Conditional deletion of Wnt5a in myeloid osteoclast precursors results in low bone mass via disruption of osteoblast migration and focal adhesion dynamics

ABSTRACT: Bone remodeling relies on the coordinated signaling between bone-resorbing osteoclasts and bone-forming osteoblasts through locally secreted coupling factors, including WNT5A. Although osteoblast-derived WNT5A is known to promote osteoclastogenesis, the contribution of osteoclast-derived WNT5A to bone homeostasis remains poorly defined. We previously showed that conditional deletion of Wnt5a in mature osteoclasts using the Ctsk-Cre driver results in low bone mass, suggesting an anabolic role for osteoclast-derived WNT5A. However, Ctsk expression in other cell types, including periosteal cells, precluded definitive attribution. Here, we used the more specific LysM-Cre line to validate the osteoclast-specific function of Wnt5a in vivo. LysM-Cre; Wnt5aF/F mice displayed significantly reduced trabecular bone driven by decreased osteoblast number and activity, while osteoclast number and resorptive function were preserved. Transcriptomic profiling of osteoblast-enriched cells revealed dysregulation of genes involved in cell adhesion, integrin binding, and cell communication, alongside upregulation of stress-related genes. Histological analyses and functional assays showed that loss of osteoclast-derived Wnt5a led to impaired extracellular matrix maturation together with defective osteoblast focal adhesion assembly and migration, respectively. Collectively, these data provide a mechanistic link between Wnt5a and osteoblast function. In summary, our study establishes osteoclast-derived Wnt5a as a clastokine supporting bone formation through regulation of osteoblast migration and adhesion dynamics, highlighting the context-dependent and cell-specific roles of WNT5A in skeletal homeostasis.

ORGANISM(S): Mus musculus

PROVIDER: GSE324013 | GEO | 2026/07/22

REPOSITORIES: GEO