Wnt signaling and orthopedics, an overview

Abstract

Wnt signaling is a ubiquitous system for intercellular communication, with multiple functions during development and in homeostasis of the body. It comprises several ligands, receptors, and inhibitors. Some molecules, such as sclerostin, appear to have bone-specific functions, and can be targeted by potential drugs. Now, ongoing clinical trials are testing these drugs as treatments for osteoporosis. Animal studies have also suggested that these drugs can accelerate fracture healing and implant fixation. This brief overview focuses on currently available information on the effects of manipulations of Wnt signaling on bone healing.

Figure 1.

Canonical Wnt signaling. In the active state, Wnt ligands (Wnt) form a complex with the receptors low-density lipoprotein receptor-related protein 5 or 6 (LRP5/6) and Frizzled (Fz). Disheveled (Dsh) is then able to bind to Fz. Dsh forms a complex with glycogen synthase kinase 3ß (GSK3ß), Axin, and adenomatous polyposis coli (APC). This protects ß-catenin from proteasomal degradation so that ß-Catenin can accumulate in the cytosol and translocate to the nucleus. In the nucleus it interacts with the T-cell factor/lymphoid enhancer factor (TCF/LEF) family of transcription factors, leading to gene transcription. Inhibitors of this system prevent the formation of the Wnt-Fz-LRP5/6 complex, inactivating Wnt signaling. This leads to GSK3ß-mediated phosphorylation of ß-catenin, causing it to be degraded. A variety of extracellular inhibitors serve as inactivators. Dickkopf (Dkk) and sclerostin (Sost) bind to LRP5/6, preventing Wnt binding. Secreted Frizzled-related protein (sFrp) has similarities with Frizzled, and can bind either to the Wnt ligand or to the Fz receptor itself. Frizzled-related protein (Frzb) acts as a decoy receptor for Wnt ligands. Wnt-inhibitory factor (Wif) also binds directly to the Wnt ligand (Komatsu and Warden 2010, MacDonald 2009, Macsai 2008).

Figure 2.

Wnt signaling in mechanotransduction: 1. The Wnt inhibitor sclerostin is secreted from osteocytes and blocks stimulation of lining cells. 2. Deformation due to mechanical loading is perceived by osteocytes, which reduce sclerostin secretion, thus permitting surface cells to be activated by Wnt ligands. 3. Bone apposition reduces deformation and sclerostin secretion is increased again.