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PubMed2003

Role of cyclooxygenase-2 in bone resorption.

Prostaglandins (PGs) are abundant in bone and are potent regulators of bone cell function. Osteoblasts produce PGs, and this production is highly regulated by local and systemic factors. Bone resorption is a highly regulated process involving interactions of osteoclastic precursors with osteoblasts or stromal cells. Many factors that stimulate PGs production also stimulate resorption in organ and marrow culture. Cyclooxygenase (COX) is the rate-limiting enzyme in the conversion of arachidonic acid to PGs. There are two forms of COX, COX-1 and COX-2. COX-2 is an inducible primary-response or immediate early gene. COX-2 expression is induced by many factors through the transcriptional pathway in osteoblasts. Stimulated production of PGs by osteoblasts requires both the induction of COX-2 expression and the availability of arachidonic acid substrate. PGs are complex, potent regulators of bone cell function in vivo. PGE2, which may be the most important local eicosanoid in skeletal regulation, can stimulate resorption. We report that COX-2 expression and associated PG production are necessary for maximal resorption responses to 1,25 (OH)2D3 and parathyroid hormone (PTH). PGs can increase osteoclast formation by enhancing induction of the receptor activator of nuclear factor-kappa B ligand (RANKL) expression in osteoblasts and enhancing the action of RANKL on osteoclast precursors by inhibiting granulocyte macropharge-colony stimulating factor (GM-CSF). In vitro, PGE2 can stimulate the differentiation of both osteoblasts and osteoclasts, and the net balance of these two effects under physiologic or pathologic conditions in vivo is not yet clear. Our in vivo data suggest that a role for COX-2 in bone resorption may be most evident when bone resorption is accelerated. Some of the complexity of PG actions on bone can be explained by the multiplicity of receptors for PGs. There are at least four distinct receptors for PGE2 with differential signaling pathways that have not yet been fully elucidated. Further studies are needed to clarify the specific pathways of PGs action in bone. Once this is accomplished, it may be possible to identify therapeutic applications of manipulating PGs in skeletal disorders.

Animals↗
PubMed2003

Relationship of early changes in bone resorption to the reduction in fracture risk with risedronate.

Changes in the level of biochemical markers of bone resorption with risedronate treatment for osteoporosis were examined as a surrogate for the decrease in fracture risk. Greater decreases in bone resorption markers were associated with greater decreases in vertebral (and nonvertebral) fractures. Antifracture efficacy of antiresorptive therapies is only partially explained by increases in bone mineral density. Early decreases in bone resorption may also play a role. We tested this hypothesis by measuring two bone resorption markers, the C-telopeptide of type I collagen (CTX) and the N-telopeptide of type I collagen (NTX), in osteoporotic patients in risedronate vertebral fracture trials. We studied 693 women with at least one vertebral deformity (mean age, 69 +/- 7 years) who received calcium (and vitamin D if required) and placebo or risedronate 5 mg daily for 3 years. The reductions in urinary CTX (median, 60%) and NTX (51%) at 3-6 months with risedronate therapy were significantly associated (p < 0.05) with the reduction in vertebral fracture risk (75% over 1 year and 50% over 3 years). The changes in both CTX and NTX accounted for approximately one-half (CTX, 55%; NTX, 49%) of risedronate's effect in reducing the risk of vertebral fractures in the first year and approximately two-thirds (CTX, 67%; NTX, 66%) over 3 years compared with placebo. The changes in CTX and NTX accounted for 77% and 54%, respectively, of risedronate's effect in reducing the risk of nonvertebral fractures over 3 years compared with placebo. The relationships between vertebral fracture risk and changes from baseline in CTX and NTX were not linear (p < 0.05). There was little further improvement in fracture benefit below a decrease of 55-60% for CTX and 35-40% for NTX. The decrease in bone resorption in patients taking risedronate accounts for a large proportion of the reduction in fracture risk. There may be a level of bone resorption reduction below which there is no further fracture benefit.

