WNT7BRTID peptide, a reconstructed WNT7B domain, drives bone regeneration in aged osteoporotic mice and pigs via non-canonical Ca2+-NFAT signaling.

Developing effective bone anabolic agents for skeletal aging and fracture repair remains a significant clinical challenge. While WNT proteins are crucial regulators of bone health, their direct therapeutic application is often hindered by high costs and the risk of activating oncogenic canonical Wnt/β-catenin signaling. Current standard-of-care treatments for osteoporosis often have limitations in promoting robust bone regeneration, especially in critical-sized defects. This research addresses the gap by seeking a WNT-derived peptide that can selectively promote bone formation without the adverse effects associated with full WNT pathway activation.

Researchers identified WNT7BRTID (reconstructed thumb and index domains of WNT7B) as a potential bone anabolic peptide using Alphafold-empowered sequence prediction and in silico docking screening. The therapeutic potential of WNT7BRTID peptides was then evaluated in aged mice and pigs models of osteoporosis. The study employed single-cell sequencing, transgenic lineage tracking, and various biochemical approaches to assess the peptide's effects on mesenchymal stromal/stem cells (MSCs) and overall bone regeneration. The primary endpoint was the improvement of osteogenic potential in MSCs and enhanced bone repair in critical-sized defects.

WNT7BRTID peptides demonstrated significant therapeutic potential in aged osteoporotic mice and pigs. They effectively improved the osteogenic potential of intrinsic tissue-residual mesenchymal stromal/stem cells (MSCs) and enhanced bone regeneration, even in critical-sized defects, without requiring MSC transplantation. This suggests the peptide can harness the body's own regenerative capacity. Mechanistically, the study revealed a novel pathway of action:

WNT7BRTID activates non-canonical Ca2+-NFAT signaling through RECK/GPR124 to drive its bone anabolic effects, crucially independent of the canonical Wnt/β-catenin signaling pathway, which is often associated with oncogenic risks. This selective activation provides a safer therapeutic window for WNT-derived bone anabolism.