Clock Gene Bmal1 Modulates Human Cartilage Gene Expression by Crosstalk With Sirt1

Jun 3, 2016Endocrinology

The Body Clock Gene Bmal1 Influences Human Cartilage Genes by Interacting With Sirt1

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Abstract

In osteoarthritis cartilage, the levels of both Bmal1 and NAD(+) decreased significantly.

The critical circadian gene Bmal1 is implicated in the regulation of cartilage homeostasis.
Decreased Bmal1 and NAD(+) levels are associated with inhibited activity of nicotinamide phosphoribosyltransferase and reduced Sirt1 expression.
Knocking down Bmal1 leads to increased osteoarthritis-like gene expression changes when stimulated by IL-1β.
Overexpressing Bmal1 can counteract the effects of IL-1β, indicating its potential role in cartilage health.
Decreasing Sirt1 levels not only reduces Bmal1 expression but also exacerbates cell survival and increases cartilage-degrading enzyme expression.

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The critical regulation of the peripheral circadian gene implicated in osteoarthritis (OA) has been recently recognized; however, the causative role and clinical potential of the peripheral circadian rhythm attributable to such effects remain elusive. The purpose of this study was to elucidate the role of a circadian gene Bmal1 in human cartilage and pathophysiology of osteoarthritis. In our present study, the mRNA and protein levels of circadian rhythm genes, including nicotinamide adenine dinucleotide oxidase (NAD(+)) and sirtuin 1 (Sirt1), in human knee articular cartilage were determined. In OA cartilage, the levels of both Bmal1 and NAD(+) decreased significantly, which resulted in the inhibition of nicotinamide phosphoribosyltransferase activity and Sirt1 expression. Furthermore, the knockdown of Bmal1 was sufficient to decrease the level of NAD(+) and aggravate OA-like gene expression changes under the stimulation of IL-1β. The overexpression of Bmal1 relieved the alteration induced by IL-1β, which was consistent with the effect of the inhibition of Rev-Erbα (known as NR1D1, nuclear receptor subfamily 1, group D). On the other hand, the transfection of Sirt1 small interfering RNA not only resulted in a reduction of the protein expression of Bmal1 and a moderate increase of period 2 (per2) and Rev-Erbα but also further exacerbated the survival of cells and the expression of cartilage matrix-degrading enzymes induced by IL-1β. Overexpression of Sirt1 restored the metabolic imbalance of chondrocytes caused by IL-1β. These observations suggest that Bmal1 is a key clock gene to involve in cartilage homeostasis mediated through sirt1 and that manipulating circadian rhythm gene expression implicates an innovative strategy to develop novel therapeutic agents against cartilage diseases.

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Clock Gene Bmal1 Modulates Human Cartilage Gene Expression by Crosstalk With Sirt1

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