenced by the endothelial cells via generation of products including PG, NO and endothelin.

Animals↗
PubMed1995

Adenyl cyclase and interleukin 6 are downstream effectors of parathyroid hormone resulting in stimulation of bone resorption.

Parathyroid hormone and other bone resorptive agents function, at least in part, by inducing osteoblasts to secrete cytokines that stimulate both differentiation and resorptive activity of osteoclasts. We previously identified two potentially important cytokines by demonstrating that parathyroid hormone induces expression by osteoblasts of IL-6 and leukemia inhibitory factor without affecting levels of 14 other cytokines. Although parathyroid hormone activates multiple signal transduction pathways, induction of IL-6 and leukemia inhibitory factor is dependent on activation of adenyl cyclase. This study demonstrates that adenyl cyclase is also required for stimulation of osteoclast activity in cultures containing osteoclasts from rat long bones and UMR106-01 rat osteoblast-like osteosarcoma cells. Since the stimulation by parathyroid hormone of both cytokine production and bone resorption depends on the same signal transduction pathway, we hypothesized that IL-6 might be a downstream effector of parathyroid hormone. We found that addition of exogenous IL-6 mimics the ability of parathyroid hormone to stimulate bone resorption. More importantly, an antibody directed against the IL-6 receptor blocks moderate stimulation of osteoclast activity induced by the hormone. Interestingly, strong stimulation of resorption overcomes this dependence on IL-6. Thus, parathyroid hormone likely induces multiple, redundant cytokines that can overcome the IL-6 requirement associated with moderate stimulation. Taken together with studies showing that many other bone resorptive agents also stimulate IL-6 production, our results suggest that IL-6 may be a downstream effector of these agents as well as of parathyroid hormone.

Adenylyl Cyclases↗
PubMed1990

Osteoblast-osteoclast interaction in bone resorption. Preliminary results.

Osteoclastic bone resorption has been evaluated in vitro by release of tritiated collagen fragments from 3H-proline prelabeled bone particles incubated for 48 hours in presence of avian isolated osteoclasts. Cells were co-incubated with periosteum-free chick calvarial fragments by interposition of 0.4 micron millipore membrane transwells, in presence or absence of 10(-8) M 1.34 bovine parathyroid hormone (PTH). Results demonstrated that i) calvaria exert a stimulating effect over osteoclastic bone resorption which was 1.8 fold enhanced with respect to controls (p less than 0.001). ii) the stimulating effect is exerted by calvarium-derived soluble molecules capable of crossing the 0.4 micron millipore membrane interposed between calvarial fragments and osteoclasts, iii) in this experimental system no further enhancement of calvarial stimulating effect is operated by PTH treatment.

Animals↗
PubMed1987

Tumor necrosis factors alpha and beta induce osteoblastic cells to stimulate osteoclastic bone resorption.

Antigen- or mitogen-stimulated leukocytes release bone-resorbing activity into culture supernatants in vitro. Among the agents likely to be present in such supernatants are monocyte-derived tumor necrosis factor (TNF-alpha) and lymphocyte-derived tumor necrosis factor (TNF-beta) (lymphotoxin), both of which have recently been shown to stimulate bone resorption in organ culture. To identify the mechanism of action of these agents, we compared bone resorption by isolated osteoclasts with bone resorption by osteoclasts cocultured with osteoblastic cells, and with bone resorption by osteoclasts incubated with supernatants from osteoblastic cells, in the presence and absence of recombinant TNF-alpha and TNF-beta. We found that neither TNF-alpha nor TNF-beta had any significant effect on bone resorption by isolated osteoclasts, but in the presence of osteoblasts the agents caused a twofold to threefold stimulation of bone resorption. A similar degree of stimulation was achieved by supernatants from osteoblasts incubated with TNF before addition to osteoclasts, compared with supernatants to which TNF were added after osteoblast incubation. These experiments suggest that TNF-alpha and TNF-beta stimulate bone resorption through a primary effect on osteoblastic cells, which are induced by TNF to produce a factor that stimulates osteoclastic resorption. Half-maximal stimulation of resorption occurred at 1.5 X 10(-10) M and 2.5 X 10(-10) M for TNF-alpha and TNF-beta, respectively. This degree of potency is comparable to that of parathyroid hormone, the major physiologic systemic regulator of bone resorption, and suggests that the TNF may exert a significant influence on osteoclastic bone resorption in vivo.

