Developing WNT-derived bone anabolic peptides for skeletal aging and fracture by reconstructing thumb and index domains of WNT7B

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.