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1.
J Clin Endocrinol Metab ; 88(7): 3321-6, 2003 Jul.
Article in English | MEDLINE | ID: mdl-12843182

ABSTRACT

Camurati-Engelmann disease (CED) is a rare autosomal dominant disorder characterized by bone pain and osteosclerosis affecting the diaphysis of long bones. CED is caused by various missense mutations in the TGFB1 gene that encodes TGFbeta1, the most common of which is an arginine-cysteine amino acid change at codon 218 (R218C) in the latency-associated peptide domain of TGFbeta1. We studied osteoclast formation in vitro from peripheral blood mononuclear cells obtained from three related CED patients harboring the R218C mutation, in comparison with one family-based and several unrelated controls. Osteoclast formation was enhanced approximately 5-fold (P < 0.001) and bone resorption approximately 10-fold (P < 0.001) in CED patients, and the increase in osteoclast formation was inhibited by soluble TGFbeta type II receptor. Total serum TGFbeta1 levels were similar in affected and unaffected subjects, but concentrations of active TGFbeta1 in conditioned medium of osteoclast cultures was higher in the three CED patients than in the unaffected family member. We concluded that the R218C mutation increases TGFbeta1 bioactivity and enhances osteoclast formation in vitro. The activation of osteoclast activity noted here is consistent with clinical reports that have shown biochemical evidence of increased bone resorption as well as bone formation in CED.


Subject(s)
Camurati-Engelmann Syndrome/genetics , Camurati-Engelmann Syndrome/physiopathology , Osteoclasts/cytology , Point Mutation , Transforming Growth Factor beta/genetics , Adult , Aged , Antibodies/pharmacology , Camurati-Engelmann Syndrome/diagnostic imaging , Carrier Proteins/pharmacology , Cell Differentiation/drug effects , Cells, Cultured , Female , Humans , In Vitro Techniques , Leukocytes, Mononuclear/cytology , Macrophage Colony-Stimulating Factor/pharmacology , Male , Membrane Glycoproteins/pharmacology , RANK Ligand , Radiography , Receptor Activator of Nuclear Factor-kappa B , Transforming Growth Factor beta/immunology , Transforming Growth Factor beta1
3.
J Bone Miner Res ; 18(2): 204-12, 2003 Feb.
Article in English | MEDLINE | ID: mdl-12568397

ABSTRACT

Nitrogen-containing bisphosphonates, such as alendronate and ibandronate, inhibit bone resorption by preventing protein prenylation in osteoclasts, whereas non-nitrogen-containing bisphosphonates, such as clodronate, are metabolized to nonhydrolyzable analogs of ATP, resulting in osteoclast apoptosis. Because these two classes of bisphosphonates have different molecular mechanisms of action, we examined in vitro whether combined treatment with clodronate and alendronate would alter antiresorptive effectiveness. Although, in cultures of rabbit osteoclasts, the antiresorptive effect of 10 microM alendronate was increased by the addition of clodronate, the effect of higher concentrations of alendronate was not altered by addition of clodronate. Furthermore, the inhibition of protein prenylation in osteoclasts caused by higher alendronate concentrations was partially prevented by cotreatment with clodronate. As in osteoclasts, the inhibition of protein prenylation in J774 cells caused by alendronate or ibandronate treatment was dose-dependently prevented by cotreatment with clodronate. Furthermore, alendronate-induced J774 apoptosis was significantly inhibited in the presence of clodronate. The presence of clodronate also decreased the short-term cellular uptake of [14C]ibandronate. These observations suggest that combined treatment with clodronate could enhance the antiresorptive effect of a low concentration of nitrogen-containing bisphosphonate, but clodronate can also antagonize some of the molecular actions and effects of higher concentrations of nitrogen-containing bisphosphonates. The exact molecular basis for the antagonistic effects between bisphosphonates remain to be determined, but could involve competition for cellular uptake by a membrane-bound transport protein.


Subject(s)
Diphosphonates/pharmacology , Macrophages/drug effects , Osteoclasts/drug effects , Adenosine Triphosphate/metabolism , Alendronate/pharmacology , Animals , Apoptosis , Blotting, Western , Bone Resorption , Cell Line , Cell Membrane/metabolism , Cell Nucleus/metabolism , Cells, Cultured , Clodronic Acid/pharmacology , Dose-Response Relationship, Drug , Ibandronic Acid , Macrophages/metabolism , Mice , Microscopy, Fluorescence , Osteoclasts/metabolism , Pinocytosis , Rabbits , Time Factors
4.
J Bone Miner Res ; 18(1): 88-96, 2003 Jan.
Article in English | MEDLINE | ID: mdl-12510809

ABSTRACT

Statins, which are inhibitors of 3-hydroxy-3-glutaryl-coenzyme A (HMG-CoA) reductase, decrease the hepatic biosynthesis of cholesterol by blocking the mevalonate pathway. Nitrogen-containing bisphosphonate drugs also inhibit the mevalonate pathway, preventing the production of the isoprenoids, which consequently results in the inhibition of osteoclast formation and osteoclast function. Therefore, we hypothesized that statins could affect bone metabolism in vivo through effects on osteoclastic bone resorption. In vitro, cerivastatin inhibited the parathyroid hormone (PTH)-stimulated bone resorption. Using a panel of 40 statin analogs, which showed variable effects on HMG-CoA reductase activity, we found that the ability of compounds to inhibit bone resorption is directly related to HMG-CoA reductase activity. However, in the thyro-parathyrodectomy (TPTX) model for bone resorption in the rat in vivo, cerivastatin did not prevent experimentally induced increases in bone resorption. The lack of effect of cerivastatin in this model is not related to a limited penetration of the target tissue (bone marrow), because a significant effect on HMG-CoA reductase activity was demonstrated in the total rat bone marrow cell extracts of rats posttreatment in vivo. Furthermore, cerivastatin inhibited protein prenylation in osteoclasts isolated from the rabbit bone marrow of rabbits after treatment in vivo. In contrast to other studies, none of the statins tested showed anabolic effects in parietal bone explant cultures. Taken together, we conclude that statins inhibit bone resorption in vitro, which correlates directly with the potency of the compounds for inhibition of HMG-CoA reductase activity. However, cerivastatin does not affect bone resorption in the rat TPTX model in vivo.


Subject(s)
Bone Resorption/enzymology , Bone Resorption/prevention & control , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Animals , Bone Resorption/metabolism , Calcium/metabolism , Female , Hydroxymethylglutaryl CoA Reductases/metabolism , In Vitro Techniques , Lovastatin/pharmacology , Male , Osteoclasts/drug effects , Osteoclasts/metabolism , Osteogenesis/drug effects , Parathyroidectomy , Pravastatin/pharmacology , Protein Prenylation/drug effects , Pyridines/pharmacology , Rabbits , Rats , Rats, Sprague-Dawley , Simvastatin/pharmacology , Thyroidectomy
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