Wnt signaling as a therapeutic target for bone diseases

Abstract

Background: There is a need to develop new bone anabolic agents because current bone regeneration regimens have limitations. The Wingless-type MMTV integration site (Wnt) pathway has emerged as a regulator of bone formation and regeneration.

Objective: To review the molecular basis for Wnt pathway modulation and discuss strategies that target it and improve bone mass.

Methods: Data in peer-reviewed reports and meeting abstracts are discussed.

Results/conclusions: Neutralizing inhibitors of Wnt signaling have emerged as promising strategies. Small-molecule inhibitors of glycogen synthase kinase 3beta increase bone mass, lower adiposity and reduce fracture risk. Neutralizing antibodies to Dickkopf 1, secreted Frizzled-related protein 1 and sclerostin produce similar outcomes in animal models. These drugs are exciting breakthroughs but are not without risks. The challenges include tissue-specific targeting and consequently, long-term safety.

Figure 1. Wnts affect multiple stages of osteoblast-linage maturation

Figure 2. Activation and inhibition of Wnt signaling pathways

A) The “canonical pathway” is stimulated when Wnts bind to Frizzled (Fzd) receptors and low-density lipoprotein receptor-related protein (Lrp)5/6 co-receptors (center). This activates Disheveled (Dsh), which inhibits a cytoplasmic complex composed of glycogen synthase kinase (GSK)3β, Axin, and adenomatous polyposis coli (APC). Cytoplasmic β-catenin levels rise and some β-catenin translocates to the nucleus where it associates with T-cell factor (Tcf)/lymphoid enhancer-binding factor (Lef) transcription factors to regulate gene expression. During non-canonical Wnt signaling (right side of the figure), Wnts bind a Fzd receptor, but the downstream signaling events do not involve GSK3β or β-catenin. Two non-canonical Wnt signaling cascades that have been identified are: 1) Wnt/calcium signaling increases intracellular Ca²⁺ levels and activates protein kinase C and calcium/calmodulin-dependent kinase; and 2) The Wnt/planar cell polarity pathway that signals through Rho/Rac GTPases and c-Jun N-terminal kinase (JNK) to modulate cytoskeletal elements and gene expression. Wnts also bind to receptor tyrosine kinases receptor-like tyrosine (Ryk) and receptor tyrosine kinase-like orphan receptor 2 (Ror2) to activate oncogene (Src) and JNK signaling, respectively (left side of figure). B) Secreted frizzled-related proteins (Sfrps) antagonize canonical Wnt signaling by binding the ligands and preventing their association with Fzd receptors. In the absence of Wnt signaling, GSK3β phosphorylates (asterisks) β-catenin, which marks it for ubiquitination and degradation by the proteosome. C) Dickkoph (Dkk1) suppresses Wnt signaling by forming a ternary complex with Lrp5/6 and Kremen (Krm)1/2. Sclerostin (Scl) also binds to Lrp5/6, but not Krm1/2, to antagonize canonical Wnt signaling.