Acidification of the osteoclastic resorption compartment provides insight into the coupling of bone formation to bone resorption
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Acidification of the osteoclastic resorption compartment provides insight into the coupling of bone formation to bone resorption. / Karsdal, Morten A; Henriksen, Kim Steen; Sørensen, Mette G; Gram, Jeppe; Schaller, Sophie; Dziegiel, Morten H; Heegaard, Anne-Marie; Christophersen, Palle; Martin, Thomas; Christiansen, Claus; Bollerslev, Jens.
I: American Journal of Pathology, Bind 166, Nr. 2, 2005, s. 467-76.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - Acidification of the osteoclastic resorption compartment provides insight into the coupling of bone formation to bone resorption
AU - Karsdal, Morten A
AU - Henriksen, Kim Steen
AU - Sørensen, Mette G
AU - Gram, Jeppe
AU - Schaller, Sophie
AU - Dziegiel, Morten H
AU - Heegaard, Anne-Marie
AU - Christophersen, Palle
AU - Martin, Thomas
AU - Christiansen, Claus
AU - Bollerslev, Jens
PY - 2005
Y1 - 2005
N2 - 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.
AB - 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.
KW - Acid Phosphatase
KW - Adult
KW - Animals
KW - Bone Density
KW - Bone Resorption
KW - Bone and Bones
KW - Cathepsin K
KW - Cathepsins
KW - Cells, Cultured
KW - Chloride Channels
KW - Dose-Response Relationship, Drug
KW - Family Health
KW - Female
KW - Humans
KW - Immunohistochemistry
KW - Indicators and Reagents
KW - Isoenzymes
KW - Macrolides
KW - Macrophage Colony-Stimulating Factor
KW - Macrophages
KW - Male
KW - Middle Aged
KW - Models, Biological
KW - Mutation
KW - Osteoclasts
KW - Osteopetrosis
KW - Ovary
KW - Oxazines
KW - Phenotype
KW - Phenylurea Compounds
KW - Rats
KW - Rats, Sprague-Dawley
KW - Tetrazoles
KW - Time Factors
KW - Xanthenes
U2 - 10.1016/S0002-9440(10)62269-9
DO - 10.1016/S0002-9440(10)62269-9
M3 - Journal article
VL - 166
SP - 467
EP - 476
JO - American Journal of Pathology
JF - American Journal of Pathology
SN - 0002-9440
IS - 2
ER -
ID: 47086266