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1.
Inflammation ; 28(1): 15-21, 2004 Feb.
Article in English | MEDLINE | ID: mdl-15072226

ABSTRACT

We compared the effects of nonaminobisphosphonate (nonamino-BP; clodronate) and amino-BP (alendronate) on the changes in local and systemic bone metabolism associated with chronic inflammation in adjuvant-arthritis rats. A given rat received one of the BPs orally each day for 28 days from the day of adjuvant inoculation. Hindpaw swelling was observed from day 10 after adjuvant inoculation up to day 28 (peak, day 21). Clodronate slightly decreased the hindpaw swelling at doses of 12.5 and 25 mg/kg, p.o./day; however, alendronate (0.125-0.5 mg/kg) did not. Radiological examination of the distal limb joints revealed that only clodronate decreased bone deformation. Urinary deoxypyridinoline increased as arthritis developed, and it was decreased by clodronate. On day 29, pQCT analysis of the 5th lumbar vertebra revealed trabecular bone loss and cortical bone thinning in the arthritis control group, leading to compressive strength being reduced. Both BPs prevented this bone loss and strength reduction. These data suggest that only clodronate decreases inflammation and local bone deformation, while both BPs inhibit the arthritis-related decreases in systemic bone mass and bone strength. Clodronate would be useful in the treatment of inflammation-induced bone deformation and osteopenia.


Subject(s)
Alendronate/pharmacology , Arthritis, Experimental/metabolism , Bone and Bones/drug effects , Clodronic Acid/pharmacology , Alendronate/therapeutic use , Animals , Arthritis, Experimental/drug therapy , Arthritis, Experimental/physiopathology , Bone and Bones/metabolism , Bone and Bones/physiopathology , Clodronic Acid/therapeutic use , Male , Osteogenesis/drug effects , Rats , Rats, Inbred Lew
2.
Eur J Pharmacol ; 477(1): 9-16, 2003 Sep 05.
Article in English | MEDLINE | ID: mdl-14512092

ABSTRACT

We investigated the direct effects of various bisphosphonates on osteoblasts. At 10(-5) M, clodronate increased alkaline phosphatase activity in cultured MC3T3-E1 (osteoblast-like line) and ST2 (pluripotent mesenchymal line) cells. Etidronate significantly increased alkaline phosphatase activity at 10(-5) M only in MC3T3-E1 cells. These effects were due to an increase in alkaline phosphatase-positive cell numbers, and the differentiation-enhanced cells were capable of mineralization (von Kossa stain). Other bisphosphonates (pamidronate, alendronate, and incadronate) did not increase alkaline phosphatase activity in either cell line. In cultured rat calvariae, clodronate stimulated the expression of genes for alkaline phosphatase and osteocalcin (osteoblast-differentiation markers), but decreased the expression of the gene for tartrate-resistant acid phosphatase (osteoclast marker). Clodronate, etidronate, and incadronate inhibited protein Tyr phosphatase and Ser/Thr phosphatase activities in MC3T3-E1 cells. These data suggest that clodronate acts directly on mesenchymal cells to enhance osteoblast differentiation, and this effect may be partly expressed through inhibition of protein Tyr phosphatase and/or Ser/Thr phosphatase activity.


Subject(s)
Cell Differentiation/drug effects , Clodronic Acid/pharmacology , Osteoblasts/drug effects , Alkaline Phosphatase/metabolism , Animals , Blotting, Northern , Cell Differentiation/genetics , Cells, Cultured , Clodronic Acid/chemistry , Female , Fetus , Mice , Organ Culture Techniques , Osteoblasts/enzymology , Osteoblasts/physiology , Rats , Rats, Sprague-Dawley , Reverse Transcriptase Polymerase Chain Reaction , Skull/drug effects , Skull/metabolism , Stem Cells/drug effects , Stem Cells/enzymology , Stem Cells/physiology , Time Factors
3.
J Bone Miner Res ; 17(3): 534-43, 2002 Mar.
Article in English | MEDLINE | ID: mdl-11874245

