Molecular mechanisms of bone resorption by the osteoclast

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Abstract
The osteoclast is a multinucleated cell that is actively engaged in the synthesis of lysosomal enzymes, their vectorial transport toward the apical membrane, and the secretion of these enzymes at its apical pole. These secreted enzymes are targeted to the apical ruffled‐border membrane by mechanisms that involve cation‐independent mannose‐6‐phosphate receptors. These receptors bind to an enzyme‐linked mannose‐6‐phosphate recognition marker in the Golgi complex, and the enzyme‐ligand‐receptor complex, carried within small coated transport vesicles, dissociates upon reaching the low pH established in the bone‐resorbing compartment by the osteoclast. The apical bone‐resorbing compartment is sealed off by the attachment of the osteoclast to the calcified matrix and is actively acidified by the osteoclast. The plasma membrane of the cell is divided into distinct domains. The apical membrane at the ruffled‐border shares common antigenic determinants with lysosomal and endosomal membranes, including a 100 kD protein and proton pumps that may be involved in the acidification of the extracellular resorbing compartment. The basolateral membrane is highly enriched in sodium pumps. Finally, the cytoplasm of the osteoclast is highly enriched in carbonic anhydrase, and bicarbonate‐chloride exchange appears to regulate the intracellular pH of this cell. These observations are consistent with a scheme in which, in the low pH environment of the bone‐resorbing lacuna produced by the osteoclast, the mineral phase dissolves, exposing the organic matrix to the action of the secreted enzymes. The activity of these enzymes is in turn presumably favored by the acidic milieu. All constituents of the matrix, whether mineral or organic, then would be reduced to their elemental forms (ions and amino acids) extracellularly. No phagocytic events would be required for the complete degradation of the bone matrix. According to these concepts, therefore, membrane iontransport mechanisms become the most important molecular aspect of bone resorption.