Vacuolar-type H+-ATPase-mediated acidosis promotes in vitro osteoclastogenesis via modulation of cell migration.

Abstract

Localized acidification of the osteoclast-bone interface is driven by a vacuolar-type H+-ATPase (V-ATPase) in the plasma membrane in a process thought to be associated with bone resorption. The present study investigated the mechanism underlying the roles of V-ATPase-induced acidosis in osteoclastogenesis. Active proton pumping due to increased V-ATPase activity during RANKL-induced osteoclastogenesis induced intracellular and extracellular acidification of osteoclast precursors. Subsequent analysis revealed blockage of extracellular acidification and induction of intracellular acidification by bafilomycin A1, a specific inhibitor of V-ATPase, indicating that extracellular acidification is mostly induced by V-ATPase-mediated proton pumping into extracellular space. Low-pH media controlled by HEPES-buffered conditions to mimic metabolic acidosis led to synergistic activation of RANKL-stimulated signals, including mitogen-activated protein kinases and transcription factor NF-kappaB, resulting in enhanced osteoclastogenesis. Low-pH media also upregulated the expression of osteopontin secreted into extracellular space, which is required for cell migration by binding to cell surface integrin alphavbeta3. Osteoclast precursor migration was significantly inhibited by treatment of antibodies to integrin alphavbeta3, resulting in the retardation of osteoclastogenesis. Taken together, these findings indicate that V-ATPase-driven acidosis modulates osteoclastogenesis.

• Authors: Jin-Man Kim, Seung-Ki Min, Hyunsoo Kim, Hyun Ki Kang, Sung Youn Jung, Seoung Hoon Lee, Yongwon Choi, Sangho Roh, Daewon Jeong, Byung-Moo Min
• Journal: International journal of molecular medicine (Int J Mol Med) Vol. 19 Issue 3 Pg. 393-400 (Mar 2007) ISSN: 1107-3756 [Print] Greece
• PMID: 17273786 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Integrin alphaVbeta3
• Macrolides
• RANK Ligand
• RNA, Messenger
• Osteopontin
• bafilomycin A1
• Vacuolar Proton-Translocating ATPases

Topics

• Acidosis (enzymology)
• Animals
• Cell Differentiation (drug effects)
• Cell Movement (drug effects)
• Female
• Gene Expression Regulation (drug effects)
• Hydrogen-Ion Concentration
• Integrin alphaVbeta3 (metabolism)
• Macrolides (pharmacology)
• Mice
• Mice, Inbred C57BL
• Osteoclasts (cytology, drug effects, enzymology)
• Osteogenesis (drug effects)
• Osteopontin (genetics, metabolism)
• RANK Ligand (pharmacology)
• RNA, Messenger (genetics, metabolism)
• Signal Transduction (drug effects)
• Stem Cells (cytology, drug effects, enzymology)
• Vacuolar Proton-Translocating ATPases (metabolism)