Date: Monday, November 6, 2017
Session Type: ACR Poster Session B
Session Time: 9:00AM-11:00AM
Background/Purpose: The anti-aging deacetylase enzymes SIRT1 and SIRT3 show potent anti-fibrotic activity, and their expression and function are markedly deregulated in patients with systemic sclerosis (SSc). SIRT activity is exquisitely regulated by cellular metabolism and requires the ubiquitous cofactor nicotinamide adenine dinucleotide (NAD+). Cellular NAD+ levels must be maintained by balanced biosynthesis and degradation, the latter mediated by NADase enzyme CD38. Elevated CD38 levels in aging contribute to decline of NAD+ levels, resulting in mitochondrial dysfunction and metabolic abnormalities. We hypothesize that SSc-associated SIRT dysfunction might be linked to elevated CD38 expression and NAD+ catabolism, contributing to persistent fibroblast activation and unresolving fibrosis.
Methods: CD38 expression was measured in skin biopsies. Expression and regulation of CD38, collagen, aSMA and p300, and Smad and SITR and FAK activation were examined in normal and SSc fibroblasts treated with CD38 inhibitors and nicotinamide riboside (NR), an orally bioavailable NAD+ precursor.
Results: SSc skin biopsies showed elevated CD38 mRNA expression. A CD38 coexpression module of 194 genes was able to differentiate SSc from control biopsies. Levels of CD38 in the skin correlated with MRSS. Moreover, explanted SSc skin fibroblasts showed 3-fold increased CD38 expression compared to age-matched healthy controls. Recombinant human CD38 caused suppression of SIRT deacetylase activity, while augmenting TGF-b-induced fibrotic responses. In contrast, CD38 inhibition or genetic ablation resulted in reduced fibrotic responses. Supplementation of fibroblasts with NR increased cellular NAD+level, and mitigated fibrotic responses induced by TGF-b. Moreover, NR supplementation markedly reduced Smad-dependent transcriptional activity via suppression of lysine acetylation mediated through coactivator p300. Modulation of age-dependent spontaneous and inducible fibrotic responses in mice by ablation of CD38 or NR supplementation, both of which augment NAD+ levels, is under investigation.
Conclusion: NAD+ levels appear to be critical in determing the amplitude/duration of tissue fibrosis through mechanisms that involve the SIRT deacetylases, and declining NAD+ plays a role in age-related tissue fibrosis. Elevated expression of the NAD+-consuming enzyme CD38 in lesional tissues in SSc is likely contributes to NAD+ depletion, impaired SIRT function and unchecked fibroblast activation in these patients. Boosting NAD+ levels using novel selective pharmacological CD38 inhibitors, NR supplementation, or augmented NAD+ biosynthesis via the salvage pathways, are promising novel approaches to the treatment of SSc.
To cite this abstract in AMA style:Shi B, Wang W, Wei J, Bhattacharyya S, Korman B, Chini E, Varga J. Metabolic Regulation of Fibrosis in Systemic Sclerosis: The CD38-NAD+ Link [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/metabolic-regulation-of-fibrosis-in-systemic-sclerosis-the-cd38-nad-link/. Accessed .
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/metabolic-regulation-of-fibrosis-in-systemic-sclerosis-the-cd38-nad-link/