The loss of the SOST gene product sclerosti leads to sclerosteosischaracterized byihigh bone mass (HBM). In this report, we found thatsclerostin could antagonize canonical, Wnt signaling in human embryonic kidneyA293 cells and mouse osteoblastic MC3T3 cells. This sclerostin-mediatedantagonism could be reversed by over-expression of Wnt coreceptor LRP5. Inaddition, we found that sclerostin bound to LRP5 as well as LRP6 andidentified the first two YWTD-EGF repeat domains of LRP5 as being responsiblefor the binding. Although these two repeat domains are required fortransducing canonical Wnt signals, canonical Wnt did not appear to competewith sclerostin for binding to LRP5. Examination of the expression ofsclerostin and Wnt7b, an autocrine canonical Wnt, during primary calvarialosteoblast differentiation revealed that sclerostin is expressed at the latestages of osteoblast differentiation coinciding with the expression ofosteogenic marker osteocalcin and trailing after the expression of Wnt7b.Given the plethora of evidence indicating that canonical Wnt signalingstimulates osteogenesis, we believe that the HBM phenotype associated with theloss of sclerostin may at least in part be attributed to an increase incanonical Wnt signaling resulting from the reduction in sclerostin-mediatedWnt antagonism.
