title: Early events of overused supraspinatus tendons involve matrix metalloproteinases and EMMPRIN/CD147 in the absence of inflammation.
abstract: BACKGROUND
  The principal feature of tendon degeneration is structural change of the extracellular matrix (ECM) including collagens. In painful tendons, alterations of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) have been described; however, the initial molecular mechanism at the origin of these alterations is still poorly understood. A rat model of supraspinatus tendon overuse has been developed, which may be predictive of pathological tendon alterations.
  
  
  OBJECTIVE
  To determine which MMPs are involved in early ECM remodeling during overuse and their relationship with the inflammatory context.
  
  
  METHODS
  Controlled laboratory study.
  
  
  METHODS
  Analyses were performed on rat supraspinatus tendons at 2 and 4 weeks of overuse on a downhill treadmill. Transcript levels of MMPs and TIMPs were assessed by semiquantitative reverse transcription polymerase chain reaction. Western blotting and/or immunolabeling were used for MMP-2, MMP-3, MMP-13, and extracellular MMP inducer (EMMPRIN, also called cluster of differentiation [CD] 147) detection. In situ and/or sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) gelatin zymography was performed for MMP-2 and MMP-9. TIMP activity was revealed by reverse zymography. Inflammation was assessed by cytokine antibody array and/or immunolabeling.
  
  
  RESULTS
  Compared with a control, overused supraspinatus tendons showed a significantly higher gelatinolytic activity at 2 weeks, which slightly decreased at 4 weeks. MMP-9 and MMP-13 were undetectable; MMP-3 was downregulated in overused tendons. Only MMP-2, particularly its active form, and the MMP-2 activator MMP-14 were upregulated at 2 weeks of overuse when an increase in TIMP-2 transcripts was observed. MMP-2 upregulation occurred in the absence of inflammation but was associated with an increase of EMMPRIN/CD147.
  
  
  CONCLUSIONS
  EMMPRIN/CD147-regulated MMP-2 and MMP-14, associated with low MMP-3, appear as the main characteristics of ECM remodeling in early overused tendons. Whether alterations in the pattern of these MMPs are an adaptive response or a repair response that may degenerate into tendinosis, is still uncertain. Moreover, there seems to be no indication for an inflammatory response to overuse, suggesting that the increased metalloproteinase activity is rather a response to a mechanical stress than an inflammatory one.
  
  
  CONCLUSIONS
  Any strategy aimed at preventing full-thickness tears resulting from initial tendon matrix alterations should consider these changes in MMP-3, MMP-2, and MMP-14, or further upstream, EMMPRIN.
authors: Laboratoire CRRET CNRS EAC 7149, Université Paris-Est Créteil, Créteil Cedex, France.
authors: Mohamed
authors: M
authors: Attia
authors: Eric
authors: E
authors: Huet
authors: Camille
authors: C
authors: Gossard
authors: Suzanne
authors: S
authors: Menashi
authors: Marie-Claude
authors: MC
authors: Tassoni
authors: Isabelle
authors: I
authors: Martelly
mesh_terms: D000818:Animals; D051926:Basigin / Q000502:physiology*; D005109:Extracellular Matrix / Q000201:enzymology* / Q000473:pathology; D018093:Gelatinases / Q000502:physiology; D007249:Inflammation / Q000503:physiopathology / Q000517:prevention & control; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000502:physiology; D020778:Matrix Metalloproteinase 2 / Q000502:physiology; D019278:Matrix Metalloproteinase 3 / Q000502:physiology; D020782:Matrix Metalloproteinases / Q000502:physiology*; D011237:Predictive Value of Tests; D051381:Rats; D017207:Rats, Sprague-Dawley; D052256:Tendinopathy / Q000201:enzymology* / Q000473:pathology; D013710:Tendons / Q000201:enzymology / Q000473:pathology; D015854:Up-Regulation / Q000502:physiology
chemical_list: D051926:Basigin; D018093:Gelatinases; D053509:Matrix Metalloproteinase 13; D020782:Matrix Metalloproteinases; D019278:Matrix Metalloproteinase 3; D020778:Matrix Metalloproteinase 2