# Divalent metal cations stimulate skeleton interoception for new bone formation in mouse injury models

## TL;DR

Divalent metal cations promote new bone formation by activating a nerve and immune cell pathway in mice.

## Contribution

The study reveals that divalent cations stimulate bone growth through a skeleton interoceptive circuit involving immune and nerve cells.

## Key findings

- Divalent cations promote prostaglandin E2 secretion from macrophages, stimulating skeleton interoception.
- Activation of skeleton interoception reduces sympathetic tone to support new bone formation.
- Macrophage depletion or sensory nerve knockout eliminates the osteogenic effects of divalent cations.

## Abstract

Bone formation induced by divalent metal cations has been widely reported; however, the underlying mechanism is unclear. Here we report that these cations stimulate skeleton interoception by promoting prostaglandin E2 secretion from macrophages. This immune response is accompanied by the sprouting and arborization of calcitonin gene-related polypeptide-α+ nerve fibers, which sense the inflammatory cue with PGE2 receptor 4 and convey the interoceptive signals to the central nervous system. Activating skeleton interoception downregulates sympathetic tone for new bone formation. Moreover, either macrophage depletion or knockout of cyclooxygenase-2 in the macrophage abolishes divalent cation-induced skeleton interoception. Furthermore, sensory denervation or knockout of EP4 in the sensory nerves eliminates the osteogenic effects of divalent cations. Thus, our study reveals that divalent cations promote bone formation through the skeleton interoceptive circuit, a finding which could prompt the development of novel biomaterials to elicit the therapeutic power of these divalent cations.

Mechanisms underlying bone formation induced by divalent metal cations remain largely unknown. Here the authors show that these cations can activate the skeleton interoceptive circuit through the immune-neural axis to initiate new bone formation.