# Identification of ephrin-A1–EphA2 signalling as a potential target for fracture prevention

## TL;DR

This study identifies ephrin-A1 as a new potential target for preventing osteoporotic fractures by strengthening bones.

## Contribution

The study introduces ephrin-A1–EphA2 signaling as a novel therapeutic target for fracture prevention.

## Key findings

- Nine circulating proteins, including ephrin-A1, are associated with forearm fracture risk.
- Ephrin-A1 increases bone mineral density and protects against fractures in experimental models.
- Ephrin-A1 interacts with EphA2 on osteoblasts, suggesting a mechanism for bone strengthening.

## Abstract

Osteoporotic fractures are a major global health burden. To uncover potential targets for fracture prevention, we use a proteome-wide Mendelian randomization (MR) approach combined with colocalization. Here we show that nine circulating proteins associate with forearm fracture risk, including sclerostin and osteoprotegerin targeted by existing osteoporosis treatments, and three other known bone-related proteins, providing proof of concept for our MRpipeline. Notably, we identify ephrin-A1 as a novel protective factor against fractures, a membrane-linked protein partly released into circulation that binds its high-affinity receptor EphA2 on osteoblasts. Experimental models and genetic analyses indicate that ephrin-A1 increases bone mineral density, supporting a mechanism by which this pathway may mediate fracture protection. Spatial expression analysis with the innovative 3D DeepBone technique suggests ephrin-A1 on endothelial cells interacts with EphA2 on adjacent osteoblasts at the bone surface. These findings position ephrin-A1–EphA2 signalling as a therapeutic target to strengthen bone and reduce fracture risk.

Osteoporotic fractures are a major global health burden. Here the authors show, using proteome wide Mendelian randomization, that nine circulating proteins influence forearm fracture risk and identify a novel protective role for ephrin A1