Extracellular acidosis accelerates bone resorption by enhancing osteoclast survival, adhesion, and migration

Abstract

Acidic extracellular pH promotes osteoporotic bone loss by osteoclast activation. However, the change of osteoclastic cell behavior in acidosis-stimulated bone resorption process is unknown. We found that lowering extracellular pH induced an increase in the survival, adhesion, and migration of mature osteoclasts with a full actin ring, leading to enhanced pit formation on dentine slices. Acidosis upregulated osteopontin, which is an Arg-Gly-Asp (RGD) motif-containing matrix protein secreted from osteoclasts and acts as a common modulator for their survival, adhesion, and migration. A synthetic RGD peptide treatment blocked acidosis-induced osteoclast adhesion and migration, likely by competing with the RGD motif-containing extracellular matrix proteins for cell surface integrin binding. We finally observed that acidosis was associated with activation of osteoclast survival/adhesion/migration-related Pyk2, Cbl-b, and Src signals. Collectively, the findings indicate that extracellular acidosis stimulates bone resorption by extending osteoclast survival and facilitating osteoclast adhesion and migration.