# Osteocytic Lipocalin-2 regulates bone formation locally through iron-dependent ferroptosis and Wnt suppression

## TL;DR

This study shows that the protein Lipocalin-2 in bone cells causes local bone weakness by triggering cell death and blocking bone growth signals.

## Contribution

The novel finding is that LCN2 regulates bone formation locally via ferroptosis and Wnt suppression, independent of systemic metabolism.

## Key findings

- LCN2 promotes iron accumulation and ferroptosis in osteocytes via SLC22A17.
- Deleting LCN2 improves mitochondrial function and increases bone connectivity.
- LCN2 deletion enhances bone formation by suppressing Wnt antagonists DKK1 and SOST.

## Abstract

Osteocytes, the most abundant bone cells, are central regulators of bone remodeling that also exert endocrine control over systemic metabolism. Among the factors they produce, Lipocalin-2 (LCN2) has emerged as a cytokine linking bone and energy homeostasis, yet its local role within the skeleton remains elusive. Here, we identify that LCN2 promotes intracellular iron accumulation, mitochondrial dysfunction, and lipid peroxidation through its receptor SLC22A17, and drives ferroptotic cell death. Dmp1-Cre–mediated deletion of Lcn2 preserves mitochondrial integrity, reduces intracellular iron and lipid peroxidation, and enhances osteocyte dendricity and lacunocanalicular connectivity. Mechanistically, loss of Lcn2 suppresses Wnt antagonists DKK1 and SOST, thereby promoting Wnt/β-catenin signaling and stimulating osteoblast-mediated bone formation. Notably, Dmp1-Cre-mediated deletion of Lcn2 does not alter systemic energy balance, underscoring LCN2’s local skeletal function. These findings define the LCN2–SLC22A17 axis as a local regulator of osteocyte ferroptosis, Wnt/β-catenin signaling, and skeletal fragility.