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

Abstract

Loss-of-function mutations in the Wnt inhibitor secreted frizzled receptor protein 4 (SFRP4) cause Pyle's disease (OMIM 265900), a rare skeletal disorder characterized by wide metaphyses, significant thinning of cortical bone, and fragility fractures. In mice, we have shown that the cortical thinning seen in the absence of <i>Sfrp4</i> is associated with decreased periosteal and endosteal bone formation and increased endocortical resorption. While the increase in Rankl/Opg in cortical bone of mice lacking <i>Sfrp4</i> suggests an osteoblast-dependent effect on endocortical osteoclast (OC) activity, whether Sfrp4 can cell-autonomously affect OCs is not known. We found that <i>Sfrp4</i> is expressed during bone marrow macrophage OC differentiation and that Sfrp4 significantly suppresses the ability of early and late OC precursors to respond to Rankl-induced OC differentiation. <i>Sfrp4</i> deletion in OCs resulted in activation of canonical Wnt/β-catenin and noncanonical Wnt/Ror2/Jnk signaling cascades. However, while inhibition of canonical Wnt/β-catenin signaling did not alter the effect of <i>Sfrp4</i> on OCgenesis, blocking the noncanonical Wnt/Ror2/Jnk cascade markedly suppressed its regulation of OC differentiation in vitro. Importantly, we report that deletion of <i>Ror2</i> exclusively in OCs (<i>CtskCreRor2</i>^<i>fl/fl</i> ) in <i>Sfrp4</i> null mice significantly reversed the increased number of endosteal OCs seen in these mice and reduced their cortical thinning. Altogether, these data show autocrine and paracrine effects of Sfrp4 in regulating OCgenesis and demonstrate that the increase in endosteal OCs seen in <i>Sfrp4</i>^<i>-/-</i> mice is a consequence of noncanonical Wnt/Ror2/Jnk signaling activation in OCs overriding the negative effect that activation of canonical Wnt/β-catenin signaling has on OCgenesis.