Activation of Volume-Sensitive OsmolytePathways in Anisotonic ConditionsThe direct activation of membrane transporters and ion chan-nels that mediate osmolyte movement and volume changescan occur without a change in intra- or extracellular osmolar-ity. A good example is in the growth plate where this driveschondrocyte swelling, hypertrophy and ultimately cell death,and the zone of calcification where osteoblasts form newbone. The stimulation of the NKCC cotransporter drives cellswelling [82] and it is necessary that RVD transporters andchannels are suppressed to allow the volume increase to pro-ceed. Chondrocyte hypertrophy in the growth plate is a formof ‘programmed cell death’in the sense that the cells must besignalled to die through swelling and lysis, in order to leavebehind the structural elements which form the advancing bonefront. However, this process in the growth plate is often de-scribed, perhaps inaccurately, as ‘apoptosis’which classicallyinvolves a decrease in cell volume, clearly identified as a keystep in the process [87,88]. Notwithstanding the apparentconfusion in the literature, the shrinkage occurring in ‘classi-cal apoptosis’occurs through the direct activation of K+andCl−channels leading to the loss of ions with associated waterand cell shrinkage (‘Apoptotic Volume Decrease’, AVD, or‘normotonic’cell shrinkage) [89]. In cartilage, the stimulationof chondrocyte volume-sensitive Cl−channels contributes tocell shrinkage and may accelerate cell death throughapoptotic-like pathways [90]. As the Cl−gradient is normallyinto the cells, the activation of these channels probably plays a‘permissive’electrochemical role in balancing the charge ofthe main osmolyte (K+), and allowing it to leave the cellsdown its gradient, thereby causing cell shrinkage . WhileAVD is identified as an essential step in classical apoptosisrequired for cell shrinking, the membrane transport pathwaysthat may otherwise protect against cell shrinking (e.g.NKCC1) are inactivated [91]. Thus, it is the balance betweenthe two opposing volume-regulatory responses (RVD andRVI) that may ultimately determine the change to cell volumeand, if required, its maintenance at a new ‘set point’. Whilethere has been considerable focus on cell volume [see [50],there is a realisation that it might not be volume per se that isthe key regulator of cell metabolism, but cellular composition. For example, a reduction in intracellular K+concentration([K+]i) in the absence of a volume change has been proposedas an essential step in the apoptotic pathway [83,92].
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