Chondrocyte AMP-activated protein kinase activity suppresses matrix degradation responses to proinflammatory cytokines interleukin-1β and tumor necrosis factor α

Abstract

Objective. Interleukin-1␤ (IL-1␤) and tumor necrosis factor ␣ (TNF␣) stimulate chondrocyte matrix catabolic responses, thereby compromising cartilage homeostasis in osteoarthritis (OA). AMP-activated protein kinase (AMPK), which regulates energy homeostasis and cellular metabolism, also exerts antiinflammatory effects in multiple tissues. This study was undertaken to test the hypothesis that AMPK activity limits chondrocyte matrix catabolic responses to IL-1␤ and TNF␣.Methods. Expression of AMPK subunits was examined, and AMPK␣ activity was ascertained by the phosphorylation status of AMPK␣ Thr 172 in human knee articular chondrocytes and cartilage by Western blotting and immunohistochemistry, respectively. Procatabolic responses to IL-1␤ and TNF␣, such as release of glycosaminoglycan, nitric oxide, and matrix metalloproteinases 3 and 13 were determined by dimethylmethylene blue assay, Griess reaction, and Western blotting, respectively, in cartilage explants and chondrocytes with and without knockdown of AMPK␣ by small interfering RNA.Results. Normal human knee articular chondrocytes expressed AMPK␣1, ␣2, ␤1, ␤2, and ␥1 subunits. Interleukin-1␤ (IL-1␤), tumor necrosis factor ␣ (TNF␣), and certain other proinflammatory cytokines stimulate chondrocyte responses that promote catabolism of type II collagen and proteoglycans (PGs), thereby compromising cartilage extracellular matrix integrity and tissue homeostasis in osteoarthritis (OA) and inflammatory arthritides (1,2). For example, IL-1␤ and TNF␣ induce expression of matrix metalloproteinase 3 (MMP-3) and MMP-13, induce activation of aggrecanases including ADAMTS-5, and stimulate inducible nitric oxide synthase expression and the generation of nitric oxide (NO), a suppressor of PG synthesis (1-3).Recently, the serine/threonine protein kinase AMP-activated protein kinase (AMPK) was observed to exert antiinflammatory effects in tissues other than cartilage, mediated in part by suppression of NF-B activation (4-10). AMPK is a "super-regulator" of

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)

“…In the present study, our data reveal that the OA-related catabolic factor IL-1β inhibits both activity of AMPK and ATP production in OA chondrocytes, suggesting that energy metabolism in chondrocytes is downregulated by OA-related factors during the progression of articular cartilage degeneration. Indeed, previous reports demonstrated that the activity of AMPK is decreased in chondrocytes in aged human and mouse OA cartilage [38,39]. Our findings of the downregulation of the AMPK ATP energy metabolic pathway in OA chondrocytes are consistent with their findings.…”

AMPK activation—protean potential for boosting healthspan

“…Oxidative stress, NF-kappaB activation, and iNOS induction are key mediators of these effects (Lo et al 1998;Grange et al 2006;Ahmad et al 2011;Pelletier et al 1998Pelletier et al , 1999. It is reasonable to suspect that AMPK might act to oppose these effects, and indeed, a recent study has found that AMPK activators notably suppress the catabolic response of chondrocytes to IL-1 or TNF-α exposure; notably, chondrocyte production of MMP-3, MMP-13, and NO was suppressed (Terkeltaub et al 2011). Conversely, knockout of AMPKa with small interfering RNA exacerbated the catabolic response of chondrocytes to IL-1 and TNF-α.…”

The Effects of Aging on the Development of Osteoarthritis

“…The altered response to TGF-β appears to occur at the receptor level due to changes in the ratio of ALK1 to ALK5 promoting more catabolic relative to anabolic activity [1,14], and for IGF-1, an altered balance of MAP kinase and Akt signaling due to ROS may be playing a role [15]. Other findings on OA chondrocytes that also might be linked to aging include reduced levels of Sirt1, a potential positive regulator of cartilage matrix gene expression [4,6], and a decline in AMPK activity, which could also promote a pro-catabolic state [13].…”