Animals↗
PubMedDate not supplied

Establishment of a rapid bone resorption in vitro assay using previously frozen mouse unfractionated bone cells pretreated with parathyroid hormone.

We established a useful assay system for evaluating osteoclast-mediated bone resorption based on the use of unfractionated bone cells obtained from 10- to 11-day-old mice. When cells from 10 to 11 mice were treated for 7 days with rat parathyroid hormone (rPTH, 10(-8) M), a total of 4 to 5 x 10(7) cells could be obtained from the culture by treatment with 0.05% trypsin and 0.02% EDTA in PBS. These harvested cells contained about 20% tartrate-resistant acid phosphatase (TRAP)-positive mononuclear cells. When the harvested cells were cultured on dentine slices without rPTH, after 1 day, they formed TRAP-positive multinucleate cells that were active in bone resorption. Eel calcitonin (eCT) decreased the number of pits in a dose-dependent manner, and its half maximal inhibition dose (ID50) was 1.08 x 10(-11) M. Even after having been frozen in liquid nitrogen for 5 months, upon thawing, these cells were capable for forming pits; and this pit formation was inhibited by eCT. Since no appropriate osteoclastic cell line for evaluating bone resorption is available at present, this system can provide a useful, practical means for assaying osteoclastic bone-resorbing activity.

Acid Phosphatase↗
PubMed1987

1,25-Dihydroxyvitamin D3 stimulates rat osteoblastic cells to release a soluble factor that increases osteoclastic bone resorption.

Although 1,25-dihydroxyvitamin D3 stimulates osteoclastic bone resorption in vivo and in organ culture, the mechanism by which it effects this stimulation is unknown. We have recently found that the agent does not stimulate resorption by osteoclasts mechanically disaggregated from bone and incubated on slices of cortical bone. This suggests that the osteoclasts were removed by disaggregation from the influence of some cell type, present in intact bone, that mediates hormone responsiveness. We therefore tested the ability of osteoblastic cells derived from neonatal rat calvariae and of cloned, hormone-responsive osteosarcoma cells (UMR106) to restore hormone responsiveness to unresponsive populations of osteoclasts. We found that osteoblastic cells from both sources induced a two- to fourfold stimulation of osteoclastic bone resorption in the presence of 1,25-dihydroxyvitamin D3. Stimulation was observed at concentrations of 10(-10) M and above. Actinomycin D and cycloheximide did not affect bone resorption by osteoclasts incubated alone, but abolished the capacity of osteoblastic cells to stimulate osteoclastic resorption in the presence of 1,25-dihydroxyvitamin D3. When calvarial cells or osteoblastlike UMR cells were incubated with the hormone, they produced a factor in cell-free supernatants that stimulated bone resorption by disaggregated osteoclasts. These experiments suggest that 1,25-dihydroxyvitamin D3 stimulates bone resorption through a primary action on osteoblastic cells, that are induced by the hormone to produce a factor that stimulates osteoclastic bone resorption.

Animals↗
PubMed1989

Glucocorticoids impair bone resorptive activity and viability of osteoclasts disaggregated from neonatal rat long bones.

It is generally believed that glucocorticoids cause osteoporosis through a combination of decreased bone formation and increased bone resorption. However, the direct effect of glucocorticoids on osteoclasts has not been determined. We therefore tested the effects of hydrocortisone and dexamethasone on bone resorption by osteoclasts disaggregated from neonatal rat long bones. Hydrocortisone and dexamethasone caused a dose-dependent inhibition of osteoclastic bone resorption in the range 10(-7) to 10(-5) M, and 10(-9) to 10(-6) M, respectively, at concentrations likely to occur during therapy and disease. Inhibition of bone resorption was found to be associated with impaired osteoclast survival: osteoclast numbers were reduced to approximately 25% of control values by 10(-6) M hydrocortisone and 10(-7) M dexamethasone. Osteoclast cytotoxicity by glucocorticoids was completely antagonized by progesterone, which itself had no effect on osteoclast survival. Analysis of the time course of these inhibitory effects showed a nonsignificant reduction in survival by 6 h and marked inhibition of survival by 12 h. We could detect no specific changes in osteoclast morphology in association with this impaired viability. The relative potencies of the glucocorticoids for impairment of osteoclast viability was similar to their relative affinities for binding the glucocorticoid receptor, and this, together with inhibition by progesterone, suggests a receptor-mediated mechanism. Such a receptor-mediated cytotoxic action of glucocorticoids has only previously been reported with lymphoid cells. The sensitivity of osteoclasts to the lethal effects of glucocorticoids suggests that glucocorticoids may have a role in physiology as inhibitors of osteoclastic bone resorption.

