Supraspinatus tendon overuse injuries lead to significant pain and disability in athletes and workers. Despite the prevalence and high social cost of these injuries, the early pathological events are not well known. We analyzed the potential relation between glycosaminoglycan (GAG) composition and phenotypic cellular alteration using a rat model of rotator cuff overuse. Total sulfated GAGs increased after 4 weeks of overuse and remained elevated up to 16 weeks. GAG accumulation was preceded by upregulation of decorin, versican, and aggrecan proteoglycans (PGs) mRNAs and proteins and biglycan PG mRNA after 2 weeks. At 2 weeks, collagen 1 transcript decreased whereas mRNAs for collagen 2, collagen 3, collagen 6, and the transcription factor Sox9 were increased. Protein levels of heparin affine regulatory peptide (HARP)/pleiotrophin, a cytokine known to regulate developmental chondrocyte formation, were enhanced especially at 4 weeks, without up-regulation of HARP/pleiotrophin mRNA. Further results suggest that the increased GAGs present in early lesions may sequester HARP/pleiotrophin, which could contribute to a loss of tenocyte's phenotype. All these modifications are characteristic of a shift towards the chondrocyte phenotype. Identification of these early changes in the extra-cellular matrix may help to prevent the progression of the pathology to more disabling, degenerative alterations. Tendon is composed primarily of type 1 collagen molecules organized into fibrils that constitute the tensionbearing structure in association with biglycan and decorin. Decorin, a small dermatan sulfate (DS) rich proteoglycan (PG) associated with collagen fibrils, regulates their diameter and longitudinal organization into fibers. 1,2 The collagen fibrils are embedded in the colloid extra-cellular matrix, containing most of the 70-80% tendinous water bound to the compressionbearing sulfated glycosaminoglycans (GAGs) of PGs. Tendon cells are surrounded by versican, a large chondroitin sulfate (CS) rich PG, which buffers load transmitted from the collagen matrix. 3 Overuse human chronic degenerative tendinopathy due to repetitive loading is characterized by structural and biochemical alterations including collagen fibrils disarray, separation, and disorganization, fibrocartilaginous cellular metaplasia, GAGs accumulation 4,5 and PGs variations at mRNA levels and protein content. 6,7 However tendinopathic biopsies are mostly available at late stages of pathology; knowledge of early pathological events is still incomplete.A rat model of tendon overuse has been developed that generates changes in histology and mechanical properties reproducing key characteristics of human supraspinatus tendinopathy. 8,9 This early experimental tendinosis is associated with collagen fragmentation, GAG accumulation, proliferating tenocytes, and higher expression of cartilage matrix markers mRNA. 10,11 These events are not primarily mediated by the presence of inflammatory cells, although mRNAs of some inflammatory mediators were detected. 12...

Increased GAGs in the pathological human patellar tendon are related to a worse clinical status. These findings indicate that the VISA score reflects the extent of tendon tissue pathology.

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.

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