Novel Mechanisms of Calcium Handling by the Osteoclast: A Review–Hypothesis

The osteoclast is a cell that is unique in its ability to resorb bone and, in doing so, becomes exposed to unusually high millimolar Ca 2+ concentrations. It is generally accepted that, during resorption, osteoclasts can “sense” changes in their ambient Ca 2+ concentration. This triggers a sharp cytosolic Ca 2+ increase through both Ca 2+ release and Ca 2+ influx. The change in cytosolic Ca 2+ is transduced finally into inhibition of bone resorption. It has been shown that a type 2 ryanodine receptor isoform, expressed uniquely in the plasma membrane, functions as a Ca 2+ influx channel and possibly as a Ca 2+ sensor. Ryanodine receptors are ordinarily Ca 2+ release channels that have a microsomal membrane location in a wide variety of eukaryotic cells, including the osteoclasts. However, only recently has it become obvious that ryanodine receptors are also expressed in osteoclast nuclear membranes, at which site they probably gate nucleoplasmic Ca 2+ influx. Nucleoplasmic Ca 2+ in turn regulates key nuclear processes, including gene expression and apoptosis. Here, we review the potential mechanisms underlying the recognition, movement, and effects of Ca 2+ in the osteoclast. We will also speculate on the general biological significance of the unique processes used by the osteoclast to handle high Ca 2+ loads during bone resorption.