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PubMed1996

Bone formation and bone resorption in failed total joint arthroplasties: histomorphometric analysis with histochemical and immunohistochemical technique.

To elucidate the reactions of bone around aseptically loosened total joint arthroplasties, 24 interface tissues with adjacent bone were obtained in 17 revision operations (11 hips and six knees). The morphology of the bone surface next to the interface membrane was investigated with histochemical and immunohistochemical techniques and then histomorphometrically analysed. One-third of the total bone surface. 32.69 +/- 5.16% (mean +/- SE) (n = 24), showed positive alkaline phosphatase activity. The bone surface in contact with the cells positive for CD11b (a macrophage marker) amounted to 19.33 +/- 5.16% (n = 24). The proportion of the osteoclastic bone resorption estimated by vitronectin receptor expression was 7.67 +/- 1.82% (n = 21). Tissues retrieved from the sites where radiographic evidence of osteolysis was present (n = 12) had a significantly larger extent of the bone surface in contact with CD11b-positive cells than did the tissues from areas without osteolysis (n = 12, p = 0.0067, Mann-Whitney U test), whereas no significant difference was observed in the extent of osteoclastic bone resorption. These data demonstrate that active bone formation, regarded as a repair process, is the most common feature even in revised cases. They also highlight the role played by macrophages, not as cells producing inflammatory mediators that could activate osteoclasts, but as cells primarily responsible for the bone loss in osteolytic lesions.

Adult↗
PubMed2002

An investigation of bone resorption and Dictyostelium discoideum growth inhibition by bisphosphonate drugs.

We report the results of 3D-QSAR/CoMFA investigations of the activity of bisphosphonate drugs, farnesyl pyrophosphate synthase (FPPSase) inhibitors, in the inhibition of bone resorption as well as the growth of Dictyostelium discoideum. In the case of D. discoideum, we find an experimental versus QSAR predicted pIC(50) R(2) value of 0.94 for 16 bisphosphonates over the 9-1200 microM range of IC(50) values, a cross-validated R(2) = 0.90, and a bootstrapped R(2) = 0.94, and we demonstrate that this approach has predictive utility (a 0.18 pIC(50) rms error for three test sets of 3 predictions). In bone resorption, we find an experimental versus predicted pLED (lowest effective dose) R(2) = 0.79 for 35 bisphosphonates over the 0.0001-1 mg of P/kg LED range, a cross-validated R(2) = 0.75, and a bootstrapped R(2) = 0.79. Two sets of 31 compounds were used as training sets for the predicted pLED values for two sets of 4 compounds which have an rms error of 0.44, larger than that found with D. discoideum. However, this can be attributed to the rather large uncertainties in the experimental bone resorption data which are almost all reported in decade steps (DeltapLED = 1). The CoMFA predicted (rat) bone antiresorptive pLED values are in agreement with literature (human recombinant) FPPSase inhibition results with an rms error of 0.45 (a factor of 2.8 error in activity prediction). We also report the single-crystal X-ray crystallographic structure of the compound most active in D. discoideum growth inhibition, 2-(3-picolyl)-aminomethylene-1,1-bisphosphonic acid. The structure clearly shows the presence of bond length alternation in the picolyl ring and a planar amino group linked by a very short (1.346 A) bond to the picolyl group, an amidinium-like structure which is also expected to occur in other highly active species such as minodronate and zoledronate. Overall, these results show that it is now possible to predict the activity of bisphosphonates using 3D-QSAR/CoMFA methods, although bone resorption studies should benefit from additional, accurate information on enzyme inhibition.

Alkyl and Aryl Transferases↗
PubMed1998

Isolation and characterization of a cDNA clone encoding a novel peptide (OSF) that enhances osteoclast formation and bone resorption.

