Sfrp4 repression of the Ror2/Jnk cascade in osteoclasts protects cortical bone from excessive endosteal resorption

Significance Cortical bone homeostasis combines periosteal bone formation and endocortical remodeling. Flaws in these processes lead to altered cortical bone mass. Yet, little is known about the regulatory specificities of the endocortical vs. the periosteal surfaces, both critical in determining cortical thickness. We have shown that Pyle’s disease is due to loss-of-function mutations in the Wnt antagonist SFRP4 and that its deletion in mice causes skeletal deformities closely mimicking those seen in Pyle’s disease: cortical bone thinning. Here, we further elucidate the mechanism by which cortical bone is affected and report that both osteoblast- and osteoclast-expressed Sfrp4 regulate osteoclastogenesis and that Sfrp4-dependent suppression of the noncanonical Wnt/Ror2/Jnk cascade in osteoclasts protects cortical bone from excessive endocortical resorption.