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Stimulation of Cell Proliferation by Calcium and a Calcimimetic Compound

Research, NOVARTIS Pharma AG, CH-4002 Basel, Switzerland; and Laboratoire de Neurobiologie Cellulaire et Moléculaire du Centre National de la Recherche Scientifique (M.R.), F-91198 Gif-sur-Yvette, France

Address all correspondence and requests for reprints to: Dr. Klaus Seuwen, Research, NOVARTIS Pharma AG, Building S-360/401, CH-4002 Basel, Switzerland. E-mail: Klaus.Seuwen{at}Pharma.Novartis.Com

Some mesenchymal cells respond to stimulation by specific cations with increased cell proliferation. In the present study we have investigated whether the parathyroid/kidney/brain calcium-sensing receptor (PCaR) can mediate such mitogenic responses. We have expressed the recombinant rat PCaR in CCL39 hamster fibroblasts, which do not express a detectable endogenous cation sensor. The transfected cells responded to increased extracellular calcium concentrations ([Ca²⁺]_e) with strong inositol phosphate (IP) formation, which was insensitive to pertussis toxin treatment of cells. We could not detect negative coupling of the receptor to adenylyl cyclase. The calcimimetic NPS R-568 left-shifted the concentration-response curve for [Ca²⁺]_e-induced IP formation and increased the maximal response. In [³H]thymidine incorporation experiments, increasing [Ca²⁺]_e from 1 to 4 mM was found to stimulate DNA synthesis weakly, but significantly. A strong potentiation of this response was observed in the presence of NPS R-568. [Ca²⁺]_e and NPS R-568 also synergized to increase cell numbers in cultures maintained in defined medium. In contrast to our expectations, no significant stimulation of IP formation or cell proliferation could be observed after stimulation of cells with the reported PCaR agonist gadolinium (Gd³⁺) or with aluminum (Al³⁺), which stimulates osteoblast proliferation. Gd³⁺ actually inhibited IP formation stimulated by increased [Ca²⁺]_e as well as by thrombin and AlF₄^-, indicating toxicity. However, submaximal receptor stimulation by Gd³⁺ was evident when intracellular calcium transients were measured in fluo-3-loaded cells. Our data show that PCaR can stimulate cell proliferation when expressed in an appropriate cellular context. However, it is unlikely that PCaR mediates the strong mitogenic effects elicited by the cations Gd³⁺ and Al³⁺ observed in osteoblasts.

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