Wnt signaling and anabolic bone strategies

Abstract

Wnt/β-catenin signaling also termed canonicalWnt signaling has emerged as a key regulatory pathway for adult bone homeostasis. Initial interestwas sparked by thediscovery of human lowandhighbonemass phenotypes associated with loss and gain of function mutations in the Wnt co-receptor LRP5. Interestingly, recent findings inmice suggest that Lrp5 might not act so much as a local Wnt signaling mediator in bone, but rather controls pre-osteoblast proliferation by inhibiting duodenal serotonin synthesis. Nevertheless an ever expanding number of genetically modified mouse models targeting various pathway components has established thatWnt/β-catenin signaling impacts osteoblasts at all stages of their life cycle and thus indirectly also osteoclast differentiation and activity. To date several lines of evidence implicate Wnt/β-catenin signaling in bone anabolism elicited by mechanotransduction and by PTH treatment. Osteocyte and osteoblast secreted sclerostin and Dkk1 are thought to antagonize Wnt signaling locally by binding to LRP5 and LRP6 co-receptors. Inhibition of their activity by neutralizing antibodies has proven to be bone anabolic in pre-clinical and in part also in clinical studies. Likewise low molecular weight inhibitors of Secreted frizzled-related protein (Sfrp) 1 have been demonstrated to increase bone formation inpre-clinical animalmodels. In contrast to sclerostin and Dkk1, Sfrps and Wnt inhibitory factors (Wifs) antagonize Wnt signaling by sequestering Wnt ligands directly. Depending on ligand specificity they can also inhibit non-canonicalWnt signaling, which has been implicated in regulation of osteoblastogenesis. Given the role of the pathway in multiple tissues, safety of bone anabolic osteoporosis therapies based onWnt signaling stimulationwill need to be established. Inhibition of secreted bone specific Wnt antagonists, such as sclerostin, represents hence a more promising approach compared to modulation of common intracellular pathway components like the serine/theorine kinase GSK3β, despite the ability of small molecule GSK3α/β inhibitors to increase bone mass in preclinical animal models. Risk of oncogenesis upon de-repression of the Wnt pathwaywill need to be explored as highlighted by recent findings linking loss ofWif1 to increased osteosarcoma susceptibility. Finally, the therapeutic window for such treatments will require optimization to avoid adverse effects from inappropriate excessive bone formation.