Hydrogen Sulfide (H2S) Based Therapeutics for Bone Diseases: Translating Physiology to Treatments

Much progress has been made in the past decade in elucidating the physiological, pathophysiological and pharmacological role of Hydrogen Sulphide (H2S). Recently a function of H2S virtually in every tissue of the human organism has emerged. However, the H2S-mediated regulation of bone homeostasis has been scarcely investigated. Despite a recent increased interest in the field, many fundamental issues remain indeterminate. The main objective of this study was to increase the basic knowledge on the role of H2S in bone through in vitro and in vivo studies and develop novel therapeutic strategies for bone diseases. Ex vivo experiments revealed that H2S-generating enzymes (Cystathionine-β-synthase, CBS; Cystathionine-γ-lyase, CSE) are expressed in human bone tissues and human bone-derived cells. In vitro experiments evidenced that CBS and CSE expression is a distinctive feature of the transition of mesenchymal stromal cells (h-MSCs) toward mature osteoblast. Furthermore, loss of function experiments on CBS and CSE during osteogenic differentiation of h-MSCs revealed an impaired mineralization ability. In vivo experiments in mice highlighted the role of CBS, CSE and H2S in the maintenance of bone homeostasis and CBS, CSE and H2S were found to be depleted in post-menopausal osteoporosis. Furthermore, our in vitro and in vivo data validated the use of H2S-donors as novel potential candidates for the treatment of bone pathologies. In particular H2S administration prevented and reversed ovariectomy-induced bone loss in mice. Based on these evidences, we firstly developed an H2S-releasing hybrid drug (DM-22) by modifying a clinically relevant anti-resorptive drug in order to improve the therapy of bone loss. DM-22 displayed improved biological properties compared to the parent drug; in particular, it increased the osteogenic differentiation ability of h-MSCs. Secondly, we developed an H2S-releasing scaffold to improve bone regeneration which was permissive for h-MSCs colonization and supported their osteogenic differentiation.