Aged↗
PubMed2002

Effects of selective prostaglandin EP4 receptor antagonist on osteoclast formation and bone resorption in vitro.

Prostaglandin estradiol (PGE(2)) stimulates bone resorption by a cyclic AMP (cAMP)-dependent mechanism that involves prostaglandin E receptors of the EP2 and EP4 subtypes. We tested a potent selective EP4 antagonist (EP4RA), which blocks PGE(2) binding to EP4 receptors. We examined the effects of EP4RA on osteoclastogenesis in murine marrow cultures, on cAMP production in primary osteoblastic (POb) cell cultures, and on bone resorption in organ cultures. EP4RA (1 micromol/L) decreased the number of tartrate-resistant acid phosphatase-positive multinucleated cells (TRAP(+) MNC) by 46%-48% in cultures treated with 0.1-1.0 micromol/L PGE(2) and by 96% in cultures treated with 0.01 micromol/L PGE(2). EP4RA also decreased TRAP(+) MNC formation by 60% in 1,25-dihydroxyvitamin D (1,25D)-treated cultures and by 62% in parathyroid hormone (PTH)-treated cultures. A chemically related analog of EP4RA that lacks antagonist activity did not inhibit TRAP(+) MNC formation. EP4RA decreased cAMP production in PGE(2)-treated POb by 44% but did not block cAMP response to PTH. EP4RA inhibited the increase in receptor activator of NF-kappaB ligand (RANKL) mRNA levels produced by PGE(2). In fetal rat long bone cultures, EP4RA decreased 45Ca release from control, unstimulated cultures by 12%-25% and from PGE(2)-stimulated cultures by 22%-37%. Because EP4RA partially inhibited osteoclastogenesis not only in response to PGE(2) but also in response to 1,25D and PTH, these results suggest that activation of the EP4 receptor may play a general role in osteoclastic bone resorption. EP4RA showed partial inhibition of PGE(2)-stimulated osteoclastogenesis at 1 micromol/L, but almost complete inhibition at 0.01 micromol/L PGE(2). This could be due to the limited efficacy of the antagonist at high concentrations of PGE(2), or an alternative pathway, such as activation of the EP2 receptor.

Acid Phosphatase↗
PubMed1998

Age-dependent effect of oral glucocorticoids on markers of bone resorption in patients with acute asthma.

It is generally accepted that bone formation is depressed during corticosteroid treatment, but the effects of glucocorticoids on bone resorption are less well characterized. We have investigated the effects of short-term treatment with high-dose oral glucocorticoids on biochemical markers of bone turnover in 20 consecutive patients with asthma who sought help for acute respiratory obstruction in our emergency department. Serum concentrations of the carboxy-terminal cross-linked telopeptide of type 1 collagen (1CTP), reflecting bone resorption, and the carboxy-terminal propeptide of type 1 procollagen (P1CP), reflecting bone formation, were measured by radioimmunoassay. Changes of the circulating levels of the bone resorption marker 1CTP after treatment were age dependent with a significant negative correlation (r = -0.54, P = 0.01). The dependency on age remained when correcting, in a multiple linear regression analysis, for 1CTP levels at admission, weight, sex, and daily maintenance dose of inhaled glucocorticoids. Circulating levels of P1CP were suppressed in the whole group 1 week after initiation of glucocorticoid therapy, from 123.3 +/- 10.2 ng/ml at admission to 88.1 +/- 6.3 ng/ml after 1 week (P < 0.01). The changes in P1CP levels were not related to age. Our data indicate that bone formation is suppressed by glucocorticoids in all age groups, whereas the effect of glucocorticoids on markers of bone resorption is dependent on age.

Acute Disease↗
PubMed2000

Impaired bone resorption to prostaglandin E2 in prostaglandin E receptor EP4-knockout mice.

