IKKβ inhibition protects against bone and cartilage destruction in a rat model of rheumatoid arthritis

Schopf, Lisa; Savinainen, Anneli; Anderson, Karen S.; Kujawa, Julie; DuPont, Michelle M.; Silva, Matthew J.; Siebert, Elizabeth; Chandra, Sudeep; Morgan, Jennifer G.; Gangurde, Pranoti; Wen, Danyi; Lane, Joan H.; Xu, Yajun; Hepperle, Michael; Harriman, Geraldine; Ocain, Timothy D.; Jaffee, Bruce

doi:10.1002/art.22081

Cited by 75 publications

(56 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…NF-B-DNA binding was significantly greater in human RA tissue compared with that from patients with osteoarthritis, and moreover, was localized to the sites of maximum tissue destruction (17). Increased NF-B-DNA binding activity has been demonstrated in synovial extracts from rats and mice following disease development (18,19). The inhibition of NF-B binding after IKK-2 inhibitor treatment has also been demonstrated in the mouse collagen-induced arthritis model (19) and the rat adjuvant-induced arthritis model (18).…”

Section: Discussionmentioning

confidence: 99%

“…Increased NF-B-DNA binding activity has been demonstrated in synovial extracts from rats and mice following disease development (18,19). The inhibition of NF-B binding after IKK-2 inhibitor treatment has also been demonstrated in the mouse collagen-induced arthritis model (19) and the rat adjuvant-induced arthritis model (18). In vivo imaging enabled us to visualize and quantify target activity in the inflamed joints of mice.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Use of molecular imaging to quantify response to IKK‐2 inhibitor treatment in murine arthritis

Izmailova¹,

Paz²,

Alencar³

et al. 2007

Arthritis & Rheumatism

Self Cite

View full text Add to dashboard Cite

Objective. The NF-B signaling pathway promotes the immune response in rheumatoid arthritis (RA) and in rodent models of RA. NF-B activity is regulated by the IKK-2 kinase during inflammatory responses. To elucidate how IKK-2 inhibition suppresses disease development, we used a combination of in vivo imaging, transcription profiling, and histopathology technologies to study mice with antibodyinduced arthritis.Methods. ML120B, a potent, small molecule inhibitor of IKK-2, was administered to arthritic animals, and disease activity was monitored. NF-B activity in diseased joints was quantified by in vivo imaging. Quantitative reverse transcriptase-polymerase chain reaction was used to evaluate gene expression in joints. Protease-activated near-infrared fluorescence (NIRF) in vivo imaging was applied to assess the amounts of active proteases in the joints.Results. Oral administration of ML120B suppressed both clinical and histopathologic manifestations of disease. In vivo imaging demonstrated that NF-B activity in inflamed arthritic paws was inhibited by ML120B, resulting in significant suppression of multiple genes in the NF-B pathway, i.e., KC, epithelial neutrophil-activating peptide 78, JE, intercellular adhesion molecule 1, CD3, CD68, tumor necrosis factor ␣, interleukin-1␤, interleukin-6, inducible nitric oxide synthase, cyclooxygenase 2, matrix metalloproteinase 3, cathepsin B, and cathepsin K. NIRF in vivo imaging demonstrated that ML120B treatment dramatically reduced the amount of active proteases in the joints.Conclusion. Our data demonstrate that IKK-2 inhibition in the murine model of antibody-induced arthritis suppresses both inflammation and joint destruction. In addition, this study highlights how gene expression profiling can facilitate the identification of surrogate biomarkers of disease activity and treatment response in an experimental model of arthritis.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Use of molecular imaging to quantify response to IKK‐2 inhibitor treatment in murine arthritis

Izmailova¹,

Paz²,

Alencar³

et al. 2007

Arthritis & Rheumatism

Self Cite

View full text Add to dashboard Cite

show abstract

“…Recently, there has been a substantial effort to develop drugs and gene therapy approaches targeted at inhibiting NF-B or IKK in order to prevent cartilage and bone destruction in arthritis (14,(19)(20)(21). Notably, appropriate biomechanical signals can inhibit both NF-B and IKK␤, suggesting that these signals can be used as an effective therapeutic intervention, without side effects, to suppress joint inflammation in arthritic diseases.…”

mentioning

confidence: 99%

“…Notably, appropriate biomechanical signals can inhibit both NF-B and IKK␤, suggesting that these signals can be used as an effective therapeutic intervention, without side effects, to suppress joint inflammation in arthritic diseases. Furthermore, these signals, while functioning as antiinflammatory cues, also act as powerful inducers of genes that contribute to cartilage repair and matrix synthesis (19,20). Hence, understanding the mechanisms of the intracellular actions by which biomechanical signals attenuate NF-B-induced proinflammatory gene transcription to limit cartilage destruction is of critical importance.…”

mentioning

confidence: 99%

Biomechanical signals inhibit IKK activity to attenuate NF‐κB transcription activity in inflamed chondrocytes

