Reactive sulfur and selenium species in the regulation of bone homeostasis

Abstract

Reactive oxygen species (ROS) are important modulators of physiological signaling and play important roles in bone tissue regulation. Both reactive sulfur species (RSS) and reactive selenium species (RSeS) are involved in ROS signaling, and recent work suggests RSS and RSeS involvement in the regulation of bone homeostasis. For example, RSS can promote osteogenic differentiation and decrease osteoclast activity and differentiation, and the antioxidant activity of RSeS play crucial roles in balancing bone remodeling. Here, we outline current research progress on the application of RSS and RSeS in bone disease and regeneration. Focusing on these investigations, we highlight different methods, tools, and sources of RSS and RSeS, and we also highlight future opportunities for delivery of RSS and RSeS in biological environments relating to bone.

Figure 1.

(a) Simplified metabolic pathways of selenium-containing compounds. (b) Selenium contribution to glutathione peroxidase function. (c) Selenium and sulfur interplay in the regulation of the thioredoxin system.

Figure 2.

H₂S and selenoprotein regulation of osteoclast and osteoblasts in a trabecular bone remodeling cavity. H₂S activates Ca²⁺ channels to increase osteoblast production. Both H₂S and selenoproteins protect hMSCs and osteoblasts against oxidative stress and decrease osteoclast generation and activity through ROS-dependent pathways. Estrogen levels have been associated with both H₂S and selenium levels, suggesting that RSS and RSeS may be important in pathways associated with estrogen-mediated regulation of bone.

Figure 3.

The transsulfuration pathway. Metabolites: SAM – S-adenosylmethionine, SAH – S-adenosylhomocysteine, CysSA – cysteine sulfinic acid, γ-GCys – γ-glutamylcysteine, 3-MP – 3-mercaptopyruvate. Enzymes: BHMT – betaine homocysteine S-methyltransferase, MTR – methionine synthase, CDO – cysteine dioxygenase, CSD – cysteine sulfinate decarboxylase, HTUDH – hypotaurine dehydrogenase, GCS – γ-glutamylcysteine synthetase, GSS – glutathione synthetase, CAT – cysteine aminotransferase.

Figure 4.

Potential therapeutic roles of H₂S throughout the four stages of the bone healing process highlighting selenoprotein modulation of oxidative stress.