Analysis of short-term treatment with the phosphodiesterase type 5 inhibitor tadalafil on long bone development in young rats

Abstract

Cyclic GMP (cGMP) is an important intracellular regulator of endochondral bone growth and skeletal remodeling. Tadalafil, an inhibitor of the phosphodiesterase (PDE) type 5 (PDE5) that specifically hydrolyzes cGMP, is increasingly used to treat children with pulmonary arterial hypertension (PAH), but the effect of tadalafil on bone growth and strength has not been previously investigated. In this study, we first analyzed the expression of transcripts encoding PDEs in primary cultures of chondrocytes from newborn rat epiphyses. We detected robust expression of PDE5 as the major phosphodiesterase hydrolyzing cGMP. Time-course experiments showed that C-type natriuretic peptide increased intracellular levels of cGMP in primary chondrocytes with a peak at 2 min, and in the presence of tadalafil the peak level of intracellular cGMP was 37% greater ( P < 0.01) and the decline was significantly attenuated. Next, we treated 1-mo-old Sprague Dawley rats with vehicle or tadalafil for 3 wk. Although 10 mg·kg·day tadalafil led to a significant 52% ( P < 0.01) increase in tissue levels of cGMP and a 9% reduction ( P < 0.01) in bodyweight gain, it did not alter long bone length, cortical or trabecular bone properties, and histological features. In conclusion, our results indicate that PDE5 is highly expressed in growth plate chondrocytes, and short-term tadalafil treatment of growing rats at doses comparable to those used in children with PAH has neither obvious beneficial effect on long bone growth nor any observable adverse effect on growth plate structure and trabecular and cortical bone structure.

Tadalafil and Steroid Hormones Interactions in Adipose, Bone and Prostate Tissues: Focus on Translational Perspectives

“…Similar observations were found by Pal et al in a model of mouse calvarial osteoblasts treated with sildenafil and vardenafil, which increased surface referent bone formation and serum bone formation marker P1NP and the expression of vascular endothelial growth factor and its receptor 2 in bones and osteoblasts, alongside increased skeletal vascularity [27]. However, neutral results came from an interesting study by Wang et al conducted on the primary cultures of chondrocytes from newborn rat epiphyses [28]. The authors demonstrated that this cell line highly expressed PDE5 and that a short-term tadalafil treatment in growing rats at doses comparable to those used in children with pulmonary arterial hypertension has neither obvious beneficial effects on long bone growth nor any observable adverse effects on growth plate structure and trabecular and cortical bone structure [28].…”

“…However, neutral results came from an interesting study by Wang et al conducted on the primary cultures of chondrocytes from newborn rat epiphyses [28]. The authors demonstrated that this cell line highly expressed PDE5 and that a short-term tadalafil treatment in growing rats at doses comparable to those used in children with pulmonary arterial hypertension has neither obvious beneficial effects on long bone growth nor any observable adverse effects on growth plate structure and trabecular and cortical bone structure [28]. Finally, we demonstrated that human osteoblasts (SAOS-2) express significant levels of both PDE5 mRNA and protein and that their exposure to increasing concentrations of tadalafil [10(-8)-10(-7) M] decreased PDE5 mRNA and protein expression.…”

Combined use of arginase II inhibitors and tadalafil for the correction of monocrotaline pulmonary hypertension

“…In addition to the treatment of erectile dysfunction, PDE-5-Is are widely used in clinical practice for the treatment of both primary and secondary pulmonary hypertension. An important feature in the correction of PDE-5-IS is not only vasodilation, but also the prevention of remodelling vessels (Wang et al 2018). The controlled randomized trial revealed the presence of a vasorelaxating effect in conditions of pulmonary arterial hypertension in sildenafil, vardenafil, and tadalafil (Mokry et al 2017) Due to the accumulation of cGMP, PDE-5 inhibitors may have a stimulating influence on the metabolic pathway of the formation of the nitrogen oxide NO/cGMP/ PDE.…”

Repurposing erectile dysfunction drugs tadalafil and vardenafil to increase bone mass

“…Likewise, PDE5A is expressed in the brain, and its inhibition affects neurogenesis, memory, and stroke progression (26)(27)(28). PDE5A is also expressed in chondrocytes, but inhibiting PDE5A in 1-mo-old rats for 3 wk did not affect long bone growth or bone modeling (29). Other studies on putative skeletal effects of PDE5A inhibition in animal models have yielded inconsistent results, including hyperresorption and low bone density (30), positive effects on bone in ovariectomized and glucocorticoid-treated mice (31,32), and accelerated fracture healing (33).…”