Prostaglandin E(2) (PGE(2)) acts as a potent stimulator of bone resorption. In this study, we first clarified in normal ddy mice the involvement of protein kinase A and induction of matrix metalloproteinases (MMPs) in PGE(2)-induced bone resorption, and then identified PGE receptor subtype(s) mediating this PGE(2) action using mice lacking each subtype (EP1, EP2, EP3, and EP4) of PGE receptor. In calvarial culture obtained from normal ddy mice, both PGE(2) and dibutyryl cyclic AMP (Bt(2)cAMP) stimulated bone resorption and induced MMPs including MMP-2 and MMP-13. Addition of an inhibitor of protein kinase A, H89, or an inhibitor of MMPs, BB94, significantly suppressed bone-resorbing activity induced by PGE(2.) In calvarial culture from EP1-, EP2-, and EP3-knockout mice, PGE(2) stimulated bone resorption to an extent similar to that found in calvaria from the wild-type mice. On the other hand, a marked reduction in bone resorption to PGE(2) was found in the calvarial culture from EP4-knockout mice. The impaired bone resorption to PGE(2) was also detected in long bone cultures from EP4-knockout mice. Bt(2)cAMP greatly stimulated bone resorption similarly in both wild-type and EP4-knockout mice. Induction of MMP-2 and MMP-13 by PGE(2) was greatly impaired in calvarial culture from EP4-knockout mice, but Bt(2)cAMP stimulated MMPs induction similarly in the wild-type and EP4-knockout mice. These findings suggest that PGE(2) stimulates bone resorption by a cAMP-dependent mechanism via the EP4 receptor.

Animals↗
PubMed1990

The pathogenesis of loosening of total hip arthroplasties. The production of factors by periprosthetic tissues that stimulate in vitro bone resorption.

The production of factors capable of stimulating bone resorption in the newly formed periprosthetic capsule and in the bone-cement membrane obtained from patients reoperated due to aseptic loosening of cemented total hip prostheses was studied using organ culture techniques. Addition of culture media conditioned by membranes from six patients and bone-cement membranes from two patients to the mouse calvarial cultures resulted in a significantly increased release of calcium. The effect of capsule-conditioned media on calcium release was dose- and time-dependent and significantly reduced by the osteoclast inhibitor of calcitonin. Histologic analysis of bones at the end of the culture period showed that capsule-conditioned media enhanced the breakdown of mineralized bone and increased the number of osteoclasts. The observations showed that newly formed periprosthetic tissues from patients with loose total hip arthroplasties (THAs) can produce one or several factors that stimulate bone resorption in vitro by an osteoclast-mediated mechanism. Not only mechanical failure but also biologic reactions in the periprosthetic tissues eventually lead to osteoclast activation and may contribute to the loosening of THAs.

Adult↗
PubMed2002

Effects of the natural and artificial menstrual cycle on the production of osteoprotegerin and the bone resorptive cytokines IL-1beta and IL-6.

Bone remodelling changes within the menstrual cycle. Though the luteal phase is accompanied by decreased bone resorption, it is also paradoxically a time of increased production of bone resorptive cytokines. The present study examined the hypothesis that changes in serum osteoprotegerin (OPG) within the menstrual cycle prevent the increase in bone remodelling, which would otherwise have been the result of the luteal increase in the capacity for producing resorptive cytokines. The study population consisted of healthy female volunteers: premenopausal women (n = 11, mean age 39.4 y +/- 6.1) without cycle irregularities. Postmenopausal women (n = 11, mean age 56.8 y +/- 3.6) receiving cyclic HRT (estradiol and noretisterone acetate). Luteal and follicular phase blood samples were diluted and cultured for 24 hours with and without lipopolysaccharide (LPS). The supernatant was assayed for IL-1 beta and IL-6 by ELISA. Serum OPG was measured by ELISA. The LPS-stimulated production of IL-1 and IL-6 was significantly higher in the luteal phase. When the analysis was restricted to the natural menstrual cycle, only the increase in IL-1 production remained statistically significant. NTX excretion was similar in the two phases of HRT, but decreased nonsignificantly (p = 0.05) in the luteal phase in the premenopausal women. OPG levels did not exhibit any menstrual cycle-dependent changes. In conclusion, bone resorption is suppressed in the luteal phase through a mechanism that does not involve increases in serum OPG. An increased cytokine secretory capacity of blood cells may be an epiphenomenon particular to the luteal phase but unrelated to bone metabolism.

