Humans lacking sclerostin display progressive bone overgrowth due to increased bone formation. Although it is well established that sclerostin is an osteocyte-secreted bone formation inhibitor, the underlying molecular mechanisms are not fully elucidated. We identified in tandem affinity purification proteomics screens LRP4 (low density lipoprotein-related protein 4) as a sclerostin interaction partner. Biochemical assays with recombinant proteins confirmed that sclerostin LRP4 interaction is direct. Interestingly, in vitro overexpression and RNAi-mediated knockdown experiments revealed that LRP4 specifically facilitates the previously described inhibitory action of sclerostin on Wnt1/-catenin signaling. We found the extracellular -propeller structured domain of LRP4 to be required for this sclerostin facilitator activity. Immunohistochemistry demonstrated that LRP4 protein is present in human and rodent osteoblasts and osteocytes, both presumed target cells of sclerostin action. Silencing of LRP4 by lentivirus-mediated shRNA delivery blocked sclerostin inhibitory action on in vitro bone mineralization. Notably, we identified two mutations in LRP4 (R1170W and W1186S) in patients suffering from bone overgrowth. We found that these mutations impair LRP4 interaction with sclerostin and its concomitant sclerostin facilitator effect. Together these data indicate that the interaction of sclerostin with LRP4 is required to mediate the inhibitory function of sclerostin on bone formation, thus identifying a novel role for LRP4 in bone.
Lifestyle plays an important role in the development of obesity during childhood and adolescence. We provide up-to-date information about the relationship between obesity and food intake and dietary patterns in adolescents. Scientific evidence is increasing about the dietary factors associated with this relationship, specifically a low meal frequency, skipping breakfast, and a high consumption of sugar sweetened beverages. Maybe some of the reviewed dietary factors could cluster in the same population of adolescents, increasing the individual risk. There is little information about dietary patterns and current time trends in adolescents; however, the available data seem to show that the tendency in the adolescent population worldwide is to increase those dietary factors related with obesity development. Public health efforts should be emphasized in order to decrease the current tendency. Regular family meals could serve as role models for healthy eating behaviors. Educational intervention programs for parents, aiming to modify the healthfulness of the diet, seems to be one of the most adequate tools to deal with the worldwide obesity epidemic.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.