Assistant Professor, Department of Physiology and Cell Biology
Assistant Professor Department of Orthopaedic Surgery
Title: “Targeting Local Lipocalin-2 to Delay Skeletal Aging”
Aging is characterized by the buildup of cellular stresses such as oxidative stress, mitochondrial dysfunction, ER stress, and senescence. Over time, the processes that normally buffer these stresses decline, leaving cells more vulnerable. In bone, this loss of resilience leads to reduced mass and quality as osteoblast-lineage cells progressively fail in survival and function. Anabolic therapies can attenuate some stress signaling, but their benefits are limited by short treatment duration and rebound bone loss after discontinuation. This underscores the need to define upstream pathways that sustain stress in bone.
We focused on Lipocalin-2 (LCN2), a secreted glycoprotein, that is abundantly produced by osteoblasts and osteocytes. LCN2 rises with age and is associated with fracture risk. Most studies emphasize LCN2’s endocrine role in the hypothalamus and attribute skeletal effects to altered energy metabolism. However, osteoblast-lineage cells also express the LCN2 receptor SLC22A17. This receptor transports iron into the cell by binding LCN2–siderophore complexes. In other tissues this pathway promotes ferroptosis, an iron-dependent, lipid peroxidation–driven cell death program. Whether LCN2-SLC22A17 signaling axis drives skeletal decline is unknown.
Our preliminary data reveal a bone-intrinsic role for LCN2. Deletion of Lcn2 in late osteoblasts/early osteocytes (Lcn2ΔDmp1) produces a strong bone anabolic phenotype. Lcn2ΔDmp1 mice show increased trabecular mass, more osteoblasts, higher bone formation, and enhanced Wnt/β-catenin signaling, without any changes in systemic energy metabolism. In vivo, SLC22A17 haploinsufficiency increases bone mineral density, partially mimicking Lcn2 deletion. Both LCN2 and SLC22A17 are upregulated in aged osteocytes. Transcriptomic profiling comparison demonstrates that Lcn2 deletion suppresses age-associated ferroptotic and oxidative stress programs.
This provided strong premise of our hypothesis that LCN2–SLC22A17 signaling in osteoblast-lineage plays a causal role in accelerates skeletal aging. The aims of this proposal are to define LCN2’s cellular sources (Aim 1), establish SLC22A17 as mediator of LCN2’s local effects on bone (Aim 2), and test necessity, sufficiency, and targetability of LCN2–SLC22A17 axis in aging bones to mitigate fragility (Aim 3).