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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.To determine which MMPs are involved in early ECM remodeling during overuse and their relationship with the inflammatory context.Controlled laboratory study.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.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.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.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.