Before digestion can occur, however, the bone matrix must be decalcified through acidification of the bony surface, which initiates dissolution of the mineral matrix. The cytoplasm of the osteoclast contains carbonic anhydrase II, which produces carbonic acid (H2CO3) from carbon dioxide and water. Subsequently, the carbonic acid dissociates to bicarbonate (HCO3) and a proton (H ). With the help of ATP-dependent proton pumps, protons are transported through the ruffled border, generating a low pH (4 to 5) in the microenvironment of the resorption bay. This local acidic environment created in the extracellular space between the bone and the osteoclast is protected by the clear zone. Chloride channels coupled with proton pumps facilitate the electroneutrality of the ruffled border membrane (see Fig. 8.15). Excess bicarbonate is removed by passive exchange with chloride ions via chloride–carbonate protein exchangers located at the basolateral membrane.
The acidic environment initiates the degradation of the mineral component of bone (composed primarily of hydroxyapatites) to calcium ions, soluble inorganic phosphates, and water. When resorption of designated bone tissue is completed, osteoclasts undergo apoptosis. Recent studies indicate that many drugs used to inhibit bone exocytosis of digested material lysosomes actin filaments vinculin, talin v 3 integrin receptors carbonic anhydrase chloride channel clear zone ruffled border ATP dependent proton pump Cl HCO3 HCO3 Cl H H CO2 H2O H2CO3 K cathepsin matrixmetalloproteinases
FIGURE 8.15 • Schematic drawing of an osteoclast. This drawing shows the structure of the osteoclasts and its three regions: the ruffled border, clear zone, and basolateral region. Note that the clear zone contains abundant actin filaments arranged in a ringlike structure surrounded on both sides by actin-binding proteins such as vinculin and talin. The plasma membrane at the site of the clear zone contains cell-to–extracellular matrix adhesion molecules (integrin receptors) that provide a tight seal between the plasma membrane and mineralized matrix of the bone. The pathways for proton and chloride transport are described in the text.
resorption in osteoporosis (i.e., bisphosphonates and estrogens) promote osteoclast apoptosis (Folder 8.2).
The phagocytotic function of osteoclasts is regulated by many factors.
Numerous coated pits and coated vesicles are also present at the ruffled border, suggesting endocytotic activity. Osteoclasts are observed at sites where bone remodeling is in progress. (The process of remodeling is described in more detail shortly.) Thus, in sites where osteons are being altered or where a bone is undergoing change during the growth process, osteoclasts are relatively numerous.
An increase in parathyroid hormone (PTH) level promotes bone resorption and has a demonstrable effect on osteoclast activity, in addition to its effects on osteocytes, described previously. In contrast, calcitonin, secreted by parafollicular cells of the thyroid gland, has a counterbalancing effect, reducing osteoclast activity. PTH has also anabolic effect on bone either through a direct stimulatory effect on osteoblasts or indirectly through a mechanism that requires it to increase activity of osteoclasts. For example, PTH might stimulate bone formation directly by increasing the local production of IGF I or other bone-stimulating growth factors.