Abstract
Inhibitors of phosphodiesterase 5 (PDE5) are widely used to treat erectile dysfunction and pulmonary hypertension in clinics. PDE5, cyclic guanosine monophosphate (cGMP), and protein kinase G (PKG) are important components of the non-canonical Wnt signaling. This study aimed to investigate the effect of PDE5 inhibition on canonical Wnt signaling and osteoblastogenesis, using both in vitro cell culture and in vivo animal models. In the in vitro experiments, PDE5 inhibition resulted in activation of cGMP-dependent protein kinase 2 and consequent inhibition of glycogen synthase kinase 3β phosphorylation, destabilization of cytosolic β-catenin and the ultimate suppression of canonical Wnt signaling and reduced osteoblastic differentiation in HEK293T and C3H10T1/2 cells. In animal experiments, systemic inhibition of PDE5 suppressed the activity of canonical Wnt signaling and osteoblastogenesis in bone marrow-derived stromal cells, resulting in the reduction of bone mass in wild-type adult C57B/6 mice, significantly attenuated secreted Frizzled-related protein-1 (SFRP1) deletion-induced activation of canonical Wnt signaling and excessive bone growth in adult SFRP1−/− mice. Together, these results uncover a hitherto uncharacterized role of PDE5/cGMP/PKG signaling in bone homeostasis and provide the evidence that long-term treatment with PDE5 inhibitors at a high dosage may potentially cause bone catabolism.
Highlights
Canonical Wnt signaling is critical to bone development in embryogenesis and to the maintenance of bone mass during adult life.[5]
By using wild-type C57BL/6 and SFRP1 knockout mice, we have uncovered that the PDE/cyclic guanosine monophosphate (cGMP)/PKG2 signaling operates in conjunction with glycogen synthase kinase 3β (GSK3β)-mediated β-cat stabilization to regulate canonical Wnt signaling in maintenance of bone mass in adult mice in vivo
Using 293T and C3H10T1/2 cells, we have shown that inhibition of PDE5 induces cGMPdependent PKG2, which activates GSK3β and thereby destabilizes β-cat in the cytosol, resulting in inhibition of canonical Wnt signaling and consequent reduction of osteoblastic differentiation in vitro (Figure 7)
Summary
Canonical Wnt signaling is critical to bone development in embryogenesis and to the maintenance of bone mass during adult life.[5]. Non-canonical Wnt signaling is β-cat independent and consists of two main pathways: the Rho small GTPasesmediated planar cell polarity pathway and the Wnt/Ca2+ pathway,[10] involved in various aspects of cell fate differentiation and cell movement. PDE5, cyclic guanosine monophosphate (cGMP), and cGMP-dependent protein kinase (PKG) are among the major components of the non-canonical Wnt signaling pathway and are involved in the regulation of intracellular Ca2+ concentration.[14,15] It is well established that PDE5 degrades 3'-5′- cGMP and its inhibition leads to an increase in intracellular cGMP levels and activation of protein
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