Abstract
Cell movement and spreading involve calcium-dependent processes and ionic channel activation. During bone resorption, osteoclasts alternate between spread, motile and resorptive phases. We investigated whether the electrical membrane properties of osteoclasts were linked to their membrane morphological changes. Rabbit osteoclasts were recorded by time-lapse videomicroscopy performed simultaneously with patch-clamp whole cell and single channel recordings. Original image analysis methods were developed and used to demonstrate for the first time an oscillatory activation of a spontaneous membrane current in osteoclasts, which is directly correlated to the membrane movement rate. This current was identified as a calcium-dependent potassium current (IK(Ca)) that is sensitive to both charybdotoxin and apamin and was generated by a channel with unitary conductance of approximately 25+/-2 pS. Blockade of this current also decreased osteoclast spreading and inhibited bone resorption in vitro, demonstrating a physiological role for this current in osteoclast activity. These results establish for the first time a temporal correlation between lamellipodia formation kinetics and spontaneous peaks of IK(Ca), which are both involved in the control of osteoclast spreading and bone resorption.
Highlights
Intracellular calcium plays a pivotal role in cell movements, as it regulates actin metabolism, cytoskeletal organisation, cellmatrix interactions and is a second messenger in many biochemical pathways (Hinrichsen, 1993)
They alternate between motile and resorptive phases of activity (Kanehisa and Heersche, 1988), both of which are necessary for effective bone resorption
We show for the first time that spontaneous membrane spreading coincides with the activation of a calcium-dependent potassium current
Summary
Intracellular calcium plays a pivotal role in cell movements, as it regulates actin metabolism, cytoskeletal organisation, cellmatrix interactions and is a second messenger in many biochemical pathways (Hinrichsen, 1993). It is well documented that ionic channel activity is linked to membrane movements. Stretch-activated cationic channels open with membrane extension, inducing a self-reinforcing calcium entry pathway involved in detachment of the rear cell margin (Wiltink et al, 1995; Lee et al, 1999). Osteoclasts are multinucleated cells that are primarily responsible for bone resorption. They alternate between motile and resorptive phases of activity (Kanehisa and Heersche, 1988), both of which are necessary for effective bone resorption. The osteoclast extends large lamellipodia (thin organelle-free processes involved in plasma membrane extension) along the movement axis while the membrane retracts at the opposite side of the cell. No study has yet investigated how ionic channel activity is linked to calcium handling and membrane movements
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