Using an expression cloning approach, we identified and cloned a novel intracellular protein produced by osteoclasts that indirectly induces osteoclast formation and bone resorption, termed OSF. Conditioned media from 293 cells transiently transfected with the 0.9 kb OSF cDNA clone stimulated osteoclast-like cell formation in both human and murine marrow cultures in the presence or absence 10(-9) M 1,25-dihydroxyvitamin D3. In addition, conditioned media from 293 cells transfected with the OSF cDNA clone enhanced the stimulatory effects of 1,25-(OH)2D3 on bone resorption in the fetal rat long bone assay. In situ hybridization studies using antisense oligomers showed expression of OSF mRNA in highly purified osteoclast-like cells from human giant cell tumors of the bone. Northern blot analysis demonstrated ubiquitous expression of a 1.3 kb mRNA that encodes OSF in multiple human tissues. Sequence analysis showed the OSF cDNA encoded a 28 kD peptide that contains a c-Src homology 3 domain (SH3) and ankyrin repeats, suggesting that it was not a secreted protein, but that it was potentially involved in cell signaling. Consistent with these data, immunoblot analysis using rabbit antisera against recombinant OSF demonstrated OSF expression in cell lysates but not in the culture media. Furthermore, recombinant OSF had a high affinity for c-Src, an important regulator of osteoclast activity. Taken together, these data suggest that OSF is a novel intracellular protein that indirectly enhances osteoclast formation and osteoclastic bone resorption through the cellular signal transduction cascade, possibly through its interactions with c-Src or other Src-related proteins.

Amino Acid Sequence↗
PubMed2006

B and T lymphocytes are the primary sources of RANKL in the bone resorptive lesion of periodontal disease.

Receptor activator of nuclear factor-kappaB (RANKL)-mediated osteoclastogenesis plays a pivotal role in inflammatory bone resorption. The aim of this study was to identify the cellular source of RANKL in the bone resorptive lesions of periodontal disease. The concentrations of soluble RANKL, but not its decoy receptor osteoprotegerin, measured in diseased tissue homogenates were significantly higher in diseased gingival tissues than in healthy tissues. Double-color confocal microscopic analyses demonstrated less than 20% of both B cells and T cells expressing RANKL in healthy gingival tissues. By contrast, in the abundant mononuclear cells composed of 45% T cells, 50% B cells, and 5% monocytes in diseased gingival tissues, more than 50 and 90% of T cells and B cells, respectively, expressed RANKL. RANKL production by nonlymphoid cells was not distinctly identified. Lymphocytes isolated from gingival tissues of patients induced differentiation of mature osteoclast cells in a RANKL-dependent manner in vitro. However, similarly isolated peripheral blood B and T cells did not induce osteoclast differentiation, unless they were activated in vitro to express RANKL; emphasizing the osteoclastogenic potential of activated RANKL-expressing lymphocytes in periodontal disease tissue. These results suggest that activated T and B cells can be the cellular source of RANKL for bone resorption in periodontal diseased gingival tissue.

B-Lymphocytes↗
PubMed2002

Inhibitory action of bisphosphonates on bone resorption does not involve the regulation of RANKL and OPG expression.

The mechanism of inhibitory action of bisphosphonates on bone resorption is not fully elucidated. Osteoclast formation and activity are regulated by osteoblast-derived factors such as the osteoclast differentiating factor, receptor activator of NF-kappaB ligand (RANKL) and the inhibitor, osteoprotegerin (OPG). To investigate in vitro effects of bisphosphonates on mouse osteoblastic cells, we examined the expression levels of RANKL and OPG in the cells treated with alendronate or pamidronate (10(-8) approximately 10(-5) M) alone, or combined with 10 nM of 1,25-(OH)2VitD3 for 24 or 48 h. Various concentrations of alendronate and pamidronate did not change the mRNA expression of RANKL and OPG consistently irrespective of 1,25-(OH)2VitD3 presence. When added into cocultures of mouse osteoblastic cells and bone marrow cells, both alendronate and pamidronate inhibited osteoclast formation and bone resorption but failed to alter the RANKL and OPG mRNA expression. These results indicate that the inhibition of bone resorption by bisphosphonates is not mediated by the regulation of RANKL and OPG expression.

Alendronate↗
PubMed2001

Bone resorption is increased in young adults with thalassaemia major.