Adolescent↗
PubMed1989

Different inhibitory actions of immunomodulating agents and immunosuppressive agents on bone resorption of mouse calvaria.

In this study, we have investigated the in vitro effects of the immunomodulators lobenzarit and traxanox and a newly synthesized immunosuppressant, mizoribine, as well as cyclosporin A, on bone resorption using neonatal mouse calvariae labelled with 45Ca. As stimulators of bone resorption, bovine parathyroid hormone (PTH), lipopolysaccharide (LPS), interleukin 1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) were used. Lobenzarit, traxanox, mizoribine and cyclosporin A inhibited or tended to inhibit bone resorption stimulated by PTH, LPS, IL-1 beta or TNF-alpha in a dose-dependent manner. Basal bone resorption was inhibited by immunosuppressant cyclosporin A or mizoribine, while immunomodulators lobenzarit and traxanox failed to inhibit basal bone resorption. Removal of lobenzarit from the culture medium resulted in the recovery of bone resorptive activity. These results suggest that the inhibitory effect of immunomodulators on bone resorption is reversible and nonselective. Also, it raises the possibility that immunomodulators and immunosuppressants may affect bone resorption by different mechanisms.

Adjuvants, Immunologic↗
PubMed1991

Vitronectin receptor has a role in bone resorption but does not mediate tight sealing zone attachment of osteoclasts to the bone surface.

During bone resorption, osteoclasts form a tight attachment, the sealing zone, around resorption lacunae. Vitronectin receptor has previously been shown to be expressed in osteoclasts and it has been suggested that it mediates the tight attachment at the sealing zone. In this study we have shown that glycine-arginine-glycine-aspartic acid-serine pentapeptide inhibits bone resorption by isolated osteoclasts and drastically changes the morphology of the osteoclasts. When the vitronectin receptor was localized by immunofluorescence in rat and chicken osteoclasts cultured on bone slices, it was found to be distributed throughout the osteoclast cell membrane except in the sealing zone areas. Immunoperoxidase staining of rat bone sections at the light microscopical level also revealed intense staining of the cell membrane with occasional small unstained areas, probably corresponding to the sealing zones. Immunoelectron microscopy confirmed the results obtained by light microscopy showing specific labeling only at the ruffled borders and basolateral membranes (0.82 and 2.43 gold particles/microns of membrane, respectively), but not at the sealing zone areas (0.06 gold particles/microns of membrane). Both alpha v and beta 3 subunits of the vitronectin receptor were similarly localized. These results strongly suggest that, although the vitronectin receptor is important in the function of osteoclasts, it is not mediating the final sealing zone attachment of the osteoclasts to the mineralized bone surface.

Animals↗
PubMed1994

Effects of calcitonin gene-related peptide on bone resorption mediated by interleukin-1.

We examined the effects of calcitonin gene-related peptide CGRP on the bone resorption stimulated by IL-1 alpha after neonatal mouse calvaria were cultured in vitro and bone resorption was determined by measuring the release of calcium into the medium after alpha 48-hour incubation. CGRP (10(-9)-10(-8) M) blocked completely the IL1 alpha-mediated increase in bone resorption and inhibited the basal bone resorption. In accordance with the effects of calcitonin on osteoclasts, CGRP caused cessation of lamellipodia activity and gradual retraction of lamellipodia when added into the culture medium. Quantitative analysis showed that CGRP (10(-6) M) caused a gradual reduction of osteoclastic surface area and convex perineum. These data show that CGRP inhibits IL1 alpha mediated bone resorption because of its direct regulation of osteoclast activity.

