SX-RDS1

Wingless tail (Wnt) pathway is crucial for osteoblast activation and action. This review summarizes the evidence published during the previous year on the emerging role of Wnt signaling alterations in the pathogenesis, diagnosis, and potential therapeutic approaches of osteoporosis.

New insights into the mechanisms regulating Wnt/β-catenin canonical pathway, including the role of Kremen-2 receptor, lamin A/C protein, periostin, and pleiotropin in bone physiology, the crosstalk between the RUNX-2 transcription-factor cascade and the Wnt pathway, and the concept that individual Wnt ligands may have a unique and distinct mission in bone milieu, are presented. Nutritional habits may affect Wnt signaling in bone. Serum sclerostin and dickkopf-1 levels may serve as markers of bone metabolism and disease, although further standardization methods are required. Finally, the effect of current antiosteoporotic treatments on Wnt signaling is discussed, as well as the therapeutic potential of drugs targeting either Wnt signaling amplification or Wnt antagonists' attenuation.

Although Wnt pathway is currently a field of thorough investigation, it is still far from been fully elucidated. Understanding its complex pathophysiology has evoked promising therapeutic approaches for osteoporosis. However, given that Wnt signaling is crucial for many tissues, emerging knowledge should be cautiously translated in therapeutics.

Autocrine Wnt signaling in the mouse mammary tumor virus model was the first identified mechanism of canonical pathway activation in cancer. In search of this transformation mechanism in human cancer cells, we identified breast and ovarian tumor lines with upregulation of the uncomplexed transcriptionally active form of beta-catenin without mutations afflicting downstream components. Extracellular Wnt antagonists FRP1 and DKK1 caused a dramatic downregulation of beta-catenin levels in these tumor cells associated with alteration of biological properties and increased expression of epithelial differentiation markers. Colorectal carcinoma cells with knockout of the mutant beta-catenin allele retained upregulated beta-catenin levels, which also could be inhibited by these Wnt antagonists. Together, these findings establish the involvement of autocrine Wnt signaling in human cancer cells.