Repurposing erectile dysfunction drugs tadalafil and vardenafil to increase bone mass

Se Min Kima, Se Min Kima, Charit Taneja, Charit Taneja, Helena Perez-Pena, Vitaly Ryu, Vitaly Ryu, Anisa Gumerova, Anisa Gumerova, Wenliang Li, Naseer Ahmad, Naseer Ahmad, Ling Ling Zhu, Ling Ling Zhu, Peng Liu, Peng Liu, Mehr Mathew, Mehr Mathew, Funda Korkmaz, Funda KorkmazSakshi Gera, Sakshi Gera, Damini Sant, Damini Sant, Elina Hadelia, Elina Hadelia, Kseniia Ievleva, Kseniia Ievleva, Kseniia Ievleva, Tan Chun Kuo, Tan Chun Kuo, Hirotaka Miyashita, Hirotaka Miyashita, Li Liu, Li Liu, Irina Tourkova, Irina Tourkova, Sarah Stanley, Daria Lizneva, Daria Lizneva, Jameel Iqbal, Jameel Iqbal, Li Sun, Li Sun, Ronald Tamler, Harry C. Blair, Harry C. Blair, Maria I. New, Maria I. New, Shozeb Haider, Tony Yuen, Tony Yuen, Mone Zaidi, Mone Zaidi

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

We report that two widely-used drugs for erectile dysfunction, tadalafil and vardenafil, trigger bone gain in mice through a combination of anabolic and antiresorptive actions on the skeleton. Both drugs were found to enhance osteoblastic bone formation in vivo using a unique gene footprint and to inhibit osteoclast formation. The target enzyme, phosphodiesterase 5A (PDE5A), was found to be expressed in mouse and human bone as well as in specific brain regions, namely the locus coeruleus, raphe pallidus, and paraventricular nucleus of the hypothalamus. Localization of PDE5A in sympathetic neurons was confirmed by coimmunolabeling with dopamine β-hydroxylase, as well as by retrograde bone-brain tracing using a sympathetic nerve-specific pseudorabies virus, PRV152. Both drugs elicited an antianabolic sympathetic imprint in osteoblasts, but with net bone gain. Unlike in humans, in whom vardenafil is more potent than tadalafil, the relative potencies were reversed with respect to their osteoprotective actions in mice. Structural modeling revealed a higher binding energy of tadalafil to mouse PDE5A compared with vardenafil, due to steric clashes of vardenafil with a singlemethionine residue at position 806 in mouse PDE5A. Collectively, our findings suggest that a balance between peripheral and central actions of PDE5A inhibitors on bone formation together with their antiresorptive actions specify the osteoprotective action of PDE5A blockade.

Original languageEnglish
Pages (from-to)14386-14394
Number of pages9
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number25
DOIs
StatePublished - 23 Jun 2020

Keywords

  • Computational modeling
  • Cyclic GMP
  • Osteoporosis
  • PDE5 inhibitor
  • Resorption

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