Bone Resorption Requires the Coordinated Function of a V-Class Proton Pump and a Specific Chloride Channel
Net bone growth in mammals subsides just after puberty, but a finely balanced, highly dynamic process of disassembly (resorption) and reassembly (bone formation) goes on throughout adulthood. Such continual bone remodeling permits the repair of damaged bones and can release calcium, phosphate, and other ions from mineralized bone into the blood for use elsewhere in the body.
Osteoclasts, the bone-dissolving cells, are macrophages, a type of cells best known for their role in protecting the body from infections. Osteoclasts are polarized cells that adhere to bone and form specialized, very tight seals between themselves and the bone, creating an enclosed extracellular space (Figure 11-32). An adhered osteoclast then secretes into this space a corrosive mixture of HCl and proteases that dissolves the inorganic components of the bone into Ca2+ and phosphate and digests its protein components. The mechanism of HCl secretion is similar to that used by the stomach to generate digestive juice (see Figure 11-31). As in gastric HCl secretion, carbonic anhydrase and an anion antiporter are important for osteoclast function. Osteoclasts employ a V-class proton pump to export H+ ions into the bone-facing space, rather than the P-class H+/K+ pump used by gastric epithelial cells.
FIGURE 11-32 Dissolution of bone by polarized osteoclast cells requires a V-class proton pump and the ClC-7 chloride channel. The osteoclast plasma membrane is divided into two domains separated by the tight seal between a ring of membrane and the bone surface. The membrane domain facing the bone contains V-class proton pumps and ClC-7 Cl− channels. The opposing membrane domain contains anion antiporters that exchange HCO3− and Cl− ions. The combined operation of these three transport proteins and carbonic anhydrase acidifies the enclosed space and allows bone resorption while maintaining the neutral pH of the cytosol. See R. Planells-Cases and T. Jentsch, 2009, Biochim. Biophys. Acta 1792:173 for discussion of ClC-7.
The rare hereditary disease osteopetrosis, marked by increased bone density, is due to abnormally low bone resorption. Many patients have mutations in the gene encoding TCIRG1, a subunit of the osteoclast V-class proton pump, whose action is required to acidify the space between the osteoclast and the bone. Other patients have mutations in the gene encoding ClC-7, the chloride channel localized to the domain of the osteoclast plasma membrane that faces the space near the bone. As with lysosomes (see Figure 11-14), in the absence of a chloride channel, the proton pump cannot acidify the enclosed extracellular space, and thus bone resorption is defective.