Coexistence of up-regulated NMDA receptor 1 and glutamate on nerves, vessels and transformed tenocytes in tendinopathy

Schizas, Nikos; Lian, Øystein Bjerkestrand; Frihagen, Frede; Engebretsen, Lars; Bahr, Roald; Ackermann, Paul W.

doi:10.1111/j.1600-0838.2009.00913.x

Cited by 49 publications

(65 citation statements)

References 24 publications

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“…The tendinopathic samples exhibited significantly increased tissue immunodensity of the glutamate receptors NMDAR1, 6 phospho-NMDAR1 and mGluR5 as compared to the control tendons (Tables 1 and 2). The occurrence of mGluR6 and mGluR7 was not elevated in tendinopathy (p ¼ 0.31; Tables 1 and 2).…”

Section: Results Presence and Tissue Density Of Glutamate Receptors Amentioning

confidence: 99%

“…6,32,33 However, tendinosis patients with increased concentrations of glutamate can be pain free. 34 We thus presume that up-regulation of NMDAR1 and SP as well as activation of NMDAR1, observed as up-regulated phospho-NMDAR1, may be critical for its role in pain regulation.…”

Section: Discussionmentioning

confidence: 99%

“…The procedure is described in detail in our previous study, which demonstrated the feasibility of performing semi-quantitative analysis of glutamate ligands and receptors. 6 In the microscopic analysis, the mean interobserver coefficient of variation was 16% and the intraobserver variation was 15%. For statistical analysis, the mean fluorescent/total area was calculated for each of the biopsies from both the patient and the control groups.…”

Section: Image Analysismentioning

confidence: 95%

“…The elevated phospho-NMDAR1, however, was in the tendinopathic biopsies observed within the tendon proper, specifically localized on morphologically altered tenocytes according to Bonar scale 6 as well as on penetrating free-nerve fibres (Fig. 1).…”

Section: Tissue Distribution Of Glutamate Receptors and Spmentioning

confidence: 99%

“…Recently, up-regulated tissue expression of NMDAR1 co-localized with its ligand glutamate was found in tendinopathic patients. 6 However, whether the activated NMDAR1, that is, phosphorylated NMDAR1 (phospho-NMDAR1) is present in tendinopathy, a prerequisite for a role in the pathogenesis of tendinosis and pain, so far has not been explored.…”

mentioning

confidence: 99%

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Glutamate receptors in tendinopathic patients

Schizas

Weiss

Lian

et al. 2012

Journal Orthopaedic Research

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Tendinopathy, pain, and degeneration, may be related to the up-regulation of substance P (SP) and its activation of glutamate receptors. We hypothesized that the pathogenesis of tendinopathy involves N-methyl-D-aspartate receptor type 1 (NMDAR1) activation (phosphorylated NMDAR1; phospho-NMDAR1) co-existing with SP. Moreover, we examined the presence of metabotropic receptors that increase (mGluR1 and mGluR5) or decrease (mGluR6 and mGluR7) NMDAR1 excitability. Biopsies from patients with patellar tendinopathy (n ¼ 10) and from controls (n ¼ 8) were immunohistochemically analyzed according to the occurrence and tissue distribution of NMDAR1, phosho-NMDAR1, mGluR (1, 5-7), and SP. The biopsies were immunohistochemically single-and doublestained and semi-quantitatively assessed. Tendinopathic biopsies exhibited increased occurrence of NMDAR1, phospho-NMDAR1, SP, and mGluR5, while mGluR6-7 were not increased and mGluR1 was not found. The occurrence of NMDAR1 and SP correlated in tendinopathy (r 2 ¼ 0.54, p ¼ 0.03), but not in the controls (r 2 ¼ 0.11, p ¼ 0.4). Co-localization of SP and phospho-NMDAR1 within the tendon proper was only found in tendinopathy, localized on hypertrophic tenocytes, blood vessels, and penetrating free-nerve fibres. Up-regulation and activation of the glutamate receptor, phospho-NMDAR1, suggests a role in the pathophysiology of tendinopathy. Increased NMDAR1 excitability may be related to increased SP and mGluR5. The unique co-existence of SP and phospho-NMDAR1 in tendinopathy presumably reflects a tissue proliferative and nociceptive role. ß

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Section: Results Presence and Tissue Density Of Glutamate Receptors Amentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Image Analysismentioning

confidence: 95%

Section: Tissue Distribution Of Glutamate Receptors and Spmentioning

confidence: 99%

mentioning

confidence: 99%

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Glutamate receptors in tendinopathic patients

Schizas

Weiss

Lian

et al. 2012

Journal Orthopaedic Research

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Concepts of Entheseal Pain

Lorenzis

Natalello

Simón

et al. 2023

Arthritis & Rheumatology

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Pain is the main symptom in entheseal diseases (enthesopathies) despite a paucity of nerve endings in the enthesis itself. Eicosanoids, cytokines, and neuropeptides released during inflammation and repeated nonphysiologic mechanical challenge not only stimulate or sensitize primary afferent neurons present in structures adjacent to the enthesis, but also trigger a "neurovascular invasion" that allows the spreading of nerves and blood vessels into the enthesis. Nociceptive pseudounipolar neurons support this process by releasing neurotransmitters from peripheral endings that induce neovascularization and peripheral pain sensitization. This process may explain the frequently observed dissociation between subjective symptoms such as pain and the structural findings on imaging in entheseal disease.

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In vitro effects of glutamate and N‐methyl‐d‐aspartate receptor (NMDAR) antagonism on human tendon derived cells

Dean

Snelling

Dakin

et al. 2015

Journal Orthopaedic Research

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It is known that extracellular glutamate concentrations are increased in tendinopathy but the effects of glutamate upon human tendon derived cells are unknown. The primary purpose was to investigate the effect of glutamate exposure on human tendonderived cells in terms of viability, protein, and gene expression. The second purpose was to assess whether NMDAR antagonism would affect the response of tendon-derived cells to glutamate exposure. Human tendon-derived cells were obtained from supraspinatus tendon tissue obtained during rotator cuff repair (tendon tear derived cells) and from healthy hamstring tendon tissue (control cells). The in vitro impact of glutamate exposure and NMDAR antagonism (MK-801) was measured using the Alamar blue cell viability assay, immunocytochemistry, and quantitative real-time PCR. Glutamate reduced cell viability at 24 h in tendon tear derived cells but not in control cells at concentrations of 7.5 mM and above. Cell viability was significantly reduced after 72 h of 1.875 mM glutamate in both cell groups; this deleterious effect was attenuated by NMDAR antagonism with 10 mM MK-801. Both 24 and 72 h of 1.875 mM glutamate exposure reduced Type 1 alpha 1 collagen (COL1A1) and Type 3 alpha 1 collagen (COL3A1) gene expression, but increased Aggrecan gene expression. We propose that these effects of glutamate on tendon derived cells including reduced cell viability and altered matrix gene expression contribute to the pathogenesis of tendinopathy.

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Coexistence of up-regulated NMDA receptor 1 and glutamate on nerves, vessels and transformed tenocytes in tendinopathy

Cited by 49 publications

References 24 publications

Glutamate receptors in tendinopathic patients

Glutamate receptors in tendinopathic patients

Concepts of Entheseal Pain

In vitro effects of glutamate and N‐methyl‐d‐aspartate receptor (NMDAR) antagonism on human tendon derived cells

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