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

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.

Cystathionine γ-Lyase–Hydrogen Sulfide Induces Runt-Related Transcription Factor 2 Sulfhydration, Thereby Increasing Osteoblast Activity to Promote Bone Fracture Healing

“…Wnt5a and Wnt10b are critical in osteoblast differentiation (2,17). Treatment with the H2S donor GYY4137 increased the mRNA expression of bone marrow Wnt10b and other Wnt family genes (12), which explains, in part, the effect of endogenous CSE-H2S on osteoblast differentiation.…”

“…As well, H2S decreases matrix metalloproteinase activity in bone matrix (34), thereby accelerating matrix mineralization. Finally, H2S promotes bone MSC mineralization by Wnt signals (12) and reduces MC3T3-E1 preosteoblast cell injury induced by H2O2 (39). CBS deficiency lowers MSC osteogenesis ability, which can be rescued by an H2S donor (26).…”

“…Recent studies reported that H2S promotes bone fracture healing in rabbit (15) and attenuates bone loss induced by estrogen deficiency (12); however, the mechanism is unclear. H2S decreases osteoclast differentiation induced by nicotine or lipopolysaccharide (23) and osteoclast progenitor differentiation (11), which decreases necrotic bone absorption during bone healing, but benefits osteoporosis.…”

“…Overexpressed CSE increased endogenous H2S production, and then increased Wnt expression (12), sulfhydrated TRPV6, and promoted MSC differentiation into preosteoblasts (26); sulfhydrated RUNX2 at the runt domain thereby increased its transcription, consequently enhancing the expression of RUNX2 target genes OCN (8), collagen aI, BSP, and OPN (9) to promote osteoblast extracellular matrix secretion and mineralization. H2S also increased BMP2 expression, an important molecule to induce osteoblast differentiation and biological function (1), but the molecular mechanism needs to be investigated.…”

Hydrogen Sulfide Regulates Homeostasis of Mesenchymal Stem Cells and Regulatory T Cells

“…H 2 S activates the Wnt signaling of BMMSCs through increased production of the Wnt ligands Wnt16, Wnt2b, Wnt6, and Wnt10b in the bone marrow. These studies imply that restoration of H 2 S levels is a potential novel therapeutic approach for postmenopausal osteoporosis (Grassi et al 2015).…”