Lipocalin-2 Regulates Osteocyte Ferroptosis and Osteocyte-Osteoblast Crosstalk via Wnt Signaling to Control Bone Formation

Osteoporosis is a multifactorial disease, and emerging evidence suggests that iron overload contributes to its progression. Here, we identify Lipocalin-2 (LCN2), a cytokine secreted by bone cells with endocrine effects on other tissues, as a local regulator of osteocyte iron metabolism and a mediator of skeletal deterioration. Our findings reveal that LCN2 promotes iron accumulation, mitochondrial dysfunction, and ferroptosis in osteocytes in a process dependent on LCN2 receptor SLC22A17. Genetic ablation of Lcn2 ( Dmp1 -Cre; Lcn2 ^fl/fl ) in osteocytes mitigates their ferroptotic vulnerability by preserving mitochondrial integrity and limiting iron overload. Remarkably, LCN2 deletion enhances osteocyte dendricity and lacunocanalicular network, supporting their function in bone remodeling. Mechanistically, we demonstrate that Lcn2 ablation in osteocytes decreases DKK1 and SOST expression in bone, leading to increased Wnt/β-catenin signaling and osteoblast-driven bone formation. Using in vitro and in vivo approaches, we establish the LCN2-SLC22A17 axis as a key pathway linking iron homeostasis, osteocyte dysfunction, and skeletal remodeling. These findings provide insight into a previously unrecognized mechanism underlying iron-driven bone loss and suggest that targeting LCN2 could offer therapeutic potential for osteoporosis.