Role of the Wnt/β-Catenin Pathway in Renal Osteodystrophy

Figure 3

Proposed mechanisms by which PTH activates Wnt/β-catenin pathway in osteoblasts and osteocytes to modulate bone turnover. In the osteoblast (left), PTH binding to Lrp6 and PTH1R activates PKA, which activates the Wnt/β-catenin pathway by phosphorylating Lrp6. The levels of β-catenin rise, which leads to modulation of RANKL and OPG expression resulting in a decreased RANKL/OPG ratio. PKA itself can also directly stabilize β-catenin through phosphorylation and also directly stimulates RANKL production. The increased production of RANKL when PTH is administered continuously might be mediated by this action of PKA. A similar mechanism occurs in the osteocyte (right), presumably also through Lrp6 signaling. While it is unconfirmed whether PKA can also directly stimulate RANKL transcription in osteocytes, continuous PTH in osteocytes activates RANKL production while only activating the Wnt/β-catenin instead increases OPG production. A notable difference between how both cell types respond to PTH is that PKA activation inhibits sclerostin production in osteocytes. The decrease in sclerostin could partly explain the resulting increase in bone formation when PTH is given intermittently. Moreover, expression of sclerostin in osteocytes seems to further upregulate RANKL in those same cells.