Calcium signaling in endothelin‐ and platelet‐derived growth factor‐stimulated chondrocytes

Abstract

In bovine articular chondrocytes, endothelin (ET) and platelet‐derived growth factor (PDGF) receptors mediate agonist‐induced increases in inositol phosphate hydrolysis, cytoplasmic calcium concentration ([Ca2+]i), and mitogenesis. In most cells, ET stimulated nonoscillatory [Ca2+]i elevations with dose‐dependent increases in both spike and plateau amplitudes. However, about 15% of cells showed oscillatory Ca2+ responses with a constant frequency and variable shape and duration of spiking. ET‐1 and ET‐2 were more potent than ET‐3 in stimulating [Ca2+]i responses in inhibiting the specific binding of 125I‐ET‐1 and 125I‐ET‐3 and in promoting internalization of the receptor‐ligand complex, consistent with actions through endothelin ETA receptors. Similar nonoscillatory and oscillatory patterns of Ca2+ responses were observed in PDGF‐stimulated cells. In cells showing nonoscillatory Ca2+ responses to ET‐1, subsequent stimulation with PDGF was frequently followed by the development of an oscillatory Ca2+ response. Nonoscillatory responses to both agonists were only slightly reduced in Ca2+‐deficient medium, but the oscillatory responses were critically dependent on Ca2+ entry. Ca2+ spiking was not altered in the presence of the voltage‐sensitive Ca2+ channel blocker, nifedipine; also, depolarization of chondrocytes by high K+ did not induce [Ca2+]i responses, confirming that voltagesensitive calcium channels are not expressed in these cells. At high agonist concentrations, ET‐ but not PDGF‐stimulated cells underwent rapid desensitization. Activation of ETA and PDGF receptors was associated with differential stimulation of thymidine incorporation; ET‐1 induced a low‐amplitude bell‐shaped doseresponse curve; PDGF induced a sustained sigmoidal and dose‐dependent rise. These data indicate that two distinct types of Ca2+‐mobilizing receptors initiate similar patterns of [Ca2+]i responses but have different capacities to maintain and reinitiate the Ca2+ signaling, as well as to promote mitogenesis. Copyright © 1994 ASBMR