Dexamethasone Attenuates the Expression of MMP-13 in Chondrocytes through MKP-1

Lehtola, Tiina; Nummenmaa, Elina; Tuure, Lauri; Hämäläinen, Mari; Nieminen, Riina; Moilanen, Teemu; Pemmari, Antti; Moilanen, Eeva

doi:10.3390/ijms23073880

Cited by 4 publications

(7 citation statements)

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“…MMP13 and RUNX2 are involved in bone remodeling and early stages of endochondral bone formation [43]. MMP13 has been proven to be a downstream target of RUNX2 [44] which directly regulates MMP13 promotor activity and MMP13 expression in vivo [45]. Takeuchi et.…”

Section: Discussionmentioning

confidence: 99%

Traumatic temporomandibular joint bony ankylosis in growing rats

Wang

Xue

et al. 2022

BMC Oral Health

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Background The pathogenesis of traumatic temporomandibular joint (TMJ) bony ankylosis remains unknown. This study aimed to explore the pathogenesis of traumatic TMJ bony ankylosis in a rat model. Methods Twenty-four 3-week-old male Sprague–Dawley rats were used in this study. Excision of the whole disc, the fibrocartilage damage of the condyle and glenoid fossa, and narrowed joint space were performed in the left TMJ of the operation group to induce TMJ bony ankylosis (experimental side). The right TMJ underwent a sham operation (sham side). The control group did not undergo any operations. At 1, 4, and 8 weeks postoperatively, rats of the operation group were sacrificed and TMJ complexes were evaluated by gross observation, Micro-CT, histological examinations, and immunofluorescence microscopy. Total RNA of TMJ complexes in the operation group were analyzed using RNA-seq. Results Gross observations revealed TMJ bony ankylosis on the experimental side. Micro-CT analysis demonstrated that compared to the sham side, the experimental side showed a larger volume of growth, and a considerable calcified bone callus formation in the narrowed joint space and on the rougher articular surfaces. Histological examinations indicated that endochondral ossification was observed on the experimental side, but not on the sham side. RNA-seq analysis and immunofluorescence revealed that Matrix metallopeptidase 13 (MMP13) and Runt-related transcription factor 2 (RUNX2) genes of endochondral ossification were significantly more downregulated on the experimental side than on the sham side. The primary pathways related to endochondral ossification were Parathyroid hormone synthesis, secretion and action, Relaxin signaling pathway, and IL-17 signaling pathway. Conclusions The present study provided an innovative and reliable rat model of TMJ bony ankylosis by compound trauma and narrowed joint space. Furthermore, we demonstrated the downregulation of MMP13 and RUNX2 in the process of endochondral ossification in TMJ bony ankylosis.

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Section: Discussionmentioning

confidence: 99%

Traumatic temporomandibular joint bony ankylosis in growing rats

Wang

Xue

et al. 2022

BMC Oral Health

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“…PCR reaction was performed as previously described. 5 The mRNA expression levels were normalized against GAPDH mRNA levels and were quantified using the standard curve method (genes detected with the optimized inhouse primers and probes) or the ΔΔCt method (genes detected with the TaqMan ® Gene Expression assays).…”

Section: Quantitative Rt-pcrmentioning

confidence: 99%

“…MKP‐1 is one of the genes upregulated by glucocorticoids, and it has been involved in the anti‐inflammatory feedforward mechanisms of glucocorticoids 4 . For instance, we have recently shown that the glucocorticoid dexamethasone suppresses catabolic enzyme expression in chondrocytes by enhancing MKP‐1 5 . We hypothesized that MKP‐1 could also be a factor involved in the mechanisms of action of glucocorticoids in allergic inflammation.…”

Section: Introductionmentioning

confidence: 99%

“…4 For instance, we have recently shown that the glucocorticoid dexamethasone suppresses catabolic enzyme expression in chondrocytes by enhancing MKP-1. 5 We hypothesized that MKP-1 could also be a factor involved in the mechanisms of action of glucocorticoids in allergic inflammation. In the present study, MKP-1 dependency of the anti-allergic effects of dexamethasone was studied for the first time in vivo using an ovalbumin-induced acute allergic reaction in mice as a model.…”

Section: Introductionmentioning

confidence: 99%

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The glucocorticoid dexamethasone alleviates allergic inflammation through a mitogen‐activated protein kinase phosphatase‐1‐dependent mechanism in mice

