Nicotinamide Phosphoribosyltransferase Is Essential for Interleukin-1β-mediated Dedifferentiation of Articular Chondrocytes via SIRT1 and Extracellular Signal-regulated Kinase (ERK) Complex Signaling

Abstract

Although much is known about interleukin (IL)-1␤ and its role as a key mediator of cartilage destruction in osteoarthritis, only limited information is available on IL-1␤ signaling in chondrocyte dedifferentiation. Here, we have characterized the molecular mechanisms leading to the dedifferentiation of primary cultured articular chondrocytes by IL-1␤ treatment. IL-1␤ or lipopolysaccharide, but not phorbol 12-myristate 13-acetate, retinoic acid, or epidermal growth factor, induced nicotinamide phosphoribosyltransferase (NAMPT) expression, showing the association of inflammatory cytokines with NAMPT regulation. SIRT1, in turn, was activated NAMPT-dependently, without any alteration in the expression level. Activation or inhibition of SIRT1 oppositevely regulates IL-1␤-mediated chondrocyte dedifferentiation, suggesting this protein as a key regulator of chondrocytes phenotype. SIRT1 activation promotes induction of ERK and p38 kinase activities, but not JNK, in response to IL-1␤. Subsequently, ERK and p38 kinase activated by SIRT1 also induce SIRT1 activation, forming a positive feedback loop to sustain downstream signaling of these kinases. Moreover, we found that the SIRT1-ERK complex, but not SIRT1-p38, is engaged in IL-1␤-induced chondrocyte dedifferentiation via a Sox-9-mediated mechanism. JNK is activated by IL-1␤ and modulates dedifferentiation of chondrocytes, but this pathway is independent on NAMPT-SIRT1 signaling. Based on these findings, we propose that IL-1␤ induces dedifferentiation of articular chondrocytes by up-regulation of SIRT1 activity enhanced by both NAMPT and ERK signaling.

Cyclic AMP Signaling Reduces Sirtuin 6 Expression in Non-small Cell Lung Cancer Cells by Promoting Ubiquitin-Proteasomal Degradation via Inhibition of the Raf-MEK-ERK (Raf/Mitogen-activated Extracellular Signal-regulated Kinase/Extracellular Signal-regulated Kinase) Pathway

“…These results agree with those published in previous reports showing that cAMP increases inhibitory Raf-1 phosphorylation at Ser-259 and reduces activating Raf-1 phosphorylation at Ser-338 in a PKA-dependent manner, thereby inducing ERK deactivation (33,34). ERK activates SIRT1 in chondrocytes (35) and induces SIRT1 expression in human endothelial cells (36); however, the effect of ERK on SIRT6 remains unknown. The present study showed that inhibiting the Raf-MEK-ERK pathway also reduces SIRT6 expression in lung cancer cells.…”

Visfatin: a new player in rheumatic diseases

“…In agreement, recent studies with porcine cartilage explants have revealed that visfatin stimulation increases MMP activity, nitric oxide production, and PG release [46]. Consistent with all these reports is the observation that stimulation of rabbit chondrocytes with IL-1β or LPS increased visfatin expression [47]. In the same study, visfatin inhibition restored the phenotype of IL-1β-mediated dedifferentiated chondrocytes.…”

“…In the same study, visfatin inhibition restored the phenotype of IL-1β-mediated dedifferentiated chondrocytes. Confirming previous work [42], the authors also showed that visfatin was able to enhance SirT1 activity [47], in turn enhancing visfatin expression and thus creating a positive feedback loop [47]. The consequence of this increased expression of visfatin and SIRT1 activation was a lowering of Sox-9 and Type II collagen expression, factors essential for the maintenance of the chondrocyte phenotype [47].…”

The role of adipocytokines in the pathogenesis of knee joint osteoarthritis

“…Yammani and Loeser [62] demonstrated that, in human cartilage, visfatin inhibited IGF-1 and led to IGF-1-mediated proteoglycan synthesis. Moreover, Hong et al [63] suggested that visfatin could alter the expression, of chondrogenic factors such as the sex-determining region Ybox 9 (SOX-9) and type II collagen. In OA patients visfatin SF level positively correlated with the degradation markers of collagen, (CTX-II) and aggrecans (AGG1, AGG2) [64].…”