TAK1 downregulation reduces IL-1β induced expression of MMP13, MMP1 and TNF-alpha

Klatt, Andreas R.; Klinger, Gabriele; Neumüller, Olga; Eidenmüller, Bernd; Wagner, Ingrid; Achenbach, Tatjana V.; Aigner, Thomas; Bartnik, Eckart

doi:10.1016/j.biopha.2005.08.007

Cited by 43 publications

(25 citation statements)

References 34 publications

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“…34 In the present study, we found the same in fetal hMSCs during early chondrogenic differentiation in OA-like circumstances. The involvement of both pathways, which are used by cytokines signaling via totally different receptors, indicates that multiple cytokines in OAS-CM jointly determine the expression of MMPs.…”

Section: Discussionsupporting

confidence: 69%

Inhibition of TAK1 and/or JAK Can Rescue Impaired Chondrogenic Differentiation of Human Mesenchymal Stem Cells in Osteoarthritis-Like Conditions

Beuningen

Melle

Vitters

et al. 2014

Tissue Engineering Part A

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Objective: To rescue chondrogenic differentiation of human mesenchymal stem cells (hMSCs) in osteoarthritic conditions by inhibition of protein kinases. Methods: hMSCs were cultured in pellets. During early chondrogenic differentiation, these were exposed to osteoarthritic synovium-conditioned medium (OAS-CM), combined with the Janus kinase ( JAK)-inhibitor tofacitinib and/or the transforming growth factor b-activated kinase 1 (TAK1)-inhibitor oxozeaenol. To evaluate effects on chondrogenesis, the glycosaminoglycan (GAG) content of the pellets was measured at the time that chondrogenesis was manifest in control cultures. Moreover, mRNA levels of matrix molecules and enzymes were measured during this process, using real-time polymerase chain reaction (RT-PCR). Initial experiments were performed with hMSCs from a fetal donor, and results of these studies were confirmed with hMSCs from adult donors. Results: Exposure to OAS-CM resulted in pellets with a much lower GAG content, reflecting inhibited chondrogenic differentiation. This was accompanied by decreased mRNA levels of aggrecan, type II collagen, and Sox9, and increased levels of matrix metalloproteinase (MMP)1, MMP3, MMP13, ADAMTS4, and ADAMTS5. Both tofacitinib ( JAK-inhibitor) and oxozeaenol (TAK1 inhibitor) significantly increased the GAG content of the pellets in osteoarthritis (OA)-like conditions. The combination of both protein kinase inhibitors showed an additive effect on GAG content. In agreement with this, in the presence of OAS-CM, both tofacitinib and oxozeaenol increased mRNA expression of sox9. The expression of aggrecan and type II collagen was also up-regulated, but this only reached significance for aggrecan after TAK1 inhibition. Both inhibitors decreased the mRNA levels of MMP1, 3, and 13 in the presence of OAS-CM. Moreover, oxozeaenol also significantly down-regulated the mRNA levels of aggrecanases ADAMTS4 and ADAMTS5. When combined, the inhibitors caused additive reduction of OA-induced MMP1 mRNA expression. Counteraction of OAS-CM-induced inhibition of chondrogenesis by these protein kinase inhibitors was confirmed with hMSCs of two different adult donors. Both tofacitinib and oxozeaenol significantly improved GAG content in cell pellets from these adult donors. Conclusions: Tofacitinib and oxozeaenol partially prevent the inhibition of chondrogenesis by factors secreted by OA synovium. Their effects are additive. This indicates that these protein kinase inhibitors can potentially be used to improve cartilage formation under the conditions occurring in osteoathritic, or otherwise inflamed, joints.

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Section: Discussionsupporting

confidence: 69%

Inhibition of TAK1 and/or JAK Can Rescue Impaired Chondrogenic Differentiation of Human Mesenchymal Stem Cells in Osteoarthritis-Like Conditions

Beuningen

Melle

Vitters

et al. 2014

Tissue Engineering Part A

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“…3) Many researches have also demonstrated that enzymatic cleavage by matrix metalloproteinases (MMPs) together with cytokines plays critical roles in the initiation and progression of cartilage destruction. 4,5) An imbalance between MMPs and tissue inhibitors of metalloproteinases (TIMPs) is an determinant of the extent of ECM turnover. 6) Hence, a therapeutic approach regulating the MMPs/TIMPs balance and apoptosis may be eŠective in the treatment of OA.…”

Section: Introductionmentioning

confidence: 99%

Protective Effect of Sinomenine on Cartilage Degradation and Chondrocytes Apoptosis