Bone disease in patients with thalassaemia major is a multifactorial and still poorly understood process. The present study evaluated 45 thalassaemic patients using dual X-ray absorptiometry at three sites (lumbar spine, head of femur and forearm) to assess bone mineral density, in parallel with a series of biochemical markers to measure bone formation and bone resorption. To identify possible interfering factors, our patients were grouped according to whether or not they needed transfusion therapy; the presence of hypogonadism was also considered. Our results showed that patients on regular transfusions had a markedly low bone mineral density in contrast to those not requiring blood support and that this finding was more pronounced in the hypogonadic group, irrespectively of sex. The decrease of bone mineral density values was more prominent in the forearm, thus making this site particularly interesting for such studies. Bone formation, as evidenced by the levels of serum alkaline phosphatase and osteocalcin, did not appear to be impaired, while bone resorption was grossly increased in all patient groups. The latter process was clearly evident using the recently introduced measurement of the urinary N-terminal peptides of collagen type I, the sensitivity of which has already been established in other groups of osteoporotic patients. Our conclusion is that, in spite of the severe bone destruction that occurs in thalassaemia major, the fact that bone formation remains intact calls for a more intensive treatment comprising hormonal replacement, bisphosphonates and other agents.

Absorptiometry, Photon↗
PubMed1980

Bone resorption stimulated by lipopolysaccharides from Bacteroides, Fusobacterium and Veillonella, and by the lipid A and the polysaccharide part of Fusobacterium lipopolysaccharide.

Lipopolysaccharides (LPS) isolated from oral strains of Veillonella, Fusobacterium and Bacteroides stimulated the release of 45Ca from prelabeled fetal rat bones in culture. There was a typical dose-response relationship between the quantities of released 45Ca and LPS used for stimulation. Bacteroides-LPS proved to be the less active inducer of 45Ca release. LPS had no stimulating effect on the release of 45Ca from devitalized bone. The stimulated 45Ca release was paralleled by an increase in the culture medium of hydroxyproline and lactate. This, together with the findings of numerous osteoclasts in stained histological specimens of the experimental bones, indicates that LPS stimulated the osteoclasts to bone resorption. Heparin, which did not directly induce 45Ca release, potentiated the bone resorption stimulating capability of LPS. The lipid A and the polysaccharide portion of Fusobacterium LPS also stimulated bone resorption and, remarkably, the polysaccharide portion showed the greatest activity. This may explain the mode of action of LPS lacking a typical lipid A. It is suggested that stimulation of osteoclasts by LPS may result from activation of complement components by lipid A or its polysaccharide portion.

Animals↗
PubMed1999

Alendronate did not inhibit instability-induced bone resorption. A study in rats.

Alendronate is a bisphosphonate that can decrease osteoclastic activity. It has been suggested as treatment for periprosthetic osteolysis. We used 48 rats, of which 32 had a plate implant on one tibia, to study the effect of alendronate on bone resorption at an unstable implant-bone interface. The plate has a handle on top, which can be grasped through the skin and turned, to create a sliding motion of a titanium surface against the underlying bone. This is known to result in bone resorption, which was studied by histomorphometry. Osmotic minipumps were used to administer alendronate at 0.063 mg/kg/day or saline. The systemic effect of the treatment was assessed by ashing the proximal metaphyses of the tibia of the contralateral unoperated leg. The ash-weight was increased in the alendronate-treated group by 43% (p = 0.0001), corresponding to histological changes in the metaphyseal bone. There was no inhibition of the instability-induced bone resorption at the test surface by alendronate: bone was being resorbed and replaced by a tissue similar to a loosening membrane.

Alendronate↗
PubMed1987

Inhibition of A23187-stimulated bone resorption in tissue culture by serum and indomethacin.

The present study addresses the controversy that currently exists concerning the effect of the divalent cation ionophore A23187 on bone resorption in tissue culture. We show here that this compound is ineffective if serum is present in the culture medium. However, in a serum-free medium it effectively stimulates bone resorption in neonatal mouse calvaria cultures. This finding does account for the various conflicting reports in the literature. Furthermore, the stimulation of bone resorption by the ionophore was accompanied by increased prostaglandin E2 production. Indomethacin inhibited both phenomena, indicating that prostaglandin E2 biosynthesis is involved in mediating the bone resorption-stimulating effect of A23187.

Animals↗
PubMed1991

Divalent cations mimic the inhibitory effect of extracellular ionised calcium on bone resorption by isolated rat osteoclasts: further evidence for a "calcium receptor".

