Dexamethasone Release from Within Engineered Cartilage as a Chondroprotective Strategy Against Interleukin-1α

RoachBrendan, L; Kelmendi-DokoArta,; BalutisElaine, C; MarraKacey, G; AteshianGerard, A; HungClark, T

doi:10.1089/ten.tea.2016.0018

Cited by 25 publications

(26 citation statements)

References 115 publications

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“…There has been much debate concerning the use of glucocorticoids for musculoskeletal injuries, with active ongoing research in multiple organisms and disease models, as well as basic studies at the cell and tissue level. Recent reports have shown benefit for DEX in preventing cytokine‐induced damage in cartilage explants . In contrast, there are many studies suggesting detrimental effects of glucocorticoid treatment in tendons .…”

Section: Discussionmentioning

confidence: 99%

Lose‐Dose Administration of Dexamethasone Is Beneficial in Preventing Secondary Tendon Damage in a Stress‐Deprived Joint Injury Explant Model

Connizzo

Grodzinsky

2019

Journal Orthopaedic Research

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Secondary joint damage is the process by which a single injury can lead to detrimental changes in adjacent tissue structures, typically through the spread of inflammatory responses. We recently developed an in vitro model of secondary joint damage using a murine rotator cuff explant system, in which injuries to muscle and bone cause massive cell death in otherwise uninjured tendon. The purpose of the present study was to test the ability cytokine‐targeted and broad‐spectrum therapeutics to prevent cell death and tissue degeneration associated with secondary joint damage. We treated injured bone‐tendon‐muscle explants with either interleukin‐1 receptor antagonist, etanercept, or dexamethasone (DEX) for up to 7 days in culture. Only the low‐dose DEX treatment was able to prevent cell death and tissue degeneration. We then identified a critical window between 24 and 72 h following injury for maximal benefit of DEX treatment through timed administration experiments. Finally, we performed two tendon‐only explant studies to identify mechanistic effects on tendon health. Interestingly, DEX did not prevent cell death and degeneration in a model of cytokine‐induced damage, suggesting other targets of DEX activity. Future studies will aim to identify factors in joint inflammation that may be targeted by DEX treatment, as well as to investigate novel delivery strategies. Statement of clinical significance: Overall, this work demonstrates beneficial effects of DEX administration on preventing tenocyte death and extracellular matrix degeneration in an explant model of secondary joint damage, supporting the clinical use of low‐dose glucocorticoids for short‐term treatment of joint inflammation. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:139–149, 2020

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Section: Discussionmentioning

confidence: 99%

Lose‐Dose Administration of Dexamethasone Is Beneficial in Preventing Secondary Tendon Damage in a Stress‐Deprived Joint Injury Explant Model

Connizzo

Grodzinsky

2019

Journal Orthopaedic Research

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“…Similarly, local dual delivery of dexamethasone/TGF‐β3 via with heparin in or on PLGA microspheres has been demonstrated to promote rabbit MSC chondrogenesis . Most recently, Roach et al, demonstrated delivery of dexamethasone via PLGA microspheres in a chondrocyte‐laden agarose hydrogel. Kopesky et al, utilized a self‐assembled peptide hydrogel (i.e., AcN‐(KLDL) 3 ‐CNH 2 ) encapsulated with TGF‐β1 for sustained delivery of TGF‐β1.…”

Section: Discussionmentioning

confidence: 99%

Role of dexamethasone in the long‐term functional maturation of MSC‐laden hyaluronic acid hydrogels for cartilage tissue engineering

Kim

Garrity

Steinberg

et al. 2017

Journal Orthopaedic Research

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The purpose of study was to investigate the maturation of mesenchymal stem cells (MSC) laden in HA constructs with various combinations of chemically defined medium (CM) components and determine the impact of dexamethasone and serum on construct properties. Constructs were cultured in CM with the addition or withdrawal of media components or were transferred to serum containing media that partially represents an in vivo-like condition where pro-inflammatory signals are present. Constructs cultured in CM+ (CM with TGF-β3) and DEX- (CM+ without dexamethasone) conditions produced robust matrix, while those in ITS/BSA/LA- (CM+ without ITS/BSA/LA) and Serum+ (10% FBS with TGF-β3) produced little matrix. While construct properties in DEX- were greater than those in CM+ at 4 weeks, properties in CM+ and DEX- reversed by 8 weeks. While construct properties in DEX- were greater than those in CM+ at 4 weeks, the continued absence or removal of dexamethasone resulted in marked GAG loss by 8 weeks. Conversely, the continued presence or new addition of dexamethasone at 4 weeks further improved or maintained construct properties through 8 weeks. Finally, when constructs were converted to Serum (in the continued presence of TGF-β3 with or without dexamethasone) after pre-culture in CM+ for 4 weeks, GAG loss was attenuated with addition of dexamethasone. Interestingly, however, collagen content and type was not impacted. In conclusion, dexamethasone influences the functional maturation of MSC-laden HA constructs, and may help to maintain properties during long-term culture or with in vivo translation by repressing pro-inflammatory signals. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1717-1727, 2018.

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“…TE synovium was compared to native tissue EXPs in the presence of a proinflammatory cytokine, interleukin-1 (IL), which has been implicated in the pathogenesis of cartilage matrix degradation in OA, 37,38 or the clinically relevant corticosteroid drug, dexamethasone (DEX). 39 First, key features of native synovium structure and protein expression were assessed (Study 1). Tissue behavior was then compared in response to IL or DEX (Study 2).…”

Section: Methodsmentioning

confidence: 99%

A Functional Tissue-Engineered Synovium Model to Study Osteoarthritis Progression and Treatment

Stefani

Halder

Estell

et al. 2019

Tissue Engineering Part A

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The synovium envelops the diarthrodial joint and plays a key regulatory role in defining the composition of the synovial fluid through filtration and biosynthesis of critical boundary lubricants. Synovium changes often precede cartilage damage in osteoarthritis. We describe a novel in vitro tissue engineered model, validated against native synovium explants, to investigate the structure-function of synovium through quantitative solute transport measures. Synovium was evaluated in the presence of a proinflammatory cytokine, interleukin-1, or the clinically relevant corticosteroid, dexamethasone. We anticipate that a better understanding of synovium transport would support efforts to develop more effective strategies aimed at restoring joint health.

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Dexamethasone Release from Within Engineered Cartilage as a Chondroprotective Strategy Against Interleukin-1α

Cited by 25 publications

References 115 publications

Lose‐Dose Administration of Dexamethasone Is Beneficial in Preventing Secondary Tendon Damage in a Stress‐Deprived Joint Injury Explant Model

Lose‐Dose Administration of Dexamethasone Is Beneficial in Preventing Secondary Tendon Damage in a Stress‐Deprived Joint Injury Explant Model

Role of dexamethasone in the long‐term functional maturation of MSC‐laden hyaluronic acid hydrogels for cartilage tissue engineering

A Functional Tissue-Engineered Synovium Model to Study Osteoarthritis Progression and Treatment

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