Hydrogen Sulfide Is a Novel Regulator of Bone Formation Implicated in the Bone Loss Induced by Estrogen Deficiency

• Type of Material: Article
• Authors: Francesco Grassi, Laboratorio Ramses Istituto Ortopedico Rizzoli; Abdul Malik Tyagi, Emory University; John Calvert, Emory University; Laura Gambari, Laboratorio Ramses Istituto Ortopedico Rizzoli; Lindsey D Walker, Emory University; Mingcan Yu, Emory University; Jerid Robinson, Emory University; Jau-Yi Li, Emory University; Gina Lisignoli, Laboratorio Ramses Istituto Ortopedico Rizzoli; Chiara Vaccaro, Emory University; Jonathan Adams, Emory University; Roberto Pacifici, Emory University
• Language: English
• Date: 2016-05-01
• Publisher: American Society for Bone and Mineral Research
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2015 American Society for Bone and Mineral Research.
• Final Published Version (URL): http://dx.doi.org/10.1002/jbmr.2757
• Title of Journal or Parent Work: Journal of Bone and Mineral Research
• ISSN: 0884-0431
• Volume: 31
• Issue: 5
• Start Page: 949
• End Page: 963
• Grant/Funding Information: This study was supported by grants from the National Institutes of Health (DK91780, DK007298, and RR028009) and by grant ‘Ricerca Finalizzata’ from the Italian Ministry of Health (RF PE-2011-02348395).; LG was supported by a fellowship granted by Spinner 2013.; JYL was supported by a grant from the National Institutes of Health (AR061453).
• Keywords: OXIDATIVE STRESS; WNT SIGNALING; CYSTATHIONINE GAMMA-LYASE; STEM-CELL FUNCTION; Endocrinology & Metabolism; HYDROGEN SULFIDE; Life Sciences & Biomedicine; OVARIECTOMY; INVOLUTIONAL OSTEOPOROSIS; OSTEOPOROSIS; BETA-SYNTHASE DEFICIENCY; OSTEOBLAST PROGENITORS; ANABOLIC ACTIVITY; RECEPTOR-ALPHA; PARATHYROID-HORMONE; Science & Technology; BONE LOSS; INTERMITTENT PTH
• Research Categories: Health Sciences, Obstetrics and Gynecology; Biology, Microbiology

Abstract

Hydrogen sulfide (H2S) is a gasotransmitter known to regulate bone formation and bone mass in unperturbed mice. However, it is presently unknown whether H2S plays a role in pathologic bone loss. Here we show that ovariectomy (ovx), a model of postmenopausal bone loss, decreases serum H2S levels and the bone marrow (BM) levels of two key H2S-generating enzymes, cystathione β-synthase (CBS) and cystathione γ-lyase (CSE). Treatment with the H2S-donor GYY4137 (GYY) normalizes serum H2S in ovx mice, increases bone formation, and completely prevents the loss of trabecular bone induced by ovx. Mechanistic studies revealed that GYY increases murine osteoblastogenesis by activating Wnt signaling through increased production of the Wnt ligands Wnt16, Wnt2b, Wnt6, and Wnt10b in the BM. Moreover, in vitro treatment with 17β-estradiol upregulates the expression of CBS and CSE in human BM stromal cells (hSCs), whereas an H2S-releasing drug induces osteogenic differentiation of hSCs. In summary, regulation of H2S levels is a novel mechanism by which estrogen stimulates osteoblastogenesis and bone formation in mice and human cells. Blunted production of H2S contributes to ovx-induced bone loss in mice by limiting the compensatory increase in bone formation elicited by ovx. Restoration of H2S levels is a potential novel therapeutic approach for postmenopausal osteoporosis.