Cross-talk of MicroRNA and hydrogen sulfide: A novel therapeutic approach for bone diseases

Abstract

Bone homeostasis requires a balance between the bone formation of osteoblasts and bone resorption of osteoclasts to maintain ideal bone mass and bone quality. An imbalance in bone remodeling processes results in bone metabolic disorders such as osteoporosis. Hydrogen sulfide (H₂S), a gasotransmitter, has attracted the focus of many researchers due to its multiple physiological functions. It has been implicated in anti-inflammatory, vasodilatory, angiogenic, cytoprotective, anti-oxidative and anti-apoptotic mechanisms. H₂S has also been shown to exert osteoprotective activity through its anti-inflammatory and anti-oxidative effects. However, the underlying molecular mechanisms by which H₂S mitigates bone diseases are not completely understood. Experimental evidence suggests that H₂S may regulate signaling pathways by directly influencing a gene in the cascade or interacting with some other gasotransmitter (carbon monoxide or nitric oxide) or both. MicroRNAs (miRNAs) are short non-coding RNAs which regulate gene expression by targeting, binding and suppressing mRNAs; thus controlling cell fate. Certainly, bone remodeling is also regulated by miRNAs expression and has been reported in many studies. MicroRNAs also regulate H₂S biosynthesis. The inter-regulation of microRNAs and H₂S opens a new possibility for exploring the H₂S-microRNA crosstalk in bone diseases. However, the relationship between miRNAs, bone development, and H₂S is still not well explained. This review focuses on miRNAs and their roles in regulating bone remodeling and possible mechanisms behind H₂S mediated bone loss inhibition, H₂S-miRNAs crosstalk in relation to the pathophysiology of bone remodeling, and future perspectives for miRNA-H₂S as a therapeutic agent for bone diseases.

Keywords: Bone remodeling; Hydrogen sulfide; Osteoblast; Osteoclast; Osteoporosis.

Fig. 1

The biogenesis of miRNAs. Pri-miRNAs are transcribed from intergenic genes and processed into a pre-miRNA by the Drosha/DGCR8 complex, creating a 70–80 nts, hairpin-looped molecule, which is then shuttled out of the nucleus via the exportin-5 mediated transportation. Cytoplasmatic digestion of the pre-miRNA is facilitated by Dicer, resulting in double-stranded mature miRNAs. Mature miRNAs modulate gene expression by RNA-induced silencing complex (RISC) which composed by the dicer, argonaute 2, and TRBP. If miRNAs perfectly base pairing with sequences in the target mRNAs, mRNA will deadenylation and decapping and then cleavage; alternatively, miRNAs could repressing the transcription of target mRNAs when the miRNAs incomplete matching with target mRNAs.

Fig. 2

miRNAs regulate the key signal molecules during the osteoblast differentiation and osteoclastogenesis. PPARγ: peroxisome proliferator-activated receptor gamma; Dlx5: distal-less homeobox 5; BMPs: bone morphogenetic proteins; M-CSF: macrophage-colony stimulating factor; RANKL: receptor activator of NF-κB ligand.

Fig. 3

Sulfide metabolism and transsulfuration pathways. Cystathionine β (CBS) and cystathionine γ-lyase (CSE) govern the flow of sulfur through homocysteine, cystathionine, and cysteine for the generating H₂S in the cytosol. While the third way for H₂S production via cysteine aminotransferase (CAT) and 3-mercaptopyruvate sulfurtransferase (3-MST). sulfide quinone oxidoreductase (SQOR) oxidizes H₂S to glutathione persulfide (GSSH) with GSH as the electron acceptor or directly to thiosulfate (SO₃²⁻) using co-enzyme Q (Co-Q) as the electron acceptor. Both the production and oxidation of H₂S were processed in the mitochondrion.

Fig. 4

Physiological functions of H₂S. Including anti-inflammatory, cytoprotective, anti-oxidative, anti-apoptosis, ATP generation, vasodilatation, and osteoprotective effects, even about crosstalk of miRNAs and H₂S. During its osteoprotective processing, H₂S stimulate the osteogenic differentiation markers (ALP, BGP, osteopontin) but inhibit osteoblast apoptosis, whereas, H₂S could promote apoptosis of osteoclast, and inhibit osteoclast differentiation and maturation.