Animals↗
PubMed2002

[The specificity of bone resorption process in the maxilla and the mandible].

The jaws comprise the maxilla and the mandible which is a tooth-bearing bone. The part of them which supports and protects the teeth is well known as an alveolar bone. In an experimental model of alveolar bone resorption, bone resorption was obvious in the cancellous bone during the early period of the experiment and then the cortical bone was seen to resorb. However, the contour of mandible, the alveolar bone proper and thin layer of bone which surrounds the mandibular canal still remained. These results suggest that the process of alveolar bone resorption is related to the mechanical forces induced by the occlusal function of the tooth.

English Abstract↗
PubMedDate not supplied

Bone resorption in experimental otosclerosis in rats.

Localized bone resorption in the otic capsules of experimental rats was induced by immunization with type II collagen. The otospongiosis-like lesion showed enlarged vascular spaces that contained many fibroblasts and macrophages as well as occasional osteoclasts. A high level of acid phosphatase activity in the sera of immunized rats suggested that this enzyme is one of the important factors causing decalcification of the bony otic capsule, the first step of bone resorption. Immunofluorescent assay showed that collagenase and cyclooxygenase (prostaglandin synthetase) appeared within macrophages, fibroblasts, and osteoclasts in the bone resorption areas. These findings suggest that the collagenase and prostaglandin synthetase being produced by macrophages, fibroblasts, and osteoclasts are also involved in the processes of bone resorption in otospongiosis. Immunolocalization assay showed deposition of immunoglobulin and fibronectin on the bone matrix and vascular wall within the otospongiotic lesions. Chemotaxis studies showed that both anti-type II collagen serum and fibronectin might play a role as chemoattractants to recruit macrophages and fibroblasts to the bone resorption sites. In vitro studies also showed anti-type II collagen serum stimulates the fusion of macrophages to become multinucleated osteoclast-like cells. The antiserum also activate these cells to produce collagenase and prostaglandin synthetase. It is concluded that the chemotactic processes of macrophages and fibroblasts, the multinucleation of macrophages, and the activation of these cells may be basic processes causing bone resorption in otosclerosis. When sodium fluoride, an inhibitor of hydrolytic and proteolytic enzymes, was given to rats immunized with type II collagen, no obvious inhibition of bone resorption was seen in histologic sections.

Acid Phosphatase↗
PubMed1986

Bone resorption induced by middle-ear implants.

The pressure produced by expanding aural cholesteatomas has been implicated as a causal factor in the induction of osteoclastic resorption of adjoining bone. This concept is supported by observations of osteoclastic bone resorption produced by expansive tympanic implants. We induced osteoclastic bone resorption in gerbils with tympanic implants of autologous and homologous cartilage, silicone rubber, and Teflon, which exerted pressure only by forces of gravity and surface tension. We estimated that the pressure exerted by these implants ranged from 2.1 X 10(-3) to 8.0 X 10(-3) dynes/sq cm (1.6 to 6.0 mm Hg). These pressures are within the range of pressures known to be exerted by cholesteatomas.

Animals↗
PubMed2003

An essential role of cytosolic phospholipase A2alpha in prostaglandin E2-mediated bone resorption associated with inflammation.

