RECENT ADVANCES TOWARD UNDERSTANDING OSTEOCLAST PHYSIOLOGY

Osteoclasts develop from precursor cells of the monocyte series. Howev er, specialized differentiation for efficient bone degradation separat es the osteoclast from the macrophage. The physical reasons for these differences are emerging from the study of osteoclastic physiology and biochemistry. Key osteoclast specializations are multinucleation, for mation of a tightly sealed extracellular compartment on bone, and high -capacity secretion of HCl and acid proteases into this extracellular site. Multinucleation increases efficiency of extracellular attachment processes. The attachment process is mediated by cell membrane integr ins, and is sensitive to changes in intracellular or extracellular cal cium. Acid production exploits carbonic acid as the source of acid and conjugate base equivalents, reflected in abundant osteoclastic carbon ic anhydrase type II expression. Secretion of acid involves extremely high expression of vacuolar-type H+-ATPase and a chloride channel in t he cell's specialized acid secreting organelle, the ruffled membrane, which is polarized to the osteoclast's bone attachment. Acid secretion is balanced by chloride-bicarbonate exchange in the cell's non-bone a ttached membranes; this functionally resembles the band 3 chloride-bic arbonate exchanger of the red cell carbon dioxide transport system. Bo ne collagen is degraded by acid proteases secreted into the acid degra dation site via the mannose-6-phosphate receptor system, which is targ eted to lysosomes in other cells. Functional deficits, as in osteopetr osis, may affect any of the elements involved in osteoclast differenti ation. Furthermore, new antiosteoclastic therapeutic agents may inhibi t osteoclast biochemistry intentionally, such as for the control of hy percalcemia of malignancy.