Degenerative tendon injury or "tendinopathy" is one of the most common disorders of the musculoskeletal system. We used a rat model (Soslowsky LJ, Thomopoulos S, Tun S, Flanagan CL, Keefer CC, Mastaw J, and Carpenter JE. J Shoulder Elbow Surg 9: 79-84, 2000) to identify novel gene expression in the exercised-induced degenerated supraspinatus tendon by microarray and real-time PCR analyses. We identified several novel groups of differentially expressed genes, including those involved in apoptosis and related stress responses, and also genes that appear to be involved in glutamate signaling in tendon tissue, similar to recent findings by us in a microarray study of healing in the transected Achilles tendon of the rat (24). Until recently this kind of cellular communication was thought only to exist in cells of the central nervous system (CNS), where it is vital for CNS function. We further show that glutamate appears to induce a proapoptotic response in cultured tendon cells, similar to the "excitotoxic" response of cells in the CNS that become overstimulated. This may prove to be at least a partial cause of degeneration in overused tendon tissue and allow the development of treatments or "prehibilitation" regimens for tendinopathy based on currently used non-toxic glutamate antagonists.