Combination therapy with dexamethasone and osteoprotegerin protects against arthritis-induced bone alterations in antigen-induced arthritis of the rat

Oelzner, Peter; Fleissner-Richter, S.; Bräuer, Rolf; Hein, Gert; Wolf, Günter; Neumann, Thomas

doi:10.1007/s00011-010-0184-6

Cited by 9 publications

(6 citation statements)

References 41 publications

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“…The inhibition of the production of cytokines (genomic effect), prostaglandins and leukotrienes (nongenomic effect) have been suggested as their anti-inflammatory mechanisms [33]. In agreement with our study, another study using rat models of CFA-induced arthritis showed significantly reduction of paw edema with the administration of corticosteroids [34]. …”

Section: Discussionsupporting

confidence: 89%

Spinal Cord Brain-Derived Neurotrophic Factor Levels Increase after Dexamethasone Treatment in Male Rats with Chronic Inflammation

Laste

Rozisky²,

Macedo³

et al. 2013

Neuroimmunomodulation

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Dexamethasone is widely used in the therapy of chronic inflammatory diseases for its pain-modulating effects. The objective of this study was to evaluate the effect of dexamethasone on nociception and local inflammation, and the levels of brain-derived neurotrophic factor (BDNF) in the spinal cord in male rats with chronic inflammation induced by complete Freund’s adjuvant (CFA). Rats were randomly divided into a control group (not manipulated) and 2 CFA-induced chronic inflammation groups (in the 15th post-CFA injection): 1 injected with vehicle (saline solution) and 1 received dexamethasone (0.25 mg/kg) for 8 days. The hot-plate and electronic von Frey tests were performed 24 h after the end of treatment. BDNF spinal cord levels were determined by enzyme-linked immunosorbent assay (ELISA). The level of inflammation in the tibiotarsal joint (the ankle region) was evaluated histologically at the end of treatment. Dexamethasone produced significantly increased latency in the hot-plate test (one-way ANOVA, p < 0.05) and withdrawal threshold in the electronic von Frey test (p < 0.005). The dexamethasone group showed increased spinal cord BDNF levels compared to the other groups (one-way ANOVA p, < 0.05). Histological analysis showed a local inflammatory response only in animals treated with vehicle, which demonstrated that the dexamethasone treatment decreased the inflammatory process. Our findings corroborate the antinociceptive and anti-inflammatory properties of dexamethasone. In addition, we showed that the dexamethasone treatment increased BDNF levels in the spinal cord; its pain- modulating effects can be attributed to this effect.

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Section: Discussionsupporting

confidence: 89%

Spinal Cord Brain-Derived Neurotrophic Factor Levels Increase after Dexamethasone Treatment in Male Rats with Chronic Inflammation

Laste

Rozisky²,

Macedo³

et al. 2013

Neuroimmunomodulation

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“…One of the most serious side effects of chronic GC treatment in humans is bone loss, which also occurs during arthritis progression (American College of Rheumatology Ad Hoc Committee on Glucocorticoid-Induced Osteoporosis, 2001;Hoes et al, 2015;Oelzner et al, 2010). After DEX treatment, healthy bone metabolism is affected, leading to changes in remodelling and eventual bone density loss and a reduction in load potential (Liu et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

“…After DEX treatment, healthy bone metabolism is affected, leading to changes in remodelling and eventual bone density loss and a reduction in load potential (Liu et al, 2015). It is unclear whether DEX worsens the progression of osteoporosis in arthritic animal models, but it is nonetheless worth exercising caution when considering the balance of side effects versus potential therapeutic gains (Islander et al, 2011;Oelzner et al, 2010;Quan et al, 2016). DEX also has been shown to stunt growth of developing bone and cartilage, explaining the effects of growth retardation and osteopenia seen in children treated with extended doses Tomaszewska et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

“…1-100 nM DEX reduces IL-17induced NO synthesis, inhibiting the production of IL-6 and iNOS transcription, suggesting a potential pathway for the anti-inflammatory effects of DEX in cartilage tissue (Shalom-Barak et al, 1998). 100 nM DEX decreases the transcription of IL-1Ra after IL-6 exposure with human primary chondrocytes, indicating that IL-1Ra production is not a method by which DEX could protect cartilage against damaging inflammatory factors (Palmer et al, 2002). A phosphoproteomics study using primary human chondrocytes treated with IL-1α and 100 nM DEX showed a decrease in the phosphorylation of JNK1 and -2 linked to the anti-catabolic effects of DEX, suggesting a major role for JNKs in regulating cartilage breakdown upon inflammatory challenge [Wang et al (2017b) Phosphoproteomics analysis of signaling changes in human chondrocytes following treatment with Il-1, IGF-1 and dexamethasone.…”

Section: Dex and Chondrocyte Studies Of Arthritis And Inflammationmentioning

confidence: 99%

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Dexamethasone: chondroprotective corticosteroid or catabolic killer?

