Dexamethasone inhibits the differentiation of rat tendon stem cells into tenocytes by targeting the scleraxis gene

Chen, Wan; Tang, Hong; Zhou, Mei; Hu, Chao; Zhang, Jiqiang; Tang, Kanglai

doi:10.1016/j.jsbmb.2015.04.010

Cited by 40 publications

(26 citation statements)

References 26 publications

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“…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 . However, most of this work has focused on 2D tenocyte or tendon stem cell culture; at least one in vivo healing study appears to demonstrate a benefit of DEX treatment on healing 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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“…In human supraspinatus tendon cells, migration is inhibited, and the levels of MMP2, MMP8, MMP9, and MMP13 are reduced, while tissue inhibitor of metalloproteinases 1, which is an MMP inhibitor, is upregulated [14]. In addition to MMPs, scleraxis is a probable gene involved in the alteration of type I collagen [37]. Therefore, a complex regulatory mechanism may determine the ultimate changes.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of type I collagen expression in the Achilles tendon by dexamethasone: a controlled laboratory study

Tang

Chen

et al. 2020

J Orthop Surg Res

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Background: Spontaneous Achilles tendon rupture associated with long-term dexamethasone (Dex) use has been reported. However, few studies have investigated the potential mechanism. The aim of this study was to evaluate the effects of oral Dex on type I collagen in humans and rats and its association with tendon rupture. Methods: First, six Achilles tendons from patients who received long-term Dex treatment, and another six normal tendons were harvested for histological evaluation. Secondly, 8-week-old rats (n = 72) were randomly assigned to a Dex group or a control group. Type I collagen was studied at the mechanical, histological, and molecular levels after 3 and 5 weeks. Tenocytes isolated from normal human and rat tendon were used to investigate the effect of Dex on cellular scale. Results: Histological analysis of human and rat tendon tissue revealed an irregular, disordered arrangement of type I collagen in the Dex group compared with the control group. In addition, In the Dex+ group, type I collagen expression decreased in comparison with the Dex− group in both human and rat tenocytes. The mechanical strength of tendons was significantly reduced in the Dex group (68.87 ± 11.07 N) in comparison with the control group (81.46 ± 7.62 N, P = 0.013) after 5 weeks. Tendons in the Dex group were shorter with smaller cross-sectional areas (10.71 ± 0.34 mm 2 , 1.44 ± 0.22 mm 2 , respectively) after 5 weeks than those in the control group (11.13 ± 0.50 mm 2 , P = 0.050, 2.74 ± 0.34 mm 2 , P < 0.001, respectively). Conclusions: This finding suggests long-term use of Dex that decreases the expression of type I collagen at molecular and tissue levels both in human and rat Achilles tendons. Furthermore, Dex decreases the mechanical strength of the tendon, thereby increasing the risk of Achilles tendon rupture.

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“…Scleraxis is a transcription factor that regulates the expression of tenomodulin, a transmembrane protein in tenocytes [22]. It is known that scleraxis is essential for the differentiation of mesenchymal stem cells towards tendon progenitor cells and tenocytes [23, 24]. Under certain conditions, tendon stem cells can become adipocytes and osteocytes [20, 39].…”

Section: Discussionmentioning

confidence: 99%

“…It has been found that scleraxis overexpression promotes the differentiation of mesenchymal stem cells into tendon progenitor cells [23]. Furthermore, reduction of scleraxis has been shown to inhibit the differentiation of rat tendon stem cells into tenocytes [24]. In addition, tenomoduline knock-out results in decreased self-renewal of tendon stem cells [25, 26].…”

Section: Introductionmentioning

confidence: 99%

Glutamate signaling through the NMDA receptor reduces the expression of scleraxis in plantaris tendon derived cells

Spang

Backman

Roux

et al. 2017

BMC Musculoskelet Disord

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BackgroundA body of evidence demonstrating changes to the glutaminergic system in tendinopathy has recently emerged. This hypothesis was further tested by studying the effects of glutamate on the tenocyte phenotype, and the impact of loading and exposure to glucocorticoids on the glutamate signaling machinery.MethodsPlantaris tendon tissue and cultured plantaris tendon derived cells were immunohisto-/cytochemically stained for glutamate, N-Methyl-D-Aspartate receptor 1 (NMDAR1) and vesicular glutamate transporter 2 (VGluT2). Primary cells were exposed to glutamate or receptor agonist NMDA. Cell death/viability was measured via LDH/MTS assays, and Western blot for cleaved caspase 3 (c-caspase 3) and cleaved poly (ADP-ribose) polymerase (c-PARP). Scleraxis mRNA (Scx)/protein(SCX) were analyzed by qPCR and Western blot, respectively. A FlexCell system was used to apply cyclic strain. The effect of glucocorticoids was studies by adding dexamethasone (Dex). The mRNA of the glutamate synthesizing enzymes Got1 and Gls, and NMDAR1 protein were measured. Levels of free glutamate were determined by a colorimetric assay.ResultsImmunoreactions for glutamate, VGluT2, and NMDAR1 were found in tenocytes and peritendinous cells in tissue sections and in cultured cells. Cell death was induced by high concentrations of glutamate but not by NMDA. Scleraxis mRNA/protein was down-regulated in response to NMDA/glutamate stimulation. Cyclic strain increased, and Dex decreased, Gls and Got1 mRNA expression. Free glutamate levels were lower after Dex exposure.ConclusionsIn conclusion, NMDA receptor stimulation leads to a reduction of scleraxis expression that may be involved in a change of phenotype in tendon cells. Glutamate synthesis is increased in tendon cells in response to strain and decreased by glucocorticoid stimulation. This implies that locally produced glutamate could be involved in the tissue changes observed in tendinopathy.

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Dexamethasone inhibits the differentiation of rat tendon stem cells into tenocytes by targeting the scleraxis gene

Cited by 40 publications

References 26 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

Downregulation of type I collagen expression in the Achilles tendon by dexamethasone: a controlled laboratory study

Glutamate signaling through the NMDA receptor reduces the expression of scleraxis in plantaris tendon derived cells

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