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N-acetylcysteine (NAC) differentially affects arterial medial calcification and bone formation: the role of L-cysteine and hydrogen sulphide

Orriss, Isabel; Bourne, Lucie E; Patel, Jessal J; Davies, Bethan K; Neven, Ellen; Verhulst, Anja; D'Haese, Patrick C; PD Wheeler-Jones, Caroline; Orriss, Isabel R


Isabel Orriss

Lucie E Bourne

Jessal J Patel

Bethan K Davies

Ellen Neven

Anja Verhulst

Patrick C D'Haese

Caroline PD Wheeler-Jones

Isabel R Orriss


Isabel Orriss
Project Leader


Arterial medial calcification (AMC) is the deposition of calcium phosphate in the arteries. AMC is widely thought to share similarities with physiological bone formation; however, emerging evidence suggests several key differences between these processes. N-acetylcysteine (NAC) displays antioxidant properties and can generate hydrogen sulphide (H2S) and glutathione (GSH) from its deacetylation to l-cysteine. This study found that NAC exerts divergent effects in vitro, increasing osteoblast differentiation and bone formation by up to 5.5-fold but reducing vascular smooth muscle cell (VSMC) calcification and cell death by up to 80%. In vivo, NAC reduced AMC in a site-specific manner by 25% but had no effect on the bone. The actions of l-cysteine and H2S mimicked those of NAC; however, the effects of H2S were much less efficacious than NAC and l-cysteine. Pharmacological inhibition of H2S-generating enzymes did not alter the actions of NAC or l-cysteine; endogenous production of H2S was also unaffected. In contrast, NAC and l-cysteine increased GSH levels in calcifying VSMCs and osteoblasts by up to 3-fold. This suggests that the beneficial actions of NAC are likely to be mediated via the breakdown of l-cysteine and the subsequent GSH generation. Together, these data show that while the molecular mechanisms driving the actions of NAC appear similar, the downstream effects on cell function differ significantly between osteoblasts and calcifying VSMCs. The ability of NAC to exert these differential actions further supports the notion that there are differences between the development of pathological AMC and physiological bone formation. NAC could represent a therapeutic option for treating AMC without exerting negative effects on bone.


Orriss, I., Bourne, L. E., Patel, J. J., Davies, B. K., Neven, E., Verhulst, A., …Orriss, I. R. (in press). N-acetylcysteine (NAC) differentially affects arterial medial calcification and bone formation: the role of L-cysteine and hydrogen sulphide. Journal of Cellular Physiology,

Journal Article Type Article
Acceptance Date Sep 8, 2021
Deposit Date Feb 3, 2021
Publicly Available Date Oct 25, 2021
Print ISSN 0021-9541
Publisher Wiley
Peer Reviewed Peer Reviewed
Public URL


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