Osteoclast activity is thought to be regulated by calcitonin, as well as by the level of ionised calcium generated locally as a result of bone resorption. The exposure of isolated osteoclasts to elevated ambient calcium levels has been shown to lower resorptive activity and to reduce rates of enzyme release. We have attempted to determine whether these effects are mediated by a divalent cation-sensitive "calcium receptor," as has been reported for the parathyroid chief cells. Thus, we compared the effect of alkaline earth metal cations on osteoclast function using a morphometric measure of bone resorption and a spectrophotometric method for measuring the activity of the released enzyme, acid phosphatase. The exposure of resorbing osteoclasts to between 5 and 20 mM extracellular ionised calcium ([Ca2+]e) inhibited bone resorption and enzyme release to an extent similar to that seen with 0.1 to 10 microM ionomycin. The effect of combining submaximal concentrations of [Ca2+]e (15 mM) and ionomycin (0.1 microM) resulted in additivity, suggesting that the influence of [Ca2+]e on bone resorption was mediated by elevated intracellular calcium levels ([Ca2+]i). The other cations studied (Mg2+, Ba2+) were effective and elicited similar effects, although some required higher concentrations. Thus, whilst Ca2+ and Mg2+ were effective at 10 to 15 mM levels, Ba2+ was effective only at high (20 mM) concentrations. These findings are consistent with an influence of [Ca2+]e on osteoclast activity through an action on a surface membrane "calcium receptor" that can also bind other divalent cations, rather than by passive changes of [Ca2+]i with [Ca2+]e elevation.

Acid Phosphatase↗
PubMed1995

The inhibitory effect of vitamin K2 (menatetrenone) on bone resorption may be related to its side chain.

Although the effects of vitamin K2 and vitamin K1 on bone metabolism have been reported, the difference between them has not been investigated. We now show the effects of menatetrenone, one of the vitamin K2 homologues, and vitamin K1 on bone resorption. Menatetrenone at greater than 3 x 10(-6) M significantly inhibited the calcium release from mouse calvaria induced by 3 x 10(-10) M of 1,25(OH)2D3 or 10(-7) M of prostaglandin E2, and it also inhibited osteoclast-like multinucleated cell (MNC) formation induced by 10(-8) M of 1,25(OH)2D3 in co-culture of spleen cells and stromal cells at the same concentrations. In contrast, the same doses of vitamin K1 had no effects on bone resorption and MNC formation in these in vitro systems. The inhibitory effect of menatetrenone on the calcium release from calvaria was not affected by the addition of 3 x 10(-5) M of warfarin, an inhibitor of vitamin K cycle. The same concentration of geranylgeraniol, the side-chain component of menatetrenone at the 3-position of the naphthoquinone, inhibited tartrate-resistant acid phosphatase (TRACP) activity and MNC formation to the same degree as menatetrenone. Phytol, the side-chain component of vitamin K1, did not affect TRACP activity at all doses tested, but weakly inhibited MNC formation. Moreover, multi-isoprenyl alcohols of two to seven units, except geranylgeraniol which contains four units, did not effect MNC formation. These findings suggest that the inhibitory effect of menatetrenone on bone resorption is not due to gamma-carboxylation and that the side chain of menatetrenone may play an important role in this inhibitory effect.

Acid Phosphatase↗
PubMed1982

Comparison of parathyroid hormone and calcium ionophore A23187 effects on bone resorption and nucleic acid synthesis in cultured fetal rat bone.

It has recently been demonstrated that calcium ionophore A23187 mimics certain of the effects of parathyroid hormone (PTH) on bone in vitro, including stimulation of 45Ca release and cAMP formation. To further examine the relative effects of these two agents on bone cell metabolism, we compared the effects of synthetic PTH 1-34 (50 ng/ml) and calcium ionophore A23187 (0.5 micrograms/ml) on 45Ca release, DNA concentration, and nucleic acid synthesis in fetal rat forelimb rudiments cultured for periods up to 120 h. Both agents stimulated 45Ca release; however, the effects of PTH were apparent after a shorter period of exposure. Bone DNA concentration (expressed as microgram DNA/mg bone) was not affected by PTH but was significantly increased relative to control values by exposure to A23187 for 8-120 h of incubation. PTH increased the incorporation of 3H-thymidine into DNA at 30 and 48 h, and increased the incorporation of 14C-uridine into RNA at 48 h, time points which corresponded to a period of accelerated PTH stimulation of 45Ca release. In contrast, 3H-thymidine and 14C-uridine incorporation were both uniformly suppressed by A23187 at all time points examined. Thus the increased DNA concentration observed in A23187-treated rudiments appeared to be the result of a decreased rate of bone maturation and mineralization. The markedly different patterns of nucleic acid synthesis in response to PTH and A23187 suggest that these agents differ significantly in their mechanisms of action on bone cell metabolism.

