Developing WNT-derived bone anabolic peptides for skeletal aging and fracture by reconstructing thumb and index...

WNT proteins have been recognized as key regulators of skeletal health. However, developing WNT-associated bone anabolic agents is clinically challenging and expensive. Here we identify the reconstructed thumb and index domains of WNT7B (WNT7B^RTID) as a WNT-derived bone anabolic peptide via Alphafold-empowered sequence prediction and in silico docking screening. In aged mice and pigs models of osteoporosis, WNT7B^RTID peptides demonstrate therapeutic potential by improving the osteogenic potential of mesenchymal stromal/stem cells (MSCs) and enhancing bone regeneration. Using single-cell sequencing, transgenic lineage tracking and biochemical approaches, we show that WNT7B^RTID harnesses the function and osteogenic lineage generation of intrinsic tissue-residual MSCs without needing MSC transplantation to repair a critical-sized defect effectively. Mechanistically, WNT7B^RTID activates non-canonical Ca²⁺-NFAT signalling through RECK/GPR124 to drive its bone anabolic effects, independent of canonical Wnt/β-catenin signalling known for its oncogenic effects. Our results suggest that WNT7B^RTID could work as bone anabolic agent for alleviating bone loss in aging and for fracture repair by promoting MSC function via Ca²⁺-NFAT signalling.