Study of the cell biology and biochemistry of cherubism.
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AIMS: To establish whether the multinucleate cells in lesions of patients with cherubism are also osteoclasts and if this is the case whether they were responsive to calcitonin; to carry out cytogenetic studies on two members of the same family affected by cherubism in an attempt to identify any major chromosomal defects; and to perform an in-depth modern biochemical study of four children in the same family. SUBJECTS AND METHODS: Four related children with cherubism were studied. Tissue taken from one of the children at elective decompression of an optic nerve was submitted to in vitro bone resorption studies. Cytogenetic studies were done on two of the children and biochemical studies on all four. RESULTS: The multinucleate cells in the cherubic lesions were shown to be osteoclasts since they synthesised tartrate resistant acid phosphatase, expressed the vitronectin receptor, and resorbed bone. Bone resorption by the cultured multinucleate cells was significantly inhibited by calcitonin. High resolution cytogenetic studies failed to detect any chromosomal abnormalities in two children with cherubism. The biochemistry profile of all four children with cherubism showed that serum calcium, parathyroid hormone, parathyroid related hormone, calcitonin, and alkaline phosphatase were within normal levels. Urine analysis of pyridinium and deoxypyridinium cross links, hydroxyproline, and calcium in relation to urine creatinine were measured to assess bone resorption in these children, and the values were at the upper end of the normal range in all four. CONCLUSIONS: Further studies are required to determine whether calcitonin treatment will control this grossly deforming disease until the time when the physiological changes that occur at puberty rectify the pathology. It is not recommended that biochemical markers of bone resorption are used in isolation to monitor the activity of cherubism in individuals because the results are based on a small number of children and because of reports of marked interindividual variation in the levels of these markers, particularly in children. (+info)
Inhibition of inflammatory actions of aminobisphosphonates by dichloromethylene bisphosphonate, a non-aminobisphosphonate.
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1. When injected intraperitoneally into mice in doses larger than those used clinically, all the amino derivatives of bisphosphonates (aminoBPs) tested induce a variety of inflammatory reactions such as induction of histidine decarboxylase (HDC, the histamine-forming enzyme), hypertrophy of the spleen, atrophy of the thymus, hypoglycaemia, ascites and accumulation of exudate in the thorax, and an increase in the number of macrophages and/or granulocytes in the peritoneal cavity of blood. On the other hand, dichloromethylene bisphosphonate (Cl2MBP) a typical non-aminoBP, has no such inflammatory actions. In the present study, we found that this agent can suppress the inflammatory actions of aminoBPs. 2. Cl2MBP, when injected into mice before or after injection of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid (AHBuBP; a typical aminoBP), inhibited the induction of HDC activity by AHBuBP in a dose- and time-dependent manner. The increase in HDC activity induced by AHBuBP was largely suppressed by the injection of an equimolar dose of Cl2MBP. Cl2MBP also inhibited other AHBuBP-induced inflammatory reactions, as well as the inflammatory actions of two other aminoBPs. However, Cl2MBP did not inhibit the increase in HDC activity induced by lipopolysaccharide (LPS). 3. We have previously reported that AHBuBP augments the elevation of HDC activity and the production of interleukin-1beta (IL-1beta) that are induced by LPS. These actions of AHBuBP were also inhibited by Cl2MBP. 4. Based on these results and reported actions of bisphosphonates, the mechanisms underlying the contrasting effects of aminoBPs and Cl2MBP, a non-aminoBP are discussed. The results suggest that combined administration of Cl2MBP and an aminoBP in patients might be a useful way of suppressing the inflammatory side effects of aminoBPs. (+info)
Serum galactosyl hydroxylysine as a biochemical marker of bone resorption.
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BACKGROUND: Serum-based biochemical markers of bone resorption may provide better clinical information than urinary markers because direct comparison with serum markers of bone formation is possible and because the within-subject variability of serum markers may be lower. We describe a method for the measurement of free beta-1-galactosyl-O-hydroxylysine (Gal-Hyl) in serum. METHODS: The assay used preliminary ultrafiltration of serum, dansylation, and separation by reversed-phase HPLC with fluorescence detection. Healthy subjects were recruited from population-based studies of bone turnover. RESULTS: The within-run (n = 15) and between-run (n = 15) CVs were 7% and 14%, respectively, at a mean value of 48 nmol/L. In women and pubertal girls, serum free Gal-Hyl correlated with urine free Gal-Hyl (r = 0.84; P <0.001). Serum Gal-Hyl was higher during puberty and increased after menopause. The fractional renal clearance of free Gal-Hyl relative to that of creatinine was 0.90 (95% confidence interval, 0.82-0.98). Serum free Gal-Hyl decreased by 36% (SE = 4%) in 14 patients with mild Paget disease treated with an oral bisphosphonate, and this decrease was significantly (P <0. 001) greater than that seen for either serum tartrate-resistant acid phosphatase (9%; SE = 4%) or serum C-terminal telopeptide of collagen I (19%; SE = 8%). CONCLUSION: Serum free Gal-Hyl may be useful as a serum marker of bone resorption. (+info)
The ligand for osteoprotegerin (OPGL) directly activates mature osteoclasts.
