Matrix Metalloproteinase-9 Production by Immortalized Human Chondrocyte Lines

Malemud, Charles J.; Meszaros, Evan; Wylie, Meredith A; Dahoud, Wissam; Skomorovska-Prokvolit, Yelenna; Mesiano, Sam

doi:10.4172/2155-9899.1000422

Cited by 8 publications

(6 citation statements)

References 22 publications

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“…However, the combination of rhIL-6 and TCZ also inhibited NGAL production by C28/I2 human chondrocytes. Taken together with other data [ 102 ], we suggested that endogenous sIL-6R could potentially be manipulated so that it would behave as an inhibitor of NGAL production. This advance could limit the potential deleterious effects of MMP-9 on articular cartilage degradation in RA and OA.…”

Section: A Role For the Adams In Oa?supporting

confidence: 79%

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A Role for Soluble IL-6 Receptor in Osteoarthritis

Akeson

Malemud

2017

JFMK

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Interleukin-6 (IL-6) is one of several pro-inflammatory cytokines present at elevated levels in the synovial fluid of individuals with confirmed clinical diagnosis of rheumatoid arthritis (RA) and osteoarthritis (OA). The mechanism of action of IL-6 was shown to involve its capacity to interact with a membrane-bound IL-6 receptor (mIL-6Rα), also known as the “classical” IL-6 pathway, or through its interaction with a soluble IL-6 receptor (sIL-6R) termed the “trans-signaling” pathway. Activation of downstream signaling is transduced via these IL-6 receptors and principally involves the Janus Kinase/Signal Transduction and Activators of Transcription (JAK/STAT) signaling pathway that is further regulated by glycoprotein-130 (gp130) interacting with the IL-6/mIL-6R complex. Phosphorylation of STAT proteins via JAK activation facilitates STAT proteins to act as transcription factors in inflammation. However, the biological function(s) of the sIL-6R in human chondrocytes requires further elucidation, although we previously showed that exogenous sIL-6R significantly suppressed the synthesis of neutrophil gelatinase-associated lipocalin (NGAL) in the immortalized line of human chondrocytes, C28/I2. NGAL was shown to regulate the activity of matrix metalloproteinase-9 (MMP-9), whose activity is crucial in OA for the destruction of articular cartilage. The “shedding” of sIL-6R from the plasma membrane is carried out by a family of enzymes known as A Distintegrin and Metalloproteinase (ADAM), which are also elevated in OA. In this paper, we have systematically reviewed the role played by IL-6 in OA. We have proposed that sIL-6R may be an important target for future drug development in OA by ameliorating cartilage extracellular protein degradation.

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Section: A Role For the Adams In Oa?supporting

confidence: 79%

“…The experimental results cited in references [ 98 – 100 , 102 ] were supported by grants from Genentech/Roche Group (South San Francisco, CA), by the CWRU Visual Sciences Research Center Core Grant, P30-EY-11373 and, by grants R01 AR-48782 and AT-002258 from the National Institutes of Health.…”

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confidence: 99%

A Role for Soluble IL-6 Receptor in Osteoarthritis

Akeson

Malemud

2017

JFMK

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“…MMP-2 and -14 were not shown to be regulated in OA cartilage 25 , whereas it has been reported that MMP-9 expression is increased in cartilage during OA. Further, it was shown previously that the expression of MMP-9 is increased in immortalized human chondrocyte cell lines under inflammatory stimulation with TNF-a and IL-6 26 . Contradictory studies have been published on the association of MMP-2 and -9 levels in synovial fluid with in OA disease severity 27e31 .…”

Section: Osteoarthritis Andcartilagementioning

confidence: 75%

MMP-9 mediated Syndecan-4 shedding correlates with osteoarthritis severity

Bollmann

Pinno

Ehnold

et al. 2021

Osteoarthritis and Cartilage

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“…Notably, all the downregulated genes contribute to the progression of osteoarthritis. Mmp9 is connected with cartilage degradation and pathologies [36,37]. Vdr polymorphisms were associated with susceptibility for primary osteoarthritis [38].…”

Section: Discussionmentioning

confidence: 99%

Caspase-1 Inhibition Impacts the Formation of Chondrogenic Nodules, and the Expression of Markers Related to Osteogenic Differentiation and Lipid Metabolism

Ramesova

Veselá

Švandová

et al. 2021

IJMS

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Caspase-1, as the main pro-inflammatory cysteine protease, was investigated mostly with respect to inflammation-related processes. Interestingly, caspase-1 was identified as being involved in lipid metabolism, which is extremely important for the proper differentiation of chondrocytes. Based on a screening investigation, general caspase inhibition impacts the expression of Cd36 in chondrocytes, the fatty acid translocase with a significant impact on lipid metabolism. However, the engagement of individual caspases in the effect has not yet been identified. Therefore, the hypothesis that caspase-1 might be a candidate here appears challenging. The primary aim of this study thus was to find out whether the inhibition of caspase-1 activity would affect Cd36 expression in a chondrogenic micromass model. The expression of Pparg, a regulator Cd36, was examined as well. In the caspase-1 inhibited samples, both molecules were significantly downregulated. Notably, in the treated group, the formation of the chondrogenic nodules was apparently disrupted, and the subcellular deposition of lipids and polysaccharides showed an abnormal pattern. To further investigate this observation, the samples were subjected to an osteogenic PCR array containing selected markers related to cartilage/bone cell differentiation. Among affected molecules, Bmp7 and Gdf10 showed a significantly increased expression, while Itgam, Mmp9, Vdr, and Rankl decreased. Notably, Rankl is a key marker in bone remodeling/homeostasis and thus is a target in several treatment strategies, including a variety of fatty acids, and is balanced by its decoy receptor Opg (osteoprotegerin). To evaluate the effect of Cd36 downregulation on Rankl and Opg, Cd36 silencing was performed using micromass cultures. After Cd36 silencing, the expression of Rankl was downregulated and Opg upregulated, which was an inverse effect to caspase-1 inhibition (and Cd36 upregulation). These results demonstrate new functions of caspase-1 in chondrocyte differentiation and lipid metabolism-related pathways. The effect on the Rankl/Opg ratio, critical for bone maintenance and pathology, including osteoarthritis, is particularly important here as well.

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Matrix Metalloproteinase-9 Production by Immortalized Human Chondrocyte Lines

Cited by 8 publications

References 22 publications

A Role for Soluble IL-6 Receptor in Osteoarthritis

A Role for Soluble IL-6 Receptor in Osteoarthritis

MMP-9 mediated Syndecan-4 shedding correlates with osteoarthritis severity

Caspase-1 Inhibition Impacts the Formation of Chondrogenic Nodules, and the Expression of Markers Related to Osteogenic Differentiation and Lipid Metabolism

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