LAUSR

Bone remodeling is achieved through the coupled activities of osteoclasts and osteoblasts that are controlled by many locally generated secreted factors, including WNT5A. While previous studies have demonstrated that osteoblast‐derived WNT5A promotes osteoclastogenesis, the function of osteoclast‐derived WNT5A on bone remodeling has remained unexplored. We examined the effects of osteoclast‐derived WNT5A on bone homeostasis by utilizing the Cathepsin K‐Cre (Ctsk‐Cre) mouse to conditionally delete Wnt5a in mature osteoclasts. These mice exhibited reduced trabecular and cortical bone. The low bone–mass phenotype was driven by decreased bone formation, not osteoclast‐mediated bone resorption, as osteoclast number and serum CTX marker were unchanged. Furthermore, molecular analysis of osteoclast‐ and osteoblast‐derived WNT5A identified a serine‐phosphorylated WNT5A that is unique to RANKL‐treated macrophages mimicking osteoclasts. This study suggests a new paradigm in which WNT5A has opposing effects on bone remodeling that are dependent on the cell of origin, an effect that may result from cell type–specific differential posttranslational modifications of WNT5A.