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Osteoprotegerin (OPG) and OPG-ligand (OPGL) potently inhibit and stimulate, respectively, osteoclast differentiation (Simonet, W.S., D.L. Lacey, C.R. Dunstan, M. Kelley, M.-S. Chang, R. Luethy, H.Q. Nguyen, S. Wooden, L. Bennett, T. Boone, et al. 1997. Cell. 89:309-319; Lacey, D.L., E. Timms, H.-L. Tan, M.J. Kelley, C.R. Dunstan, T. Burgess, R. Elliott, A. Colombero, G. Elliott, S. Scully, et al. 1998. Cell. 93: 165-176), but their effects on mature osteoclasts are not well understood. Using primary cultures of rat osteoclasts on bone slices, we find that OPGL causes approximately sevenfold increase in total bone surface erosion. By scanning electron microscopy, OPGL-treated osteoclasts generate more clusters of lacunae on bone suggesting that multiple, spatially associated cycles of resorption have occurred. However, the size of individual resorption events are unchanged by OPGL treatment. Mechanistically, OPGL binds specifically to mature OCs and rapidly (within 30 min) induces actin ring formation; a marked cytoskeletal rearrangement that necessarily precedes bone resorption. Furthermore, we show that antibodies raised against the OPGL receptor, RANK, also induce actin ring formation. OPGL-treated mice exhibit increases in blood ionized Ca++ within 1 h after injections, consistent with immediate OC activation in vivo. Finally, we find that OPG blocks OPGL's effects on both actin ring formation and bone resorption. Together, these findings indicate that, in addition to their effects on OC precursors, OPGL and OPG have profound and direct effects on mature OCs and indicate that the OC receptor, RANK, mediates OPGL's effects. (+info)
Glucocorticoid-induced secondary osteopenia in female rats: a time course study as compared with ovariectomy-induced osteopenia and response to salmon calcitonin.
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Previously we reported that 8-week treatment with methylprednisolone acetate (MPA: 0.1 mg/kg, s.c., 3 days a week) of male rats caused a novel type of osteopenia whose development was prevented by salmon calcitonin (SCT) in a dose-dependent manner. In this study, to compare the MPA-inducible osteopenia with the ovariectomy (OVX)-inducible one, female rats were used instead of male rats and a time-course study of development was made. MPA treatments for 1, 2, 4 and 8 weeks histologically induced characteristic osteopenic changes in a time-dependent manner that were histomorphometrically detectable in tibiae within 4 weeks as reduced bone mass, accelerated bone resorption, and suppressed bone formation and mineralization. Node-strut analysis revealed that the connectivity of the trabecular structure remained unaffected. Such MPA-induced changes in the trabecular structure, to be defined as thinned-but-uncut, is in a good contrast with OVX-induced unthinned-but-cut structure, although the latter osteopenic changes became detectable 2 weeks earlier. Another previous finding confirmed herein was that MPA-induced osteopenia in female rats was also completely masked by SCT (10 U/kg, s.c., 5 days a week). The results indicate that the MPA-inducible secondary osteopenic model in either sex of rats would be usable for testing anti-osteopenic drugs. (+info)
Morphometric evidence that YM175, a bisphosphonate, reduces trabecular bone resorption in ovariectomized dogs with dietary calcium restriction.
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We examined mechanisms by which incadronate disodium (YM175) prevented bone resorption in ovariectomized dogs with dietary calcium restriction using the morphometrical method. YM175 (0.01-1.0 mg/kg) was given to ovariectomized dogs for 18 months. Because lumbar bone mineral density remained constant at month 17, we assumed that the trabecular bone resorption rate was equal to the bone formation rate and that wall thickness equaled resorption cavity depth. YM175 decreased both the bone resorption rate per number of osteoclasts and resorption cavity depth of cancellous pockets which were increased in ovariectomized dogs. These results suggest that YM175 reduces bone loss by decreasing the resorbing activity of osteoclasts. (+info)
Growth plate cartilage formation and resorption are differentially depressed in growth retarded uremic rats.
