IntroductionOsteoarthritis is influenced by genetic and environment factors, including mechanical stress; however, the relationship between running and the development of osteoarthritis remains a matter of controversy. We investigated whether osteoarthritic change could be obtained in a rat strenuous running model, whether serum keratan sulfate in rats could be detected by HPLC and was associated with onset or progression of osteoarthritis, and whether hyaluronan injection suppressed development of osteoarthritis and elevation of serum keratan sulfate.MethodsWistar rats were forced to run 30 km in 6 weeks on a treadmill machine. Articular cartilage of the knees was evaluated macroscopically and immunohistologically. Serum keratan sulfate was examined every week by HPLC. The effect of weekly knee injection of hyaluronan was also investigated.ResultsCartilage surfaces stained with India ink became irregular, metachromasia by safranin-O staining appeared to be almost lost, and Mankin's score significantly worsened after 30 km of running. Serum keratan sulfate in rats was detected by HPLC and transiently increased (peaked at 3 to 4 weeks) along with depletion of keratan sulfate in cartilage tissue. Hyaluronan treatment suppressed morphological progression of osteoarthritis and elevation of serum keratan sulfate.ConclusionRat strenuous running induced osteoarthritis. Serum keratan sulfate was associated with progression of osteoarthritis. Weekly intraarticular injection of hyaluronan controlled the development of osteoarthritis, and the effect was reflected by serum keratan sulfate.

Strenuous running of rats enhances mechanical stress on the knee, thereby inducing degeneration of articular cartilage. Bone morphogenetic protein-7 (BMP-7) has an inhibitory effect on cartilage degeneration, suggesting its usefulness for human osteoarthritis patients. However, its mode of administration should be investigated. We examined whether weekly knee injections of BMP-7 delayed the progression of cartilage degeneration. Wistar rats were forced to run 30 km in 6 weeks on a rodent treadmill, and BMP-7 was injected weekly into the knee. Macroscopically and histologically, this strenuous running regimen induced cartilage degeneration. Weekly injections of 250 ng BMP-7 delayed the progression of cartilage degeneration. Immunohistochemically, in the control knee, type II collagen expression decreased, while BMP-7 expression in chondrocytes slightly increased. Interestingly, weekly injection of BMP-7 increased BMP-7 expression even 9 days after the final injection. Disulfate disaccharide keratan sulfate in serum transiently increased in the control group, while it remained at a low level in the BMP-7 group. Weekly BMP-7 injection increased BMP-7 expression in chondrocytes and its effect seemed to last more than 7 days. The effect of BMP-7 could be monitored by serum keratan sulfate concentration. Periodical injections of BMP-7 delayed progression of cartilage degeneration induced by excessive running in rats. Keywords: BMP-7; articular cartilage; strenuous running; keratan sulfate; weekly injection Osteoarthritis (OA) in the knees constitutes an increasingly common medical problem for aging people. 1 Mechanical stress is one of the factors contributing to the progression of OA. Strenuous running of rats enhances mechanical stress on weight bearing joints, inducing OA of the knees. 2,3 This model requires no surgery or drugs, making it possible to detect subtle changes accompanying OA.Bone morphogenetic proteins (BMPs) have a variety of biological effects including enhancement of cartilage repair. 4 Among BMPs, BMP-7 is especially attractive, because it is one of two BMPs already approved for clinical use in various applications by the FDA. Recent data from an anterior cruciate ligament transection model in rabbits demonstrated that continuous intraarticular infusion of BMP-7 had a protective effect on cartilage degeneration, 5 suggesting the possible utility of BMP-7 as a treatment for human OA patients. However, given the challenges associated with clinical delivery by continuous infusion, further consideration should be given to the mode of administration.We speculated that periodic injections of BMP-7 into the knee joint might suppress the loss of cartilage matrix and consequently prevent OA progression. The purpose of this study was to examine whether weekly knee injections of BMP-7 delay development of OA and to investigate the possible mechanisms for this action in a strenuous running model of OA in rats. MATERIALS AND METHODS Strenuous Running of RatsWistar rats at 15-16 weeks of age (Sankyo L...