期刊
JOURNAL OF BONE AND MINERAL RESEARCH
卷 31, 期 5, 页码 949-963出版社
WILEY
DOI: 10.1002/jbmr.2757
关键词
HYDROGEN SULFIDE; OSTEOPOROSIS; OVARIECTOMY; BONE LOSS; WNT SIGNALING
资金
- National Institutes of Health [DK91780, DK007298, RR028009, AR061453]
- Italian Ministry of Health [RF PE-2011-02348395]
- Spinner
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 beta-synthase (CBS) and cystathione gamma-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 17 beta-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. (C) 2015 American Society for Bone and Mineral Research.
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