THE CRUCIAL ROLE OF THE WNT SYSTEM IN BONE REMODELLING

Abstract

The maintenance of bone mass is critically dependent on the balance between bone formation by osteoblasts and bone resorption by osteoclasts, processes in which osteocytes play also an important role. The activities of these bone cells are regulated by a variety of endocrine and paracrine factors of which sex steroids, parathyroid hormone, 1.25(OH)²-vitamin D3, glucocorticoids, retinoids and thyroid hormones are the most well known systemic factors. To the long list of locally acting factors belong cytokines and growth factors. This list was extended some 15 years ago by the discovery of the very important role of the WNT signalling system for the maintenance of bone mass. The first evidence of its role was the findings that mutations in the LRP5 gene, encoding a co-receptor in WNT-signaling, could result in either gain or loss of bone mass, i.e. either high bone mass or osteoporosis. This was a most unexpected observation since no indications existed prior to this discovery that the WNT signalling system had a role in bone remodeling. Since then, many observations have been made demonstrating the important role of different WNTs in regulating bone formation and resorption. Interestingly, some of these findings have demonstrated that trabecular and cortical bone are regulated by different mechanisms. It is the aim of the present overview to give the readers an insight into the WNT signalling system and its role in bone remodeling.

Keywords: WNTs; bone; bone resorption; osteoclasts; sclerostin.

Figure 1.

A. When the co-receptor LRP and the signaling receptor Frizzled are not activated by WNTs, the heterotetrameric destruction complex made up of the four components Axin, adenomatous polyposis coli, casein kinase and the constitutively active enzyme GSK3, phosphorylates β-catenin in the cytosol. This makes β-catenin directed to proteasomal degradation. B. When WNTs bind to LRP and Frizzled, the destruction complex becomes inactivated and non-phosphorylated β-catenin accumulates in the cytosol and translocates to the nuclei. In the nuclei, β-catenin activates the transcription factor complex TCF/LEF which binds to promoter regions of many genes including genes in osteoblasts which are involved in new bone formation.

Figure 2.

Different inhibitors can interact with WNT signaling. A. Sclerostin (Scler.) acts by binding to the extracellular part of the co-receptor LRP and thereby inhibits the binding of WNTs. Loss-of-function mutations in the SOST gene encoding sclerostin enhances binding of WNT and thereby increases WNT signalling and bone mass in patients with van Buchem´s disease and sclerosteosis. B. Dickkopf 1-4 (DKK) also binds to the extracellular part of the co-receptor LRP and inhibits binding of WNTs. C. Secreted Frizzled-related proteins (SFRP1-5) and WNT inhibitory protein (WIF) act as decoy receptors to bind soluble WNTs. Mutations in the SFRP4 gene are the cause of low bone mass in patients with Pyle´s disease.