Calcium handling by the osteoclast

The bone resorbing osteoclast is unique in that it is exposed to unusually high, millimolar, Ca²⁺ concentrations during resorption. It is generally accepted that during this process, osteoclasts can 'sense' changes in their ambient Ca²⁺ concentration. This triggers a sharp cytosolic Ca²⁺ elevation through both Ca²⁺ release and Ca²⁺ influx. The change in cytosolic Ca²⁺ is transduced finally into an inhibition of bone resorption. We have shown that a type 2 ryanodine receptor isoform is expressed uniquely in the plasma membrane and functions as a Ca²⁺ influx channel, and possibly a Ca²⁺ sensor. Ryanodine receptors are ordinarily Ca²⁺ 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 other locations, such as nuclear membranes, at which site they likely gate nucleoplasmic Ca²⁺ influx. Nucleoplasmic Ca²⁺, in turn, regulates key nuclear processes, including gene expression and apoptosis. Here, we review potential mechanisms underlying the recognition, movement, and effects of Ca²⁺ in the osteoclast. We will also speculate on the general biological significance of the somewhat unique processes used by the osteoclast to handle high Ca²⁺ loads during bone resorption.