Animals↗
PubMed1986

Effects of acetylsalicylic acid and naproxen on bone resorption and formation in rats.

The influence of acetylsalicylic acid (ASA) (150 mg/kg/12 h) and naproxen (20 mg/kg/12 h) on bone metabolism in young male rats has been studied. The doses were chosen to provide serum concentrations comparable with ordinary anti-inflammatory steady-state levels in humans. After the rats had been prelabeled with collagen- and mineral-tracing radioisotopes the rats received the drugs by gavage twice a day for 9 and 18 days. Bone resorption was measured as loss of carbon-labeled hydroxyproline (collagen) and strontium-85 (minerals). At 9 days ASA had retarded both collagen and mineral resorption in the femur by about 10% compared with controls. The resorption of both collagen and minerals was inhibited. After 18 days' treatment there were no differences regarding bone resorption, but bone formation had decreased by about 10% in the ASA-treated animals, as measured by net increases of collagen and calcium in the femur. Naproxen did not influence bone resorption or formation significantly. The results indicate an inhibitory effect of ASA on bone resorption and formation in growing rats, whereas the effect of naproxen seems negligible.

Animals↗
PubMed1986

Bone resorption and hypercalciuria in calcium stoneformers.

The circadian rhythm of urinary total hydroxyproline (THP) excretion was determined in matched groups of ten male idiopathic calcium stoneformers and ten normal subjects in order to determine whether enhanced resorption of bone might contribute to hypercalciuria in these patients. THP increased progressively in normal subjects in successive eight-hour urine collections from period 1 (8 AM to 4 PM) to period 3 (12 midnight to 8 AM), the nocturnal high level in period 3 being significantly greater than in period 1 (P less than 0.01) and in period 2 (P less than 0.05). By contrast, no significant circadian rhythm was observed in THP excretion in the stoneformers. Their THP excretion was similar to that of normal subjects in period 3, but was significantly higher than that of normal subjects in period 1 (THP/creatinine ratio(mg/mg): 0.026 +/- 0.003 v 0.017 +/- 0.001; P less than 0.05. Indices of parathyroid hormone activity were not significantly different between stoneformers and normal subjects; mean serum 1,25(OH)2 vitamin D levels were higher in the stoneformers than the normal subjects (44 v 37 pg/mL) but the difference was not significant (P greater than 0.05). These studies suggest that increased bone turnover may contribute to hypercalciuria in these calcium stoneformers.

Adult↗
PubMed1987

[Subtotal bone resorption following reimplantation of a bone flap. 2 case examples].

This is a report on two cases of an extensive absorption of bone following reimplantation of an osteoplastic flap of the cranial vault. Although it is not yet possible to give a final explanation of the phenomenon, this complication must always be considered as a possible event in this kind of cranial vault implant and the patient should therefore be informed about such an eventuality.

Adult↗
PubMed1986

Monoclonal antibodies against osteoclasts inhibit bone resorption in vitro.

Several recently-derived monoclonal antibodies (mcabs) that bind with a high degree of specificity to membrane antigens of osteoclasts were tested for their effects on the function of giant cells from osteoclastomas. None of the antibodies stimulated bone resorption when incubated with giant cells on bone slices, nor did we find any evidence that the mcabs were able to block calcitonin-inhibition of bone resorption. However, three of the mcabs strongly inhibited bone resorption. This inhibition was unaccompanied by impaired survival or morphological evidence of toxicity, but the same mcabs induced a state of cytoplasmic quiescence we have previously found to be characteristic of the response of osteoclasts to local and systemic inhibitors of osteoclastic bone resorption. These results suggest that the mcabs bind to antigens of functional importance in bone resorption or its regulation, and the similarity between the response of giant cells to mcabs and hormonal inhibitors of bone resorption raises the possibility that the mcabs may bind to and cause activation of surface receptors for one or more of these hormones. Whether this is so or not, the mcabs which influence giant cell function may represent valuable probes for an analysis of the mechanism and regulation of osteoclastic bone resorption.