ABSTRACT

Over 16 months, we evaluated the effects of ovariectomy (OVX) and bisphosphonate clodronate (CLO) on bone in 48 cynomolgus monkeys (9-15 years old) fed a normal calcium diet. We established three OVX groups (oral CLO at 0 [OVX control], 12, or 60 mg/kg per day) and one sham-operated (SHAM) group. At 16 months, the bone mineral density (BMD) values (percentage of group baseline; OVX control vs. SHAM) for lumbar bone (L3-L5), proximal femur, midfemur, radius, and tibia were -2.6% versus 11.2%, -3.5% versus 8.9%, -3.0% versus 9.0%, -5.5% versus 15.7%, and -6.7% versus 13.9%, respectively. In OVX control (i) tibia showed significant loss of bone mineral content (BMC; vs. baseline), (ii) urinary deoxypyridinoline (DPD) and serum osteocalcin (OC) levels increased (peak = 182% and 168%, respectively, of SHAM), (iii) in lumbar bone and midfemur, ultimate load (UL) was reduced (vs. SHAM), (iv) in lumbar bone, trabecular bone-formation rates (BFRs) were not changed significantly, but tibial endocortical and intracortical bone formation rates were significantly raised (vs. SHAM), (v) the volumetric BMD (vBMD) and geometry of the tibial cortex (measured by peripheral quantitative computed tomography [pQCT]) were significantly reduced (vs. SHAM). CLO, 60 mg/kg per day but not 12 mg/kg per day, significantly inhibited OVX-induced changes, age-dependent increases in bone mass, and ability to maintain structure. Thus, in OVX mature cynomolgus monkeys (possibly, a unique model of the cortical bone loss secondary to estrogen deficiency), the post-OVX increases in systemic bone markers were slight, but stimulation of local turnover in the cortical envelope was enough to cause bone loss (more so in tibia than in lumbar trabecular bone). High-dose CLO prevented these changes.


Subject(s)
Bone Density/drug effects , Clodronic Acid/pharmacology , Amino Acids/urine , Animals , Biomarkers/analysis , Biomechanical Phenomena , Bone Remodeling/drug effects , Female , Femur/drug effects , Femur/physiology , Lumbar Vertebrae/drug effects , Lumbar Vertebrae/physiology , Macaca fascicularis , Ovariectomy , Time Factors
4.
Biochem Biophys Res Commun ; 290(1): 131-9, 2002 Jan 11.
Article in English | MEDLINE | ID: mdl-11779144

ABSTRACT

In this study, we used a coactivator-dependent receptor-ligand interaction assay (CARLA), which is a semifunctional in vitro assay, to determine whether hypolipidemic drugs are ligands for the three peroxisome proliferator-activated receptor isotypes (PPARalpha, delta, and gamma). We also evaluated the transcriptional activities of the three PPAR isotypes by transient transfection assays. We found that bezafibrate was a ligand for PPARalpha, delta, and gamma in the CARLA and that bezafibrate induced transcriptional activation of PPARalpha/RXRalpha, PPARdelta/RXRalpha, and PPARgamma/RXRalpha. Although the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors cerivastatin, fluvastatin, and pitavastatin were not ligands for these three nuclear receptors in the CARLA, they induced transcriptional activation of PPARalpha/RXRalpha, PPARdelta/RXRalpha, and PPARgamma2/RXRalpha. Moreover, cerivastatin, fluvastatin, and pitavastatin synergistically and dose-dependently increased the transcriptional activation of PPARalpha/RXRalpha induced by bezafibrate. In addition, the cerivastatin-induced transcriptional activation of PPARalpha/RXRalpha was decreased by addition of mevalonate, farnesol, geranylgeraniol, or cholesterol and by co-transfection with sterol regulatory element-binding protein-1 (SREBP-1). Moreover, concomitant administration of statins and fibrates also decreased the transactivation of nuclear factor kappaB (NFkappaB) and the activation of NFkappaB by mitogen-activated protein kinase kinase kinase (MEKK) also decreased the transactivation of PPARalpha/RXRalpha.


Subject(s)
Anticholesteremic Agents/pharmacology , Bezafibrate/pharmacology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Hypolipidemic Agents/pharmacology , NF-kappa B/metabolism , Receptors, Cytoplasmic and Nuclear/metabolism , Receptors, Retinoic Acid/metabolism , Transcription Factors/metabolism , Transcription, Genetic , Transcriptional Activation , Blotting, Western , CCAAT-Enhancer-Binding Proteins/metabolism , Cell Nucleus/metabolism , DNA, Complementary/metabolism , DNA-Binding Proteins/metabolism , Dose-Response Relationship, Drug , Drug Synergism , Enzyme Inhibitors/pharmacology , Fatty Acids, Monounsaturated/pharmacology , Fluvastatin , Gene Library , Humans , Indoles/pharmacology , Ligands , Liver/metabolism , Mitogen-Activated Protein Kinase Kinases/metabolism , Models, Biological , Muscle, Skeletal/metabolism , Nuclear Proteins/metabolism , Protein Structure, Tertiary , Pyridines/pharmacology , Quinolines/pharmacology , Recombinant Fusion Proteins/metabolism , Retinoid X Receptors , Sequence Analysis, DNA , Sterol Regulatory Element Binding Protein 1 , Trans-Activators/metabolism , Transfection
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