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

Abstract

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.

Timing metabolism in cartilage and bone: links between circadian clocks and tissue homeostasis

“…Analysis of gene expression patterns in human cartilage revealed that circadian rhythm pathways were among the most disrupted in OA patients (Akagi et al 2017, Soul et al 2018. Several studies have also demonstrated that expression of BMAL1/BMAL1 is significantly reduced in human osteoarthritic cartilage (Dudek et al 2016, Snelling et al 2016, Yang et al 2016a, Akagi et al 2017. Knockdown of BMAL1 in human chondrocytes altered TGF-β signalling and was associated with increased expression of catabolic factors (e.g.…”

“…Knockdown of BMAL1 in human chondrocytes altered TGF-β signalling and was associated with increased expression of catabolic factors (e.g. MMP1, MMP3, MMP13 and ADAMTS5) (Snelling et al 2016, Yang et al 2016a, Akagi et al 2017, Khurana et al 2019.…”

The Nicotinamide Adenine Dinucleotide (NAD)-Dependent Deacetylase Sirtuin-1 Regulates Chondrocyte Energy Metabolism through the Modulation of Adenosine Monophosphate-Activated Protein Kinase (AMPK) in Osteoarthritis(OA)

“…We and other groups have already demonstrated that sirtuin-1 (Sirt-1) has a functional role and is a key regulator of many molecules in both catabolic and anabolic pathways in OA chondrocytes [18][19][20][21][22][23]. Sirt-1 has been reported to participate in stress responses by regulating cell death and cellular metabolism through the deacetylation of target proteins in chondrocytes [19,20,22].…”

“…Sirt-1 has been reported to participate in stress responses by regulating cell death and cellular metabolism through the deacetylation of target proteins in chondrocytes [19,20,22]. It has also been shown to promote the expression of cartilage-specific genes in chondrocytes [22,24,25].…”

“…Sirt-1 has been reported to participate in stress responses by regulating cell death and cellular metabolism through the deacetylation of target proteins in chondrocytes [19,20,22]. It has also been shown to promote the expression of cartilage-specific genes in chondrocytes [22,24,25]. In addition, it has been demonstrated that Sirt-1 inhibits chondrocyte apoptosis by suppressing protein tyrosine phosphatase 1B, caspases and mitochondria-related apoptotic signaling proteins or activating the insulin-like growth factor receptor pathway [26,27].…”