Antibodies, Monoclonal↗
PubMed2001

Indapamide, a thiazide-like diuretic, decreases bone resorption in vitro.

We recently showed that indapamide (IDP), a thiazide-related diuretic, increases bone mass and decreases bone resorption in spontaneously hypertensive rats supplemented with sodium. In the present study, we evaluated the in vitro effects of this diuretic on bone cells, as well as those of hydrochlorothiazide (HCTZ), the reference thiazide, and acetazolamide (AZ), a carbonic anhydrase (CA) inhibitor. We showed that 10(-4) M IDP and 10(-4) M AZ, as well as 10(-5) M pamidronate (APD), decreased bone resorption in organ cultures and in cocultures of osteoblast-like cells and bone marrow cells in the presence of 10(-8) M 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]. We investigated the mechanism of this antiresorptive effect of IDP; IDP decreased osteoclast differentiation as the number of osteoclasts developing in coculture of marrow and osteoblast-like cells was decreased markedly. We then investigated whether IDP affected osteoblast-like cells because these cells are involved in the osteoclast differentiation. Indeed, IDP increased osteoblast-like cell proliferation and alkaline phosphatase (ALP) expression. Nevertheless, it did not modify the colony-stimulating factor 1 (CSF-1) production by these cells. In addition, osteoblast-like cells expressed the Na+/Cl- cotransporter that is necessary for the renal action of thiazide diuretics, but IDP inhibited bone resorption in mice lacking this cotransporter, so the inhibition of bone resorption and osteoclast differentiation did not involve this pathway. Thus, we hypothesized that IDP may act directly on cells of the osteoclast lineage. We observed that resorption pits produced by spleen cells cultured in the presence of soluble osteoclast differentiation factor (sODF) and CSF-1 were decreased by 10(-4) M IDP as well as 10(-5) M APD. In conclusion, in vitro IDP increased osteoblast proliferation and decreased bone resorption at least in part by decreasing osteoclast differentiation via a direct effect on hematopoietic precursors.

Animals↗
PubMed1994

Evaluation of urinary pyridinium crosslink excretion as a marker of bone resorption in the rat.

The aim of this study was to evaluate the value of the urinary excretion of the pyridinium crosslinks, pyridinoline (Pyr) and deoxypyridinoline (D-Pyr), as markers of bone resorption in the rat. The excretion of the crosslinks was compared with that of urinary [3H]tetracycline ([3H]TC) excretion from chronically [3H]TC-prelabeled animals, a technique established to monitor bone resorption in the rat. Bone resorption was modulated by Ca restriction, infusion of PTH, thyroparathyroidectomy, and administration of different bisphosphonates. Furthermore, the urinary crosslinks were assessed in three different osteopetrotic mutations in the rat. We found a delayed response of Pyr and D-Pyr excretion to acute changes in bone resorption compared with [3H]TC excretion. This delay was 1 day after Ca restriction and longer after other treatments, such as PTH administration or bisphosphonate treatment, with which it was more than 3 weeks. In contrast, chronic states with stimulation or inhibition of bone resorption showed similar changes in excretion of the urinary crosslinks and [3H]TC, except after PTH administration. The excretion of the crosslinks was greatly reduced in osteopetrotic rats (op/op, tl/tl, and ia/ia) and increased to normal levels in tl/tl rats after stimulation of bone resorption by M-CSF administration. These results suggest that, in rats, urinary excretion of the pyridinium crosslinks reflects bone resorption in chronic but not always in acute conditions. The cause of this discrepancy is still unclear.

Amino Acids↗