Lehtola,

Nummenmaa,

Nieminen

et al. 2024

Basic Clin Pharma Tox

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Glucocorticoids are widely used in the treatment of allergic and inflammatory diseases. Glucocorticoids have a widespread action on gene expression resulting in their pharmacological actions and also an array of adverse effects which limit their clinical use. It remains, however, to be studied which target gene effects are essential for the anti‐allergic activity of glucocorticoids. Mitogen‐activated protein kinase phosphatase‐1 (MKP‐1) inhibits proinflammatory signalling by suppressing the activity of mitogen activated protein kinase (MAP kinase) pathways. MKP‐1 is one of the anti‐inflammatory genes whose expression is enhanced by glucocorticoids. In the present study, we aimed to investigate the role of MKP‐1 in the therapeutic effects of the glucocorticoid dexamethasone in acute allergic reaction. The effects of dexamethasone were studied in wild‐type and MKP‐1 deficient mice. The mice were first sensitized to ovalbumin, and the allergic reaction was then induced by a subcutaneous ovalbumin injection in the hind paw. Inflammatory edema was quantified with plethysmometer and expression of inflammatory factors was measured by quantitative reverse transcription polymerase chain reaction (RT‐PCR). Dexamethasone reduced the ovalbumin‐induced paw edema at 1.5, 3 and 6 h time points in wild‐type mice by 70%, 95% and 89%, respectively. The effect was largely abolished in MKP‐1 deficient mice. Furthermore, dexamethasone significantly attenuated the expression of ovalbumin‐induced inflammatory factors cyclooxygenase‐2 (COX‐2); inducible nitric oxide synthase (iNOS); interleukins (IL) 1β, 6 and 13; C‐C motif chemokine 11 (CCL‐11); tumour necrosis factor (TNF) and thymic stromal lymphopoietin (TSLP) in wild‐type mice by more than 40%. In contrast, in MKP‐1 deficient mice dexamethasone had no effect or even enhanced the expression of these inflammatory factors. The results suggest that dexamethasone alleviates allergic inflammation through an MKP‐1‐dependent mechanism. The results also demonstrate MKP‐1 as an important conveyor of the favourable glucocorticoid effects in ovalbumin‐induced type I allergic reaction. Together with previous findings, the present study supports the concept of MKP‐1 enhancing compounds as potential novel anti‐inflammatory and anti‐allergic drugs.

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“…However, multiple administrations of glucocorticosteroid drugs may destroy the articular cartilage, induce human chondrocytes’ mitochondrial dysfunction, and increase ROS ( Li, Chen, Li, Zhang, & Chen, 2022 ). In turn, dexamethasone may significantly attenuate the expression of MMP-13 in human OA chondrocytes through an mitogen-activated protein kinase phosphatase-1 and p38 mitogen-activated protein kinases-dependent manner ( Lehtola et al, 2022 ). A study found that increased autophagy is an adaptive response to protect chondrocytes from short-term glucocorticosteroid exposure, whereas prolonged glucocorticosteroid drug treatment decreases autophagy and increases apoptosis ( Liu, Wang, Zhao, Zhang, & Song, 2014 ).…”

Section: Drugs Targeting Autophagy For Osteoarthritis Treatmentmentioning

confidence: 99%

New insights into the interplay between autophagy and cartilage degeneration in osteoarthritis

Zhao

Dai

et al. 2022

Front. Cell Dev. Biol.

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Autophagy is an intracellular degradation system that maintains the stable state of cell energy metabolism. Some recent findings have indicated that autophagy dysfunction is an important driving factor for the occurrence and development of osteoarthritis (OA). The decrease of autophagy leads to the accumulation of damaged organelles and macromolecules in chondrocytes, which affects the survival of chondrocytes and ultimately leads to OA. An appropriate level of autophagic activation may be a new method to prevent articular cartilage degeneration in OA. This minireview discussed the mechanism of autophagy and OA, key autophagy targets regulating OA progression, and evaluated therapeutic applications of drugs targeting autophagy in preclinical and clinical research. Some critical issues worth paying attention to were also raised to guide future research efforts.

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Dexamethasone Attenuates the Expression of MMP-13 in Chondrocytes through MKP-1

Cited by 4 publications

References 52 publications

Traumatic temporomandibular joint bony ankylosis in growing rats

Traumatic temporomandibular joint bony ankylosis in growing rats

The glucocorticoid dexamethasone alleviates allergic inflammation through a mitogen‐activated protein kinase phosphatase‐1‐dependent mechanism in mice

New insights into the interplay between autophagy and cartilage degeneration in osteoarthritis

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