title: Sodium hydrosulfide inhibits the differentiation of osteoclast progenitor cells via NRF2-dependent mechanism.
abstract: Hydrogen sulfide (H2S), which recently emerged as a potent regulator of tissues and organs, is broadly produced in mammalian cells but whether it can regulate bone cell function is still elusive. The main objective of this study was to establish the role of H2S in the regulation of human osteoclast differentiation and function. Sodium hydrosulfide (NaHS), a common H2S-donor, was administered in vitro to CD11b+ human monocytes, the pool of circulating osteoclasts precursors which are critically involved in osteoclast development and function in bone. NaHS dose-dependently decreased human osteoclast differentiation at concentrations which did not induce toxicity. The inhibition of human osteoclast differentiation was associated with a down-regulation in RANKL-dependent intracellular ROS levels in human pre-osteoclasts cells. Furthermore, NaHS up-regulated NRF2 protein expression, its nuclear translocation, and the transcription of the two key downstream antioxidant genes Peroxiredoxin-1 and NAD(P)H dehydrogenase quinone 1, suggesting that NRF2 activation may inhibit human osteoclast differentiation by activating a sustained antioxidant response in osteoclast progenitors; furthermore, NRF2 activators Sulforaphane and Tert-butylhydroquinone inhibited in vitro human osteoclast differentiation. Moreover, silencing NRF2 in human pre-osteoclasts totally abolished NaHS-mediated inhibition of osteoclastogenesis, suggesting that NRF2 is essential to the inhibitory function of NaHS in osteoclast development. Finally, we found that NaHS also downregulated the RANKL/OPG mRNA ratio in human mesenchymal stem cells, the key osteoclast-supporting cells. Our results suggest that NaHS shows a potential therapeutical role in erosive diseases of bone by regulating both direct and indirect mechanisms controlling the differentiation of circulating osteoclasts precursors.
authors.affiliation: S.C. Laboratorio di Immunoreumatologia e Rigenerazione Tissutale, Istituto Ortopedico Rizzoli, Via di Barbiano 1/10, 40136 Bologna, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Gambari
authors.affiliation: S.C. Laboratorio di Immunoreumatologia e Rigenerazione Tissutale, Istituto Ortopedico Rizzoli, Via di Barbiano 1/10, 40136 Bologna, Italy; Laboratorio RAMSES, Istituto Ortopedico Rizzoli, Via di Barbiano 1/10, 40136 Bologna, Italy.
authors.forename: Gina
authors.initials: G
authors.lastname: Lisignoli
authors.affiliation: S.C. Laboratorio di Immunoreumatologia e Rigenerazione Tissutale, Istituto Ortopedico Rizzoli, Via di Barbiano 1/10, 40136 Bologna, Italy; Laboratorio RAMSES, Istituto Ortopedico Rizzoli, Via di Barbiano 1/10, 40136 Bologna, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Cattini
authors.affiliation: S.C. Laboratorio di Immunoreumatologia e Rigenerazione Tissutale, Istituto Ortopedico Rizzoli, Via di Barbiano 1/10, 40136 Bologna, Italy; Laboratorio RAMSES, Istituto Ortopedico Rizzoli, Via di Barbiano 1/10, 40136 Bologna, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Manferdini
authors.affiliation: S.C. Laboratorio di Immunoreumatologia e Rigenerazione Tissutale, Istituto Ortopedico Rizzoli, Via di Barbiano 1/10, 40136 Bologna, Italy; Laboratorio RAMSES, Istituto Ortopedico Rizzoli, Via di Barbiano 1/10, 40136 Bologna, Italy; Dipartimento di Scienze Mediche e Chirurgiche, Università di Bologna, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Facchini
authors.affiliation: Laboratorio RAMSES, Istituto Ortopedico Rizzoli, Via di Barbiano 1/10, 40136 Bologna, Italy. Electronic address: francesco.grassi@ior.it.
authors.forename: Francesco
authors.initials: F
authors.lastname: Grassi
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D006801:Humans; D059630:Mesenchymal Stem Cells; D009000:Monocytes / Q000166:cytology; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects*; D053245:RANK Ligand / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D013440:Sulfides / Q000494:pharmacology*
chemical_list: D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D053245:RANK Ligand; D017382:Reactive Oxygen Species; D013440:Sulfides; C025451:sodium bisulfide
keywords: Bone; Hydrogen sulfide; Mesenchymal stem cells; NRF2; Osteoclasts; Osteoporosis; Sodium hydrosulfide