Hydrogen sulfide (H2S), a gaseous signaling molecule produced by cystathionine gamma-lyase (CSE) and cystathionine beta-synthase (CBS), influences bone remodeling in many ways. Osteoclasts play an important role in bone remodeling during tooth movement induced by mechanical loading, which increases the rate of tooth movement. Recently, we found that osteoclasts could produce H2S. However, whether H2S modulates bone remodeling by affecting osteoclasts remains unclear. In this study, we found that CSE-H2S was a dominant H2S generating system in osteoclasts, while CBS did not generate H2S. A significant increase in CSE mRNA expression and H2S production was observed in periodontal ligament (PDL) tissues of wild-type (WT) mice after 3 days of mechanical loading. CSE gene knockout led to a significant reduction in the number of maxillary osteoclasts and in the amount of tooth movement. The number of RANKL-induced TRAP-positive osteoclasts and the mRNA expression of osteoclast markers were downregulated after 6 days of incubation in monocytes extracted from CSE-/- mice. The expression of IL 1, IL-6 and TNE-alpha, which can stimulate osteoclastogenesis in periodontal tissue and serum samples, was lower in CSE-/- mice after mechanical loading. Application of the H2S donor GYY4137 increased the number of RANKL-induced osteoclasts, the number of osteoclasts in periodontal tissues and tooth movement distance in CSE-/- mice. The results suggested that endogenous H2S and CSE play vital roles in the osteoclastogenesis and alveolar bone resorption induced by mechanical loading. (C) 2018 Elsevier Inc. All rights reserved.