Prostaglandin E (PGE)2 produced by osteoblasts acts as a potent stimulator of bone resorption. Inflammatory bone loss is accompanied by osteoclast formation induced by bone-resorbing cytokines, but the mechanism of PGE2 production and bone resorption in vivo is not fully understood. Using cytosolic phospholipase A2alpha (cPLA2alpha)-null mice, we examined the role of cPLA2alpha in PGE2 synthesis and bone resorption. In bone marrow cultures, interleukin (IL)-1 markedly stimulated PGE2 production and osteoclast formation in wild-type mice, but not in cPLA2alpha-null mice. Osteoblastic bone marrow stromal cells induced the expression of cyclooxygenase (COX)-2 and membrane-bound PGE2 synthase (mPGES) in response to IL-1 and lipopolysaccharide (LPS) to produce PGE2. Osteoblastic stromal cells collected from cPLA2alpha-null mice also induced the expression of COX-2 and mPGES by IL-1 and LPS, but could not produce PGE2 due to the lack of arachidonic acid release. LPS administration to wild-type mice reduced femoral bone mineral density by increased bone resorption. In cPLA2alpha-null mice, however, LPS-induced bone loss could not be observed at all. Here, we show that cPLA2alpha plays a key role in PGE production by osteoblasts and in osteoclastic bone resorption, and suggest a new approach to inflammatory bone disease by inhibiting cPLA2alpha.

Animals↗
PubMedDate not supplied

The role of cathepsin K in normal bone resorption.

Cathepsin K is essential for normal bone resorption; humans lacking cathepsin K exhibit pycnodysostosis, which is characterized by short stature and osteosclerosis. Cathepsin K knockout mice develop osteopetrosis and display features characteristic of pycnodysostosis, and osteoclasts isolated from these mice exhibit impaired bone resorption in vitro. Bone resorption depends upon the synthesis of cathepsin K by osteoclasts and its secretion into the extracellular compartment at the attachment site between osteoclasts and the bone surface, wherein the organic matrix is subsequently degraded by cathepsin K. Factors that directly modulate osteoclastic bone resorption, including cytokines (RANK ligand, tumor necrosis factor-alpha and interferon gamma), hormones (retinoic acid and estrogen) and nuclear transcriptional factors (c-jun and Mitf) also regulate cathepsin K gene expression. Osteoporosis is one of the leading causes of morbidity in the elderly and is characterized by a persistent excess of osteoclastic bone resorption. Therefore, cathepsin K is an attractive target for therapeutic intervention to prevent and ameliorate the significant deleterious impact of osteoporosis.

Animals↗
PubMed2000

Posttransplant bone disease: evidence for a high bone resorption state.

Loss of bone is a significant problem after renal transplant. Although bone loss in the first post transplant year has been well documented, conflicting data exist concerning bone loss after this time. It is equally unclear whether bone loss in long-term renal transplant recipients correlates with bone turnover as it does in postmenapausal osteoporosis. To examine these issues, we conducted a cross-sectional study to define the prevalence of osteoporosis in long-term (> 1 year) renal transplant recipients with preserved renal function (mean creatinine clearance 73 +/- 23 ml/min). Bone mineral density (BMD) was measured at the hip, spine and wrist by DEXA in 69 patients. Markers for bone formation (serum osteocalcin) and bone resorption [urinary levels of pyridinoline (PYD) and deoxypyridinoline (DPD)] were also measured as well as parameters of calcium metabolism. Correlations were made between these parameters and BMD at the various sites. The mean age of the patients was 45 +/- 11 years. Eighty eight percent of patients were on cyclosporine (12% on tacrolimus) and all but 2 were on prednisone [mean dose 9 +/- 2 mg/day)]. Osteoporosis (BMD more than 2.5 SD below peak adult BMD) at the spine or hip was diagnosed in 44% of patients and osteopenia was present in an additional 44%. Elevated levels of intact parathyroid hormone (i PTH) were observed in 81% of patients. Elevated urinary levels of PYD or DPD were present in 73% of patients and 38% had elevated serum levels of osteocalcin. Levels of calcium, and of 25(OH) and 1,25(OH)2 vitamin D were normal. In a stepwise multiple regression model that included osteocalcin, PYD, DPD, intact PTH, age, years posttransplant, duration of dialysis, cumulative prednisone dose, smoking, and diabetes: urinary PYD was the strongest predictor of bone mass. These results demonstrate that osteoporosis is common in long-term renal transplant recipients. The data also suggest that elevated rates of bone resorption contribute importantly to this process.

Adult↗
PubMed1994

Urinary excretion of pyridinium crosslinks of collagen in oophorectomized women as markers for bone resorption.

