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

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.