Deng

et al. 2010

YAKUGAKU ZASSHI

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Sinomenine (SIN), an alkaloid extracted from the stem of the Chinese medicinal plant sinomenium acutum, has been used for treating rheumatoid arthritis. But little is known whether SIN has a protective eŠect on osteoarthritis (OA). In this study, we investigated the protective eŠect of SIN on IL-1b-induced proteoglycan degradation and apoptosis in rabbit articular cartilage and chondrocytes. Treatment with 10 ng/ml IL-1b increased the level of glycosaminoglycan (GAG) released into the culture media, and up-regulated the activity and mRNA expression of matrix metalloproteinase 13 (MMP-13) and down-regulated the activity and mRNA expression of tissue inhibitor of metalloproteinase 1 (TIMP-1) in cartilage explants, as conˆrmed by the methods of GAG quantitation, MMP-13/TIMP-1 enzyme-linked immunosorbent assay (ELISA) and real-time quantitative RT-PCR. Treatment with 10 ng/ml IL-1b resulted in marked apoptosis in chondrocytes, as demonstrated by decreased cell viability, occurrence of DNA laddering and increased caspase-3 activity and annexin V binding of phosphatidylserine. However, simultaneous treatment with SIN (10, 50 or 250 mM) inhibited the GAG release and the activity and mRNA expression of MMP-13, and enhanced the activity and mRNA expression of TIMP-1 in a dose-dependent manner in cartilage explants. Furthermore, DNA fragment, caspase-3 activity and apoptosis rate were down-regulated, and cell viability was up-regulated dose-dependently in chondrocytes. Thus, SIN has the protective capacity to antagonize cartilage degradation and chondrocyte apoptosis, which suggest that SIN may act as an agent for pharmacological intervention in the progress of OA.

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“…Further downstream of adaptor proteins, TRAF6 could recruit TAK1 to phosphorylate IKK and activate NF-B. The major collagenolytic enzyme in arthritis, MMP-13, is also a known target of TAK1 (63). Thus, based on our results, we propose the following overlapping signaling pathways for ADAMTS-4 gene induction by IL-1␤.…”

Section: Discussionmentioning

confidence: 53%

Adaptor Proteins and Ras Synergistically Regulate IL-1-Induced ADAMTS-4 Expression in Human Chondrocytes

Ahmad

Sylvester

Ahmad

et al. 2009

The Journal of Immunology

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Aggrecanases (a dystrophin and metalloproteinase with thrombospondin motif, ADAMTSs) are principal proteases involved in cartilage extracellular matrix aggrecan degradation. The role and relative contribution of MyD88, IRAK1, and TRAF6 adaptor proteins in IL-1β regulation of aggrecanase-1 (ADAMTS-4) is unknown. By small interfering RNAs-mediated knockdown, we show that IL-1β-induced up-regulation of ADAMTS-4 in chondrocytes requires MyD88, IRAK1, and TRAF6 adaptor proteins. However, partial inhibition of ADAMTS-4 induction by their knockdown suggested the involvement of additional signaling proteins. Because IL-1β is also known to induce reactive oxygen species (ROS) through Ras-mediated activation of NADPH oxidase, we investigated the implication of Ras in ADAMTS-4 regulation. Ras knockdown, or inhibition of ROS by antioxidants along with the ablation of MyD88, IRAK1, or TRAF6 more potently down-regulated IL-1β-induced ADAMTS-4. In addition, IL-1β-induced phosphorylation of downstream effectors, IκB kinase αβ, IκBα, and activation of transcription factor NF-κB was significantly reduced in the MyD88-, IRAK1-, TRAF6-, or Ras-deficient cells. The combined knockdown of Ras and individual adaptor proteins strongly blocked the activation of IKKαβ, IκBα, and NF-κB. These findings suggest that Ras, ROS along with MyD88, IRAK1, or TRAF6 synergistically mediate ADAMTS-4 regulation by IL1-β. Thus, complete ablation of ADAMTS-4 induction could be achieved by combined inhibition of Ras and individual adaptor proteins, which may be of therapeutic value in arthritis.

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TAK1 downregulation reduces IL-1β induced expression of MMP13, MMP1 and TNF-alpha

Cited by 43 publications

References 34 publications

Inhibition of TAK1 and/or JAK Can Rescue Impaired Chondrogenic Differentiation of Human Mesenchymal Stem Cells in Osteoarthritis-Like Conditions

Inhibition of TAK1 and/or JAK Can Rescue Impaired Chondrogenic Differentiation of Human Mesenchymal Stem Cells in Osteoarthritis-Like Conditions

Protective Effect of Sinomenine on Cartilage Degradation and Chondrocytes Apoptosis

Adaptor Proteins and Ras Synergistically Regulate IL-1-Induced ADAMTS-4 Expression in Human Chondrocytes

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