Wnt signaling pathways and bone turnover

Both the "canonical" Wnt signaling pathway with beta-catenin as its key downstream effector as well as the "non-canonical" Wnt/Ca++ pathway, which uses intracellular Ca++ as "second messenger", play a key role in the control of bone remodeling. The Wnt signaling cascades coordinate the multiple phases in the process of bone formation (from osteogenic differentiation of pluripotent mesenchymal stem cells to matrix maturation and mineralization by fully differentiated osteoblasts and osteocytes), and also regulate differentiation and activation of osteoclasts. Accrual and maintenance of bone mass is genetically determined, mainly through expression of the genes that encode the components of the Wnt/beta-catenin signaling pathway, particularly the Wnt co-receptor LRP5. Modulation of efficiency of Wnt-activated pathways, e. g. by costimulatory signals from pathways activated by RANK/RANKL, PTH, 1,25-(OH)(2)D-3/VDR, and Ca++/CaR, or by blocking Wnt-lnhibitors like Dkk-1 and sclerostin, respectively, provides a means for prevention and therapy of primary and secondary osteoporosis.