No 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 ofSfrp4is associated with decreased periosteal and endosteal bone formation and increased endocortical resorption. While the increase in Rankl/Opg in cortical bone of mice lackingSfrp4suggests an osteoblast-dependent effect on endocortical osteoclast (OC) activity, whether Sfrp4 can cell-autonomously affect OCs is not known. We found thatSfrp4is 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.Sfrp4deletion 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 ofSfrp4on OCgenesis, blocking the noncanonical Wnt/Ror2/Jnk cascade markedly suppressed its regulation of OC differentiation in vitro. Importantly, we report that deletion ofRor2exclusively in OCs (CtskCreRor2fl/fl) inSfrp4null 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 inSfrp4−/−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.

Polyunsaturated fatty acids are required for the brain development and significantly impact aging and stroke. Due to the hydrophobicity of fatty acids, fatty acids transportation related proteins that include fatty acid binding proteins (FABPs), long chain acyl-coA synthase (ACS), fatty acid transportation proteins (FATPs), fatty acid translocase (FAT/CD36) and newly reported major facilitator superfamily domain-containing protein (Mfsd2a) play critical roles in the uptake of various fatty acids, especially polyunsaturated fatty acids. They are not only involved in neurodevelopment, but also have great impact on neurological disease, such as aging related dementia and stroke.