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To characterize the modifications of growth plate in individuals with growth impairment secondary to chronic renal failure, young rats were made uremic by subtotal nephrectomy (NX) and, after 14 d, their tibial growth plates were studied and compared with those of sham-operated rats fed ad libitum (SAL) or pair-fed with NX (SPF). NX rats were growth retarded and severely uremic. Growth plate height (mean +/- SD) was much greater (P<0.05) in NX (868.4+/-85.4 microm) than SAL (570.1+/-93.5 microm) and SPF (551.9+/-99.7 microm) rats as a result of a higher (P<0.05) hypertrophic zone (661.0+/-89.7 versus 362.8+/-71.6 and 353.0+/-93.9 microm, respectively). The increased size of the growth plate was associated with a greater number of chondrocytes and modifications in their structure, particularly in the hypertrophic zone adjacent to bone. In this zone, chondrocytes of NX animals were significantly (P<0.05) smaller (12080.4+/-1158.3 microm3) and shorter (34.1+/-2.5 microm) than those of SAL (16302.8+/-1483.4 microm3 and 37.8+/-2.0 microm) and SPF (14465.8+/-1521.0 microm3 and 36.3+/-1.8 microm). The interface between the growth plate cartilage and the metaphyseal bone appeared markedly irregular in NX rats. Kinetics of chondrocytes was also modified (P<0.05) in the NX rats, which had lower cell turnover per column per day (5.4+/-0.9), longer duration of hypertrophic phase (89.0+/-15.2 h), and reduced cellular advance velocity (7.4+/-2.2 microm/h) compared with SAL (8.0+/-1.6, 32.1+/-6.7 h, and 11.3+/-2.7 microm/h) and SPF (7.2+/-1.1, 34.8+/-5.1 h, and 10.1+/-2.5 microm/h). Cell proliferation was no different among the three groups. Because the growth plates of SPF and SAL rats were substantially not different, modifications observed in the NX rats cannot be attributed to the nutritional deficit associated with renal failure. These findings indicate that chronic renal failure depresses both the activity of the growth plate cartilage by altering chondrocyte hypertrophy and the replacement of cartilage by bone at the metaphyseal end. The two processes are differentially depressed since cartilage resorption is more severely lowered than cartilage enlargement and this leads to an accumulation of cartilage at the hypertrophic zone. (+info)
One year prospective open study of the effect of high dose inhaled steroids, fluticasone propionate, and budesonide on bone markers and bone mineral density.
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BACKGROUND: Inhaled corticosteroids are recognised as the most effective agents in the treatment of asthma. However, concerns have been expressed about the effects of high doses of inhaled corticosteroids on safety in relation to bone resorption and formation. This study measures the effects of two inhaled corticosteroids on bone markers and bone mineral density (BMD) over one year. METHODS: A one year randomised, prospective, open parallel study comparing inhaled fluticasone propionate (FP), 500 micrograms twice daily in 30 patients, and budesonide (BUD), 800 micrograms twice daily in 29 patients, delivered by metered dose inhaler and large volume spacers was performed in adults with moderate to severe asthma. Biochemical markers of bone turnover (osteocalcin, procollagen type 1 C-terminal propeptide (PICP), immunoreactive free deoxypyridinoline (iFDpd), N-terminal crosslinked telopeptides of type I collagen (NTx)), BMD at the spine and femoral neck, and serum cortisol concentrations were measured at baseline and 12 months later. RESULTS: There were no significant differences between the inhaled steroids on bone markers of bone resorption and formation or bone mineral density. Bone mineral density of the spine increased slightly in both groups over the 12 month period. Serum osteocalcin levels increased from baseline in both treatment groups (FP 16.9%, p = 0.02; BUD 14.3%, p = 0.04). PICP did not differ significantly from baseline. Both markers of bone resorption (iFDpd, NTx) varied considerably with no significant changes after one year. There was a significant correlation in percentage change from baseline between BMD of the spine and osteocalcin at 12 months (r = 0.4, p = 0.017). Mean serum cortisol levels remained within the normal range in both groups following treatment. CONCLUSION: There was no evidence of a decrease in BMD during 12 months of treatment with high doses of either FP or BUD. The change in spine BMD correlated with the increase in osteocalcin. Studies extending over several years are needed to establish whether these findings persist. (+info)