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To determine whether repeated exposure of rabbit patellar tendon to prostaglandin-E2 leads to degenerative changes in the tendon.Laboratory animal study.Intratendinous changes including cellularity, matrix organization, collagen fibril packing, and diameter.Skeletally mature New Zealand White rabbits (n = 10) were transcutaneously injected in the midsubstance of the patellar tendon with prostaglandin-E2 (PGE2; 50 ng or 500 ng). The contralateral tendons were used as 3 different controls (no injection, saline injection, and needlestick only). The injection was repeated once a week for 4 weeks, and the rabbits were killed 1 week after the last injection. The patellar tendons were harvested and examined using hematoxylin and eosin staining and transmission electron microscopy.Compared with the control groups, tendons exposed to PGE2 by injection showed focal areas of hypercellularity, loss of normal tissue architecture, and focal areas of tendon disorganization and degeneration. Tendons injected with PGE2 exhibited loosely organized collagen fibrils and had thinner collagen fibril diameter compared with control tendons (P < 0.005). Tendons injected with 500 ng PGE2 appeared to be more disorganized and degenerated than those injected with 50 ng PGE2.Repeated exposure of the tendon to PGE2 leads to degenerative changes within the tendon.It is known that human tendon fibroblasts produce PGE2 in vitro and in vivo in response to repetitive mechanical loading. This study demonstrates that repetitive exposure of the tendon to PGE2 can result in degenerative changes within the tendon. Therefore, PGE2 produced by tendon fibroblasts in response to repetitive mechanical loading in vivo might contribute to the development of exercise-induced tendinopathy.