Acidification of the osteoclastic resorption compartment provides insight into the coupling of bone formation to bone resorption

Morten A Karsdal; Kim Steen Henriksen; Mette G Sørensen; Jeppe Gram; Sophie Schaller; Morten H Dziegiel; Anne-Marie Heegaard; Palle Christophersen; Thomas Martin; Claus Christiansen; Jens Bollerslev

doi:10.1016/S0002-9440(10)62269-9

Acidification of the osteoclastic resorption compartment provides insight into the coupling of bone formation to bone resorption

Morten A Karsdal, Kim Steen Henriksen, Mette G Sørensen, Jeppe Gram, Sophie Schaller, Morten H Dziegiel, Anne-Marie Heegaard, Palle Christophersen, Thomas Martin, Claus Christiansen, Jens Bollerslev

125 Citations (Scopus)

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.

Original language	English
Journal	American Journal of Pathology
Volume	166
Issue number	2
Pages (from-to)	467-76
Number of pages	10
ISSN	0002-9440
DOIs	https://doi.org/10.1016/S0002-9440(10)62269-9
Publication status	Published - 2005
Externally published	Yes

Keywords

Acid Phosphatase
Adult
Animals
Bone Density
Bone Resorption
Bone and Bones
Cathepsin K
Cathepsins
Cells, Cultured
Chloride Channels
Dose-Response Relationship, Drug
Family Health
Female
Humans
Immunohistochemistry
Indicators and Reagents
Isoenzymes
Macrolides
Macrophage Colony-Stimulating Factor
Macrophages
Male
Middle Aged
Models, Biological
Mutation
Osteoclasts
Osteopetrosis
Ovary
Oxazines
Phenotype
Phenylurea Compounds
Rats
Rats, Sprague-Dawley
Tetrazoles
Time Factors
Xanthenes

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10.1016/S0002-9440(10)62269-9

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Karsdal, M. A., Henriksen, K. S., Sørensen, M. G., Gram, J., Schaller, S., Dziegiel, M. H., Heegaard, A.-M., Christophersen, P., Martin, T., Christiansen, C., & Bollerslev, J. (2005). Acidification of the osteoclastic resorption compartment provides insight into the coupling of bone formation to bone resorption. American Journal of Pathology, 166(2), 467-76. https://doi.org/10.1016/S0002-9440(10)62269-9

Karsdal, MA, Henriksen, KS, Sørensen, MG, Gram, J, Schaller, S, Dziegiel, MH, Heegaard, A-M, Christophersen, P, Martin, T, Christiansen, C & Bollerslev, J 2005, 'Acidification of the osteoclastic resorption compartment provides insight into the coupling of bone formation to bone resorption', American Journal of Pathology, vol. 166, no. 2, pp. 467-76. https://doi.org/10.1016/S0002-9440(10)62269-9

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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.",

keywords = "Acid Phosphatase, Adult, Animals, Bone Density, Bone Resorption, Bone and Bones, Cathepsin K, Cathepsins, Cells, Cultured, Chloride Channels, Dose-Response Relationship, Drug, Family Health, Female, Humans, Immunohistochemistry, Indicators and Reagents, Isoenzymes, Macrolides, Macrophage Colony-Stimulating Factor, Macrophages, Male, Middle Aged, Models, Biological, Mutation, Osteoclasts, Osteopetrosis, Ovary, Oxazines, Phenotype, Phenylurea Compounds, Rats, Rats, Sprague-Dawley, Tetrazoles, Time Factors, Xanthenes",

author = "Karsdal, {Morten A} and Henriksen, {Kim Steen} and S{\o}rensen, {Mette G} and Jeppe Gram and Sophie Schaller and Dziegiel, {Morten H} and Anne-Marie Heegaard and Palle Christophersen and Thomas Martin and Claus Christiansen and Jens Bollerslev",

year = "2005",

doi = "10.1016/S0002-9440(10)62269-9",

language = "English",

volume = "166",

pages = "467--76",

journal = "American Journal of Pathology",

issn = "0002-9440",

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TY - JOUR

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

SN - 0002-9440

VL - 166

SP - 467

EP - 476

JO - American Journal of Pathology

JF - American Journal of Pathology

IS - 2

ER -

Acidification of the osteoclastic resorption compartment provides insight into the coupling of bone formation to bone resorption

Abstract

Keywords

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