NAMPT (visfatin), a direct target of hypoxia-inducible factor-2α, is an essential catabolic regulator of osteoarthritis

Abstract

ObjectiveHypoxia-inducible factor 2α (HIF-2α), encoded by Epas1, causes osteoarthritic cartilage destruction by regulating the expression of matrix-degrading enzymes. We undertook this study to explore the role of nicotinamide phosphoribosyltransferase (NAMPT or visfatin) in HIF-2α-mediated osteoarthritic cartilage destruction.MethodsThe expression of HIF-2α, NAMPT and matrix-degrading enzymes was determined at the mRNA and protein levels in human osteoarthritis (OA) cartilage, mouse experimental OA cartilage and primary cultured mouse chondrocytes. Experimental OA in mice was induced by destabilisation of the medial meniscus (DMM) surgery or intra-articular injection of Ad-Epas1 or Ad-Nampt in wild-type, Epas1+/−, Epas1fl/fl;Col2a1-Cre and Col2a1-Nampt transgenic (TG) mice. Primary cultured mouse chondrocytes were treated with recombinant NAMPT protein or were infected with adenoviruses.ResultsWe found that the Nampt gene is a direct target of HIF-2α in articular chondrocytes and OA cartilage. NAMPT protein, in turn, increased mRNA levels and activities of MMP3, MMP12 and MMP13 in chondrocytes, an action that was necessary for HIF-2α-induced expression of catabolic enzymes. Gain-of-function studies (intra-articular injection of Ad-Nampt; Col2a1-Nampt TG mice) and loss-of-function studies (intra-articular injection of the NAMPT inhibitor FK866) demonstrated that NAMPT is an essential catabolic regulator of osteoarthritic cartilage destruction caused by HIF-2α or DMM surgery.ConclusionsOur findings indicate that NAMPT, whose corresponding gene is a direct target of HIF-2α, plays an essential catabolic role in OA pathogenesis and acts as a crucial mediator of osteoarthritic cartilage destruction caused by HIF-2α or DMM surgery.

The Role of Sirtuins in Cartilage Homeostasis and Osteoarthritis

“…Given that NAMPT is the rate-limiting enzyme of this process, its activity within the cell could affect the activity of many NAD + -dependent sirtuins (SIRT1, 2, 3, 5, 6, 7). Recent data showed that HIF-2α induces NAMPT expression, which in turn exerts a catabolic effect in cartilage by [50,51]. These observations oppose previous data showing that NAMPT has a positive anabolic effect by activating SIRT1 [8].…”

“…This discrepancy could be explained by the fact that NAMPT is also secreted by OA chondrocytes (i.e., eNAMPT), and may not only act intracellularly, but may also possess endocrine activity [52•, 53], and as such is often referred to as pre-B cell colony-enhancing factor (PBEF) or visfatin. In fact, inhibiting NAMPT shows protective effects in reducing pro-inflammatory gene expression in mice models [50,53]. Moreover, Pecchi has revealed that extracellular NAMPT stimulates NGF secretion and neuropathic pain in OA [54].…”

“…Hence, active HIF2α may contribute to enhanced NAMPT expression and thereby enhance Sirt2 and Sirt4, which correlate reciprocally with HIF2α stability and activity [50,51].…”

Pleiotropic roles of metallothioneins as regulators of chondrocyte apoptosis and catabolic and anabolic pathways during osteoarthritis pathogenesis

“…Human OA cartilage was sourced from individuals undergoing arthroplasty, as described previously 18 19. Mice were maintained under pathogen-free conditions, and all experiments involving mice were approved by the Gwangju Institute of Science and Technology Animal Care and Use Committee.…”

Arthrose : des grandes avancées physiopathologiques aux perspectives thérapeutiques

“…Également exprimée par les chondrocytes, elle induit un phénotype pro-inflammatoire des chondrocytes et des ostéoblastes de l'os sous-chondral [15]. Ainsi, des stratégies anti-visfatine pourraient être envisagées avec une publication montrant un effet protecteur d'un anti-visfatine dans un modèle d'arthrose chez la souris [16]. Enfin, l'adiponectine, qui a des propriétés antiinflammatoires sur les vaisseaux et cellules endothéliales, peut aussi avoir une action pro-inflammatoire sur le cartilage.…”