Calcium-sensing receptor induces the apoptosis of chondrocytes in cooperation with phosphate transporter

Excess extracellular inorganic phosphate ions (Pi) and calcium ions (CA²⁺) cause Apoptosis and subsequent mineralization of chondrocytes. Here, we investigated the mechanism underlying the effect of these Minerals. The chondrogenic cell line ATDC5 was treated with 2 mm Pi and/or CA²⁺, and Apoptosis, mineralization, and intracellular Pi concentrations were determined. Further, Pi- and CA²⁺-treated cells were incubated with the Pi transporter (Pit-1) blocker phosphonoformic acid (PFA), the calcium-sensing receptor (CaSR) antagonist NPS-2143, and the CaSR agonist GdCl₃. Individual addition of Pi and CA²⁺ did not induce Apoptosis and mineralization, while combined addition of the Minerals induced both. The Pit-1 blocker and the CaSR Antagonist completely inhibited the Apoptosis induced by combined addition of Pi and CA²⁺. Intracellular Pi concentration was remarkably increased by combined addition of Pi and CA²⁺ as compared to the findings for individual addition. The Pit-1 blocker and CaSR Antagonist completely inhibited the increase in intracellular Pi concentration induced by the combined addition of Pi and CA²⁺. The CaSR agonist considerably increased the intracellular Pi concentration. Our results indicate that excess extracellular CA²⁺ activates CaSR, which induces the intake of excess extracellular Pi through Pit-1 into ATDC5 cells. The resulting increase in intracellular Pi concentration induces Apoptosis.

apoptosis; calcium‐sensing receptor; chondrocyte; mineralization; phosphate transporter.