Acidification of the Osteoclastic Resorption Compartment Provides Insight into the Coupling of Bone Formation to Bone Resorption
| Autor: | Jens Bollerslev, Kim Henriksen, Jeppe Gram, Sophie Schaller, Anne-Marie Heegaard, Mette G Sørensen, Thomas J. Martin, Morten Hanefeld Dziegiel, Palle Christophersen, Morten A. Karsdal, Claus Christiansen |
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| Rok vydání: | 2005 |
| Předmět: |
Male
Time Factors Bone density Cathepsin K Osteoclasts Tetrazoles Rats Sprague-Dawley Bone Density Cells Cultured Tartrate-resistant acid phosphatase biology Chemistry Middle Aged Immunohistochemistry Resorption Isoenzymes Original Research Paper Phenotype medicine.anatomical_structure Osteopetrosis Osteocalcin Female Macrolides Adult musculoskeletal diseases medicine.medical_specialty Acid Phosphatase Models Biological Bone and Bones Bone resorption Pathology and Forensic Medicine Chloride Channels Osteoclast Internal medicine Oxazines medicine Animals Humans Bone Resorption Family Health Cathepsin Dose-Response Relationship Drug Tartrate-Resistant Acid Phosphatase Macrophage Colony-Stimulating Factor Macrophages Phenylurea Compounds Ovary Cathepsins Rats Endocrinology Xanthenes Mutation biology.protein Indicators and Reagents |
| Zdroj: | The American Journal of Pathology. 166:467-476 |
| ISSN: | 0002-9440 |
| Popis: | Patients with defective osteoclastic acidification have increased numbers of osteoclasts, with decreased resorption, but bone formation that remains unchanged. We demonstrate that osteoclast survival is increased when acidification is impaired, and that impairment of acidification results in inhibition of bone resorption without inhibition of bone formation. We investigated the role of acidification in human osteoclastic resorption and life span in vitro using inhibitors of chloride channels (NS5818/NS3696), the proton pump (bafilomycin) and cathepsin K. We found that bafilomycin and NS5818 dose dependently inhibited acidification of the osteoclastic resorption compartment and bone resorption. Inhibition of bone resorption by inhibition of acidification, but not cathepsin K inhibition, augmented osteoclast survival, which resulted in a 150 to 300% increase in osteoclasts compared to controls. We investigated the effect of inhibition of osteoclastic acidification in vivo by using the rat ovariectomy model with twice daily oral dosing of NS3696 at 50 mg/kg for 6 weeks. We observed a 60% decrease in resorption (DPYR), increased tartrate-resistant acid phosphatase levels, and no effect on bone formation evaluated by osteocalcin. We speculate that attenuated acidification inhibits dissolution of the inorganic phase of bone and results in an increased number of nonresorbing osteoclasts that are responsible for the coupling to normal bone formation. Thus, we suggest that acidification is essential for normal bone remodeling and that attenuated acidification leads to uncoupling with decreased bone resorption and unaffected bone formation. |
| Databáze: | OpenAIRE |
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