title: Inhibition of phosphodiesterase 5 reduces bone mass by suppression of canonical Wnt signaling.
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.
authors.affiliation: Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou 310058, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Gong
authors.affiliation: Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou 310058, China.
authors.forename: C Y
authors.initials: CY
authors.lastname: Xu
authors.affiliation: Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou 310058, China.
authors.forename: J R
authors.initials: JR
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou 310058, China.
authors.forename: X H
authors.initials: XH
authors.lastname: Hu
authors.affiliation: Department of Orthopedics, Taizhou Hospital, Linhai 317000, China.
authors.forename: D
authors.initials: D
authors.lastname: Hong
authors.affiliation: Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou 310058, China.
authors.forename: X
authors.initials: X
authors.lastname: Ji
authors.affiliation: Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou 310058, China.
authors.forename: W
authors.initials: W
authors.lastname: Shi
authors.affiliation: Department of Orthopedics, Taizhou Hospital, Linhai 317000, China.
authors.forename: H X
authors.initials: HX
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: H B
authors.initials: HB
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou 310058, China.
authors.forename: X M
authors.initials: XM
authors.lastname: Wu
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000033:anatomy & histology* / Q000187:drug effects / Q000378:metabolism*; D002243:Carbolines / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D006152:Cyclic GMP / Q000378:metabolism; D017869:Cyclic GMP-Dependent Protein Kinases; D005269:Femur / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism; D006023:Glycoproteins / Q000172:deficiency / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D009929:Organ Size / Q000187:drug effects; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology*; D055550:Protein Stability / Q000187:drug effects; D000068581:Tadalafil; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D051176:beta Catenin / Q000378:metabolism; D000099274:Frizzled-Related Proteins
chemical_list: D002243:Carbolines; D006152:Cyclic GMP; D017869:Cyclic GMP-Dependent Protein Kinases; D006023:Glycoproteins; D047908:Intracellular Signaling Peptides and Proteins; D058986:Phosphodiesterase 5 Inhibitors; D000068581:Tadalafil; D051176:beta Catenin; D000099274:Frizzled-Related Proteins