A new WNT on the bone: WNT16, cortical bone thickness, porosity and fractures

Abstract

The last decade has provided abundant data implicating the WNT pathway in bone development and in the regulation of skeletal homeostasis. Rare human mutations together with gain-and loss-of-function approaches in mice have clearly demonstrated that disrupted regulation of this pathway leads to altered bone mass. In addition to these rare human and mice mutations, large population-based genome-wide association studies (GWASs) have identified single-nucleotide polymorphisms in B60 loci strongly associated with variations in bone mineral density (BMD) at different skeletal sites. Among the loci/genes identified by BMD GWAS, components of the WNT signaling pathway are numerous and have been shown to contribute to skeletal development and homeostasis. Within the components of WNTsignaling, the gene coding for WNT16, one of the 19 WNT ligands of the human genome, has been found strongly associated with specific bone traits such as cortical bone thickness, cortical porosity and fracture risk. Recently, the first functional characterization of Wnt16 has confirmed the critical role of Wnt16 in the regulation of cortical bone mass and bone strength in mice. These reports have extended our understanding of Wnt16 function in bone homeostasis and have not only confirmed the unique association of Wnt16 with cortical bone and fracture susceptibility, as suggested by GWAS in human populations, but have also provided novel insights into the biology of this WNT ligand and the mechanism(s) by which it regulates cortical but not trabecular bone homeostasis. Most interestingly, Wnt16 appears to be a strong anti-resorptive soluble factor acting on both osteoblasts and osteoclast precursors. WNT Signaling and Skeletal HomeostasisSkeletal homeostasis is maintained throughout life by the balance between bone formation by osteoblasts (which derive from mesenchymal cells) and bone resorption by osteoclasts (which have hematopoietic origin), regulated in part by the third bone cell type, the osteocyte, itself derived from osteoblasts. The adult skeleton continuously undergoes remodeling, and failure to balance these two processes can lead to skeletal diseases, such as osteoporosis, characterized by decreased bone mass, altered bone micro-structure and increased risk of fragility fractures.1 Most studies have, however, focused on trabecular bone remodeling despite the fact that 80% of the skeleton is constituted by cortical bone. [2][3][4] The findings that with aging 80% of fractures are associated with cortical bone (non-vertebral fractures) indicate that cortical bone mass is a key determinant of bone strength. [2][3][4] Although the risk of vertebral fractures, which arise mainly at trabecular sites, is significantly decreased by the currently available anti-resorptive or anabolic treatments, the risk of non-vertebral fractures is reduced only by B20%, confirming a dichotomy between the homeostatic regulation of the trabecular and cortical bone compartments 1,[5][6][7][8]

Role and mechanism of action of sclerostin in bone

“…Osteocytes are key players in the regulation of the canonical Wnt signaling pathway as producers and targets of Wnt ligands and as secretors of molecules that modulate Wnt actions (1;2). A potent antagonist of Wnt signaling secreted by osteocytes is sclerostin, a protein encoded by the Sost gene primarily expressed by mature osteocytes but not by early osteocytes or osteoblasts (3).…”

Multiscale characterization of cortical bone composition, microstructure, and nanomechanical properties in experimentally induced osteoporosis

“…In experimentally induced osteoporosis, that is, the ovariectomised rat, anatomical site specific and observation time dependent alterations in bone mineral density (BMD) and microarchitecture of trabecular bone have been reported . But although cortical bone plays a vital role in determining bone strength, and nearly 80% of non‐vertebral fractures in humans are associated with cortical bone, alterations in cortical bone quality in osteoporosis are less extensively studied. An intracortical and endocortical remodeling imbalance produces cortical porosity and thinning, resulting in a high proportion of age‐related bone loss—it is therefore essential to recognize the role of cortical bone deterioration as a critical determinant of bone strength .…”

Identification of IDUA and WNT16 Phosphorylation-Related Non-Synonymous Polymorphisms for Bone Mineral Density in Meta-Analyses of Genome-Wide Association Studies

“…(22) The human WNT16 gene spans ~16 kb from initiation to termination codons, encoding two protein isoforms — WNT16A (40.5 kD) and WNT16B (40.7 kD). (23) As depicted in Supplementary Figure S1, these two WNT16 isoforms have different first exons (i.e., 1a and 1b, respectively), independently controlled by two alternative promoters P1 and P2, respectively.…”