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

## TL;DR

High levels of calcium and phosphate cause chondrocyte death by increasing intracellular phosphate through a receptor and transporter mechanism.

## Contribution

The study reveals a novel mechanism where calcium activates a receptor that promotes phosphate uptake, leading to chondrocyte apoptosis.

## Key findings

- Combined calcium and phosphate induce apoptosis and mineralization in chondrocytes.
- Blocking the calcium-sensing receptor or phosphate transporter prevents apoptosis and intracellular phosphate accumulation.
- Calcium-sensing receptor activation increases intracellular phosphate levels.

## Abstract

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.

Excess Ca2+ ions activate the Calcium‐Sensing Receptor (CaSR), which subsequently drives the uptake of excess inorganic phosphate (Pi) via the Pi transporter (Pit−1) in chondrocytes. This mechanism causes a toxic increase in intracellular Pi concentration, ultimately leading to chondrocyte apoptosis and pathological mineralization.