Parathyroid hormone (PTH) via the PTH/PTH related protein (PTHrP) receptor type 1 (PTHR1) that couples to both protein kinase A (PKA) and protein kinase C (PKC) pathways, and the canonical Wnt--catenin signaling pathway, play important roles in bone formation. In the present study, we have examined the interaction between the PTH and Wnt signaling pathways in mouse osteoblastic MC3T3-E1 cells. PTH dose- and time-dependently increased the concentrations of -catenin. The PKA activator, forskolin, and the PKC activator, phorbol 12-myristate-13-acetate (PMA), as well as the PTH analog, [Nle^{8, 18}, Tyr³⁴]hPTH- (3-34)amide, all increased the -catenin levels. Both H-89, a specific PKA inhibitor, and PKC inhibitors, staurosporine and calphostin C, antagonized the PTH stimulation of -catenin levels. Transforming growth factor- (TGF-), as well as transfection of the TGF- signaling molecule, Smad3, enhanced -catenin levels, and this was antagonized by transfection of a dominant-negative Smad3. The transcriptional activity of transfected dominant-active -catenin was enhanced by PTH, an effect that was antagonized by cotransfection of a dominant-negative Smad3. PTH, as well as LiCl₂, which mimics the effects of the Wnt--catenin pathway, rescued the dexamethasone- and etoposide-induced apoptosis of the osteoblastic cells. In conclusion, the data demonstrate that PTH stimulates osteoblast -catenin levels via Smad3, and that both PKA and PKC pathways are involved. The canonical Wnt--catenin pathway is likely to be involved in the anti-apoptotic actions of PTH by acting through Smad3 in osteoblasts.