Osteoclast Activity: Bone Resorption, Polarization, Acidification, Proton Pumps, and Chloride Channels

Bone resorption by activated osteoclasts occurs in three successive steps: attachment of the osteoclasts to the bone surface to form the sealing zone, bone mineral solubilization, and organic matrix degradation. In the last two decades, great advances have been made in understanding the mechanisms underlying osteoclast-mediated bone resorption. Mature osteoclasts on the bone surface become polarized, a process regulated by small G proteins, which leads to the formation of the sealing zone, which is the highly compact superstructure formed by podosomes. Integrins, which mediate both podosome formation and osteoclast-bone interaction, transduce pivotal signaling for osteoclast activation. Osteoclasts generate an isolated extracellular microenvironment between themselves and the bone known as the sealing zone surrounding the ruffled membrane to release hydrogen ions (H+) and chloride ions (Cl−) through the V-type ATPase proton pump and the CLC chloride channel into the resorption lacuna to reach an acidic pH which favors bone resorption. V-ATPase proton pump subunit Atp6i and chloride channels subunit ClC-7 are essential for osteoclast-mediated extracellular acidification. Cathepsin K was revealed to be the lysosomal protease that is essential for organic matrix degradation in bone resorption. In humans, mutations of Atp6i and ClC-7, and Cathepsin K lead to malignant osteopetrosis and pycnodysostosis respectively. In this article, we summarize recent advances in understanding the mechanisms of osteoclast-mediated bone resorption and signaling that regulates osteoclast activation, polarization, acidification, and matrix degradation. Further understanding of the mechanisms underlying osteoclast activation and the signaling that regulates osteoclast polarization, acidification, lysosome trafficking, and bone resorption will provide unprecedented therapeutic strategies to treat osteolytic diseases such as osteoporosis, periodontal disease, and rheumatoid arthritis.