Calcium fluxes at the bone/plasma interface: Acute effects of parathyroid hormone (PTH) and targeted deletion of PTH/PTH-related peptide (PTHrP) receptor in the osteocytes

Calcium ion concentration ([Ca ²⁺ ]) in the systemic extracellular fluid, ECF-[Ca ²⁺ ], is maintained around a genetically predetermined set-point, which combines the operational level of the kidney and bone/ECF interfaces. The ECF-[Ca ²⁺ ] is maintained within a narrow oscillation range by the regulatory action of Parathyroid Hormone (PTH), Calcitonin, FGF-23, and 1,25(OH) ₂ D ₃ . This model implies two correction mechanisms, i.e. tubular Ca ²⁺ reabsorption and osteoclast Ca ²⁺ resorption. Although their alterations have an effect on the ECF-[Ca ²⁺ ] maintenance, they cannot fully account for rapid correction of the continuing perturbations of plasma [Ca ²⁺ ], which occur daily in life. The existence of Ca ²⁺ fluxes at quiescent bone surfaces fulfills the role of a short-term error correction mechanism in Ca ²⁺ homeostasis. To explore the hypothesis that PTH regulates the cell system responsible for the fast Ca ²⁺ fluxes at the bone/ECF interface, we have performed direct real-time measurements of Ca ²⁺ fluxes at the surface of ex-vivo metatarsal bones maintained in physiological conditions mimicking ECF, and exposed to PTH. To further characterize whether the PTH receptor on osteocytes is a critical component of the minute-to-minute ECF-[Ca ²⁺ ] regulation, metatarsal bones from mice lacking the PTH receptor in these cells were tested ex vivo for rapid Ca ²⁺ exchange. We performed direct real-time measurements of Ca ²⁺ fluxes and concentration gradients by a scanning ion-selective electrode technique (SIET). To validate ex vivo measurements, we also evaluated acute calcemic response to PTH in vivo in mice lacking PTH receptors in osteocytes vs littermate controls. Our data demonstrated that Ca ²⁺ fluxes at the bone-ECF interface in excised bones as well as acute calcemic response in the short-term were unaffected by PTH exposure and its signaling through its receptor in osteocytes. Rapid minute-to-minute regulation of the ECF-[Ca ²⁺ ] was found to be independent of PTH actions on osteocytes. Similarly, mice lacking PTH receptor in osteocytes, responded to PTH challenge with similar calcemic increases.