Black¹,

Grodzinsky

2019

eCM

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While glucocorticoids have been used for over 50 years to treat rheumatoid and osteoarthritis pain, the prescription of glucocorticoids remains controversial because of potentially harmful side effects at the molecular, cellular and tissue levels. One member of the glucocorticoid family, dexamethasone (DEX) has recently been demonstrated to rescue cartilage matrix loss and chondrocyte viability in animal studies and cartilage explant models of tissue injury and post-traumatic osteoarthritis, suggesting the possibility of DEX as a disease-modifying drug if used appropriately. However, the literature on the effects of DEX on cartilage reveals conflicting results on the drug's safety, depending on the dose and duration of DEX exposure as well as the model system used. Overall, DEX has been shown to protect against arthritis-related changes in cartilage structure and function, including matrix loss, inflammation and cartilage viability. These beneficial effects are not always observed in model systems using initially healthy cartilage or isolated chondrocytes, where many studies have reported significant increases in chondrocyte apoptosis. It is crucially important to understand under what conditions DEX may be beneficial or harmful to cartilage and other joint tissues and to determine potential for safe use of this glucocorticoid in the clinic as a disease-modifying drug.

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“…Durch Gabe des anti-RANKL-Antikörpers Denosumab konnte der mit einer Hemmung der Knochenformation und einer gesteigerten Knochenresorption einhergehende GK-induzierte vertebrale Knochenmasseverlust im Modell der hRANKL-knockin Maus verhindert und die biomechanische Belastbarkeit des Knochens erhalten werden [53]. Bei der Antigeninduzierten Arthritis der Ratte wurde gezeigt, dass die Kombination einer antiinflammatorischen Therapie mit Dexamethason mit einer RANKL-Inhibition durch Gabe von OPG einen deutlichen knochenprotektiven Effekt sowohl am periartikulären als auch am gelenkfernen Knochen hat [54].…”

Section: Erkrankungsgruppeunclassified

Prophylaxe und Therapie der Glukokortikoid-induzierten Osteoporose

Oelzner

Wolf

2017

Akt Rheumatol

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ZusammenfassunGDie Glukokortikoid-induzierte Osteoporose (GK-OP) ist eine der häufigsten Formen der Osteoporose. Epidemiologischen Untersuchungen zufolge nehmen 0,5-0,9 % der Bevölkerung Glukokortikoide (GK) ein, bei den über 50-jährigen liegt diese Zahl bei ca. 3 %. Das Frakturrisiko ist unter chronischer GKTherapie auf das Doppelte erhöht und liegt auf Grund der bevorzugten Wirkung von GK auf den trabekulären Knochen für Wirbelkörperfrakturen noch höher. Pathogenetisch liegt der GK-OP eine Verminderung von Knochenmasse und -qualität zugrunde, welche aus suppressiven Effekten von GK auf die Zahl Übersichtsarbeit abstr ac t Glucocorticoid-induced osteoporosis (GC-OP) is one of the most frequent forms of osteoporosis. Based on epidemiological investigations, 0.5-0.9 % of the community population use oral glucocorticoids (GC); in persons aged 50 or more, the number of GC users is about 3 %. The fracture risk is increased twofold in patients with chronic GC treatment and is even higher for vertebral fractures because GCs predominantly affect trabecular bone. The pathogenetic origin of GC-OP is a loss of bone mass and quality resulting from the suppressive effects of GC on the number and function of osteoblasts and osteocytes and an increase in bone resorption. Systemic effects inducing sarcopenia with an increased risk of falls, hormonal changes and a negative calcium balance may further amplify the unfavourable effects of GCs on bone. Basic diagnostic evaluation for osteoporosis including osteodensitometry is indicated when GC treatment with a minimum daily dose of 2.5 mg/d prednisolone equivalent is planned for more than 3 months. The fracture risk is already increased in the first 3 months of GC treatment. Therefore an early intervention to prevent GC-induced loss of bone mass is necessary. The guidelines given by the umbrella organisation of the German osteology societies provide the foundation for prophylaxis and treatment of GC-OP based on the calculated fracture risk. General measures include the prevention of falls and improvement of muscle mass and coordination as well as a sufficient supply of calcium and vitamin D. The indication for specific drug treatment exceeding these basic measures depends on the individual fracture risk, which is determined by daily GC dose, duration of GC treatment, age, gender and other risk factors including the underlying disease that is treated with GC. For the implementation of the recommendations, particularly in the prophylactic approach, the calculation of the duration and dose of planned GC treatment is essential. In this context the guidelines for treatment of the different inflammatory rheumatic diseases provide crucial orientation. Treatment with GC doses of ≥ 7.5 mg/d prednisolone equivalent for more than 3 months requires specific drug treatment if T scores are < − 1.5 or if low-traumatic vertebral fractures or multiple peripheral fractures are present. GC doses between 2.5 und 7.5 mg/d require a lowering of the treatment threshold, which is determined by age, gende...

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Combination therapy with dexamethasone and osteoprotegerin protects against arthritis-induced bone alterations in antigen-induced arthritis of the rat

Abstract: The principle of combining a glucocorticoid together with inhibition of the receptor activator of NF-kappaB ligand (RANKL) may be an effective bone-saving therapy in rheumatoid arthritis.

Cited by 9 publications

References 41 publications

Spinal Cord Brain-Derived Neurotrophic Factor Levels Increase after Dexamethasone Treatment in Male Rats with Chronic Inflammation

Spinal Cord Brain-Derived Neurotrophic Factor Levels Increase after Dexamethasone Treatment in Male Rats with Chronic Inflammation

Dexamethasone: chondroprotective corticosteroid or catabolic killer?

Prophylaxe und Therapie der Glukokortikoid-induzierten Osteoporose

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