Which pathway regulates bone metabolism though osteoblast signaling?
The Wnt/β-catenin signaling pathway is a critical component of bone mass regulation and is required for bones to respond to mechanical loading. The Wnt signaling cascade is triggered upon binding of members of the Wnt family of lipid-modified proteins (more than 12) to a coreceptor complex comprising low-density lipoprotein receptor-related proteins 5 or 6 (LRP 5 or 6) and frizzled protein (Frz). Activation of this receptor complex leads to activation of Dishevelled, which then inactivates glycogen synthase kinase (GSK)-3β.
This prevents GSK-3β from phosphorylating β-catenin which, when phosphorylated, is targeted for ubiquitination and proteosomal degradation. Thus, β-catenin is able to accumulate in the cytoplasm. Upon reaching a certain concentration, the β-catenin translocates to the nucleus where it combines with the Tcf/Lef family of transcription factors, which regulate the expression of specific osteoblastic genes necessary for bone formation. There are three extracellular proteins that regulate Wnt binding. One is secreted Frz protein which binds and neutralizes Wnt protein. The other two are sclerostin (Scler) and dickkopf (Dkk-1) proteins which are produced by osteocytes and bind to LRP5/6 and prevent Wnt signaling through these receptors. Notably LRP5 mutations have been associated with both low and high bone mass. Sclerostin mutations have been linked to osteosclerosis (van Buchem syndrome) because of their inability to block Wnt signaling. Monoclonal antibodies against sclerostin are being tested as a therapy for osteoporosis.