title: Acidification of the osteoclastic resorption compartment provides insight into the coupling of bone formation to bone resorption.
abstract: 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.
authors.affiliation: Nordic Bioscience A/S, Herlev Hovedgade 207, DK-2730 Herlev, Denmark. mk@nordicbioscience.com
authors.forename: Morten A
authors.initials: MA
authors.lastname: Karsdal
authors.forename: Kim
authors.initials: K
authors.lastname: Henriksen
authors.forename: Mette G
authors.initials: MG
authors.lastname: Sørensen
authors.forename: Jeppe
authors.initials: J
authors.lastname: Gram
authors.forename: Sophie
authors.initials: S
authors.lastname: Schaller
authors.forename: Morten H
authors.initials: MH
authors.lastname: Dziegiel
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Heegaard
authors.forename: Palle
authors.initials: P
authors.lastname: Christophersen
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Martin
authors.forename: Claus
authors.initials: C
authors.lastname: Christiansen
authors.forename: Jens
authors.initials: J
authors.lastname: Bollerslev
mesh_terms: D000135:Acid Phosphatase / Q000378:metabolism; D000328:Adult; D000818:Animals; D015519:Bone Density; D001862:Bone Resorption; D001842:Bone and Bones; D056657:Cathepsin K; D002403:Cathepsins / Q000494:pharmacology; D002478:Cells, Cultured; D018118:Chloride Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005192:Family Health; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007202:Indicators and Reagents / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism; D018942:Macrolides / Q000494:pharmacology; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009154:Mutation; D010010:Osteoclasts / Q000378:metabolism*; D010022:Osteopetrosis / Q000235:genetics; D010053:Ovary / Q000378:metabolism; D010078:Oxazines / Q000494:pharmacology; D010641:Phenotype; D010671:Phenylurea Compounds / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D000071681:Tartrate-Resistant Acid Phosphatase; D013777:Tetrazoles / Q000494:pharmacology; D013997:Time Factors; D014966:Xanthenes / Q000494:pharmacology
chemical_list: D018118:Chloride Channels; D007202:Indicators and Reagents; D007527:Isoenzymes; D018942:Macrolides; C498043:N-(3,5-dichlorophenyl)-N'-(2-(1H-tetrazol-5-yl)biphenyl-4-yl-4'-carboxylic acid dimethylamide)urea; C498044:N-(3-bromophenyl)-N'-(4-bromo-2-(1H-tetrazol-5-yl)phenyl)urea; D010078:Oxazines; D010671:Phenylurea Compounds; D013777:Tetrazoles; D014966:Xanthenes; C057620:bafilomycin A; C005843:resazurin; D016173:Macrophage Colony-Stimulating Factor; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase; D002403:Cathepsins; C534130:CTSK protein, human; D056657:Cathepsin K; C534133:Ctsk protein, rat