To detect increased bone resorption in estrogen-deficient women, the urinary excretion of hydroxylysylpyridinoline (HP) and lysylpyridinoline (LP), which are intermolecular crosslinkings of collagen fibers, were measured and their chronological changes were evaluated following oophorectomy. Seventy-five women were divided into three groups; 15 premenopausal women (mean age 44.0 years), 15 postmenopausal women (mean age 54.2 years) and 45 surgically menopausal women who had a normal menstrual cycle before surgery (mean age 42.2 years). There was a significant increase in HP and LP of the postmenopausal women (P < 0.001). In the oophorectomized women, both HP and LP were three times higher than those of premenopausal women within 1 year after oophorectomy, and decreased to the same level of the postmenopause between 2 and 3 years after surgery. In the six oophorectomized women after the administration of estrogen, HP and LP both decreased remarkably in all cases. The present study thus indicates that an increase of bone resorption which was evaluated by urinary HP and LP occurs in the early stage after oophorectomy. It may, therefore, be good to begin estrogen replacement therapy as soon as possible after oophorectomy.

Adult↗
PubMed1991

Inhibitory effects of gamma-interferon on bradykinin-induced bone resorption and prostaglandin formation in cultured mouse calvarial bones.

The effects of mouse recombinant gamma-interferon (gamma-IFN) and indomethacin on bone resorption stimulated by bradykinin, Lys-bradykinin, Met-Lys-bradykinin, des-Arg9-bradykinin and prostaglandin E2 (PGE2) have been studied using cultures of neonatal calvarial bones and analyzing the release of 45Ca from prelabelled bones as a parameter of bone resorption. In addition, the effects of gamma-IFN and indomethacin on formation of PGE2 in bone cultures stimulated by bradykinin was analyzed. Indomethacin (1 mumol/l) totally abolished bradykinin (1 mumol/l) induced 45Ca release. The inhibitory effect of indomethacin could be fully reversed by addition of PGE2 (1 mumol/l). gamma-IFN (1000 U/ml) almost totally inhibited 45Ca release stimulated by bradykinin (1 mumol/l), but the inhibitory effect could only be partially overcome by PGE2. gamma-IFN and indomethacin also inhibited the stimulatory effects of Lys-bradykinin, Met-Lys-bradykinin and des-Arg9-bradykinin (1 mumol/l) on 45Ca release. The stimulatory effects of PGE2 (1 mumol/l) on radioactive calcium mobilization was partially inhibited by gamma-IFN (1000 U/ml), whereas indomethacin (1 mumol/l) was without effect. The inhibitory effect of gamma-IFN on 45Ca release stimulated by bradykinin and PGE2 was dose-dependent with threshold for action at 3-30 U/ml. Comparative dose-response curves showed that gamma-IFN was most potent as inhibitor of bradykinin induced 45Ca release. Bradykinin (1 mumol/l) significantly stimulated PGE2 formation by a mechanism that was completely inhibited by indomethacin (1 mumol/l). gamma-IFN (1000 U/ml) partially inhibited the stimulatory effect of bradykinin on PGE2 formation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Evaluation of tartrate-resistant acid phosphatase (TRACP) 5b as bone resorption marker in irradiated bone metastases.

BACKGROUND: The aim of our study was to evaluate if the determination of the active isoform 5b of tartrate-resistant acid phosphatase (TRACP 5b) provides the possibility to monitor the effect of local radiotherapy in bone metastases and if TRACP 5b will predict further osseous progression. MATERIALS AND METHODS: In 48 breast cancer patients with bone metastases, patients' characteristics, diagnostic imaging and laboratory investigation, tumor- and therapy-related parameters were registered at the beginning and the end of radiotherapy, as well as 6 and 12 weeks afterwards. TRACP 5b activity was measured using a solid phase immunofixed enzyme activity assay with the monoclonal antibody O1A. RESULTS: During follow-up, progression in another part of the skeleton was diagnosed in 31 patients (65%). There was a significant decrease of TRACP 5b in patients without progression in non-irradiated regions, whereas in progressive disease, TRACP 5b levels remained stable with a slightly increasing tendency (p < 0.007). In patients with < or =3 metastases, all TRACP 5b values were significantly lower than the values of those with >3 metastases (p = 0.01). CONCLUSION: In patients without further osseous progression, TRACP 5b is able to monitor the effectiveness of local radiotherapy. The estimation of sensitivity and specificity based on each TRACP 5b value demonstrates that the ability to discriminate between those patients with or without osseous progression increases with time.

Acid Phosphatase↗