Dossumbekova¹,

Anghelina²,

Madhavan³

et al. 2007

Arthritis & Rheumatism

View full text Add to dashboard Cite

Objective. While the effects of biomechanical signals in the form of joint movement and exercise are known to be beneficial to inflamed joints, limited information is available regarding the intracellular mechanisms of their actions. This study was undertaken to examine the intracellular mechanisms by which biomechanical signals suppress proinflammatory gene induction by the interleukin-1-␤ (IL-1␤)-induced NF-B signaling cascade in articular chondrocytes.Methods. Primary rat articular chondrocytes were exposed to biomechanical signals in the form of cyclic tensile strain, and the effects on the NF-B signaling cascade were examined by Western blot analysis, real-time polymerase chain reaction, and immunofluorescence.Results. Cyclic tensile strain rapidly inhibited the IL-1␤-induced nuclear translocation of NF-B, but not its IL-1␤-induced phosphorylation at serine 276 and serine 536, which are necessary for its transactivation and transcriptional efficacy, respectively. Examination of upstream events revealed that cyclic tensile strain also inhibited the cytoplasmic protein degradation of IB␤ and IB␣, as well as repressed their gene transcription. Additionally, cyclic tensile strain induced a rapid nuclear translocation of IB␣ to potentially prevent NF-B binding to DNA. Furthermore, the inhibition of IL-1␤-induced degradation of IB by cyclic tensile strain was mediated by down-regulation of IB kinase activity.Conclusion. These results indicate that the signals generated by cyclic tensile strain act at multiple sites within the NF-B signaling cascade to inhibit IL-1␤-induced proinflammatory gene induction. Taken together, these findings provide insight into how biomechanical signals regulate and reduce inflammation, and underscore their potential in enhancing the ability of chondrocytes to curb inflammation in diseased joints.

show abstract

“…As for Micro-computer tomography (CT) assay, legs were excised from the surrounding soft tissues and fixed in formalin. Micro-CT was performed as previous described (26).…”

Section: Histological and Radiographic Analysismentioning

confidence: 99%

Target Identification and Validation of (+)-2-(1-Hydroxyl-4-Oxocyclohexyl) Ethyl Caffeate, an Anti-Inflammatory Natural Product

Zeng

Liu

et al. 2012

Eur J Inflamm

View full text Add to dashboard Cite

The first two authors contributed equally to this work (+)-2-(1-hydroxyl-4-oxocyclohexyl) ethyl caffeate (HOEC) was isolated from Incarvillea matret var. granditlora (Wehrhahn) Grierson. The plants of the Incarvillea genus have long been used as folk medicines for the treatment of inflammation-related diseases in China. 5-Lipoxygenase (5-LOX), a key enzyme in the arachidonic acid (AA) cascade, was identified as a potential target of HOEC by a pulldown assay, and then extensively validated by biosensor-based affinity detection, enzyme-based activity assays, cell-based AA metabolite analysis and computer-aided AA network simulation. Further in vivo studies of AA-induced ear oedema, ovalbumin (OVA)-induced lung inflammation and collagen-induced arthritis demonstrated the anti-inflammatory potency and validated the therapeutic target of HOEC. This work revealed that HOEC acted as an anti-inflammatory agent targeting 5-LOX, which not only confirmed the key role of 5-LOX in inflammation but also provided a paradigm for the exploration of natural product mechanisms of action.Identification and validation of disease-relevant targets is an essential step in drug discovery. Although substantial improvement has been made in past decades, target identification is labour-intensive, time-consuming, and can be difficult and highrisk work (1, 2). Ever-emerging new techniques, including' omic' techniques, biosensor-based assays, computer-aided molecular docking and network analysis, speed up the process of target discovery and mechanism elucidation (3, 4). However, the

show abstract

IKKβ inhibition protects against bone and cartilage destruction in a rat model of rheumatoid arthritis

Cited by 75 publications

References 48 publications

Use of molecular imaging to quantify response to IKK‐2 inhibitor treatment in murine arthritis

Use of molecular imaging to quantify response to IKK‐2 inhibitor treatment in murine arthritis

Biomechanical signals inhibit IKK activity to attenuate NF‐κB transcription activity in inflamed chondrocytes

Target Identification and Validation of (+)-2-(1-Hydroxyl-4-Oxocyclohexyl) Ethyl Caffeate, an Anti-Inflammatory Natural Product

Contact Info

Product

Resources

About