title: Glucocorticoids induce specific ion-channel-mediated toxicity in human rotator cuff tendon: a mechanism underpinning the ultimately deleterious effect of steroid injection in tendinopathy?
abstract: BACKGROUND
  Glucocorticoid injection (GCI) and surgical rotator cuff repair are two widely used treatments for rotator cuff tendinopathy. Little is known about the way in which medical and surgical treatments affect the human rotator cuff tendon in vivo. We assessed the histological and immunohistochemical effects of these common treatments on the rotator cuff tendon.
  
  
  METHODS
  Controlled laboratory study.
  
  
  METHODS
  Supraspinatus tendon biopsies were taken before and after treatment from 12 patients undergoing GCI and 8 patients undergoing surgical rotator cuff repair. All patients were symptomatic and none of the patients undergoing local GCI had full thickness tears of the rotator cuff. The tendon tissue was then analysed using histological techniques and immunohistochemistry.
  
  
  RESULTS
  There was a significant increase in nuclei count and vascularity after rotator cuff repair and not after GCI (both p=0.008). Hypoxia inducible factor 1α (HIF-1α) and cell proliferation were only increased after rotator cuff repair (both p=0.03) and not GCI. The ionotropic N-methyl-d-aspartate receptor 1 (NMDAR1) glutamate receptor was only increased after GCI and not rotator cuff repair (p=0.016). An increase in glutamate was seen in both groups following treatment (both p=0.04), while an increase in the receptor metabotropic glutamate receptor 7 (mGluR7) was only seen after rotator cuff repair (p=0.016).
  
  
  CONCLUSIONS
  The increases in cell proliferation, vascularity and HIF-1α after surgical rotator cuff repair appear consistent with a proliferative healing response, and these features are not seen after GCI. The increase in the glutamate receptor NMDAR1 after GCI raises concerns about the potential excitotoxic tendon damage that may result from this common treatment.
authors.affiliation: Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (NDORMS), Botnar Research Centre, Institute of Musculoskeletal Sciences, Nuffield Orthopaedic Centre, Oxford, UK.
authors.forename: Benjamin John Floyd
authors.initials: BJ
authors.lastname: Dean
authors.affiliation: Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (NDORMS), Botnar Research Centre, Institute of Musculoskeletal Sciences, Nuffield Orthopaedic Centre, Oxford, UK.
authors.forename: Sarah Louise
authors.initials: SL
authors.lastname: Franklin
authors.affiliation: Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (NDORMS), Botnar Research Centre, Institute of Musculoskeletal Sciences, Nuffield Orthopaedic Centre, Oxford, UK.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Murphy
authors.affiliation: Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (NDORMS), Botnar Research Centre, Institute of Musculoskeletal Sciences, Nuffield Orthopaedic Centre, Oxford, UK.
authors.forename: Muhammad K
authors.initials: MK
authors.lastname: Javaid
authors.affiliation: Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (NDORMS), Botnar Research Centre, Institute of Musculoskeletal Sciences, Nuffield Orthopaedic Centre, Oxford, UK.
authors.forename: Andrew Jonathan
authors.initials: AJ
authors.lastname: Carr
mesh_terms: D000328:Adult; D000368:Aged; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000009:adverse effects; D001265:Athletic Injuries / Q000628:therapy; D016022:Case-Control Studies; D049109:Cell Proliferation / Q000502:physiology; D005260:Female; D005938:Glucocorticoids / Q000008:administration & dosage / Q000009:adverse effects*; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D061705:Image-Guided Biopsy; D007150:Immunohistochemistry; D007270:Injections, Intra-Articular; D008297:Male; D008775:Methylprednisolone / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D000077555:Methylprednisolone Acetate; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000378:metabolism; D015588:Observer Variation; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D017006:Rotator Cuff / Q000473:pathology / Q000601:surgery*; D000070636:Rotator Cuff Injuries; D020069:Shoulder Pain / Q000628:therapy; D052256:Tendinopathy / Q000139:chemically induced* / Q000473:pathology; D013708:Tendon Injuries / Q000628:therapy*; D018084:Ultrasonography, Interventional; D014945:Wound Healing / Q000502:physiology
chemical_list: D000893:Anti-Inflammatory Agents; C485668:GRIN1 protein, human; D005938:Glucocorticoids; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009419:Nerve Tissue Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D000077555:Methylprednisolone Acetate; D008775:Methylprednisolone
keywords: Orthopaedics; Shoulder Injuries; Soft Tissue Injuries; Steroids; Tendons