Animals↗
PubMed1995

Acute effects of bisphosphonates on new and traditional markers of bone resorption.

Bisphosphonates are known to be potent inhibitors of osteoclast activity and their only clinically relevant effect in the short-term is the selective inhibition of bone resorption. The purpose of this study was to compare the response to the intravenous administration of two bisphosphonates, clodronate and alendronate, of several biochemical markers of bone resorption, including tartrate-resistant acid phosphatase (TRAP) and cross-linked carboxyterminal telopeptide of collagen I (ICTP) in serum and hydroxyproline (OHP), free pyridinium cross-links (Pyr), and cross-linked N-telopeptides of collagen I (NTx) in urine. The study was carried out on 11 osteoporotic and 12 Pagetic subjects of both sexes, treated with clodronate (600 mg/day for 2 days) or alendronate (5 mg/day for 2 days), and monitored for 28 days after bisphosphonate administration. All the urinary markers of bone resorption showed a prompt decline after bisphosphonates, with maximum reductions after 7-14 days: Pyr decreased by 43% +/- 9% and 42% +/- 22% (mean +/- SD), respectively in osteoporotic and pagetic subjects, OHP by 51% +/- 14% and 51% +/- 20%, and NTx by 55% +/- 15% and 65% +/- 26%. In the osteoporotic group, the urinary markers began to increase again at 30 days, though still remaining well below the basal level, whereas in the pagetic group, the excretion of all markers remained depressed until the end of the observation period. The reduction of NTx was significantly greater than that of Pyr and OHP in pagetic patients (P < 0.05) and tended to be greater than that of Pyr in osteoporotic patients (p = 0.07).(ABSTRACT TRUNCATED AT 250 WORDS)

Acid Phosphatase↗
PubMed2005

Serum concentrations of cross-linked N-telopeptides of type I collagen: new marker for bone resorption in hemodialysis patients.

BACKGROUND: Urinary cross-linked N-telopeptide of type I collagen (NTX) is a reliable bone resorption marker in patients with metabolic bone disease. We assessed a clinically available serum NTX assay suitable for anuric patients on hemodialysis (HD). METHODS: Serum concentrations of NTX, C-terminal telopeptide of type I collagen (beta-CTX), pyridinoline (PYD), and deoxypyridinoline (DPD) were determined as bone resorption markers, and those of bone alkaline phosphatase (BAP) and intact osteocalcin (OC) as bone formation markers, in 113 male HD patients (mean age, 59.3 years; mean HD duration, 67.7 months). Each patient's bone mineral density (BMD) in the distal third of the radius was measured twice, with a 2-year interval between measurements, by dual-energy x-ray absorptiometry. RESULTS: Serum NTX correlated significantly with beta-CTX, PYD, DPD, BAP, and intact OC. NTX, as well as beta-CTX, PYD, DPD, BAP, and intact OC, correlated significantly with BMD at the time of measurement. NTX, beta-CTX, and DPD correlated significantly with the annual change in BMD during the 2-year period thereafter, in contrast to PYD, BAP, and intact OC. Patients in the highest quartile of serum NTX concentrations showed the fastest rate of bone loss. The sensitivity and specificity for detecting rapid bone loss were 48% and 83%, respectively, for serum NTX. CONCLUSION: Serum NTX may provide a clinically relevant serum assay to estimate bone turnover in HD patients.

Adult↗
PubMed2001

[Mechanisms of bone resorption in periodontal disease].

Periodontal diseases are infectious, chronic inflammatory diseases that result both in loss of alveolar bone and destruction of connective tissue in periodontal regions. The bone resorption is triggered through immune responses, and results from inflammatory reactions directed against periodontopathic bacteria. Osteoclasts, bone resorbing cells, differentiate from macrophage/monocyte lineage cells, and are activated by various cytokines including osteoclast differentiation factor (ODF) / receptor activator of NF-kappaB ligand (RANKL). Activated antigen-specific CD4 positive T-cells directed against periodontopathic bacteria produce ODF/RANKL, which has been shown to play a critical role in bone resorption in periodontal diseases. This review describes recent progress towards elucidating mechanisms of bone resorption in periodontal disease.

English Abstract↗