Periodic knee injections of BMP‐7 delay cartilage degeneration induced by excessive running in rats

Abstract

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...

BMP-7 inhibits cartilage degeneration through suppression of inflammation in rat zymosan-induced arthritis

“…Compared with these reports, the dose of BMP-7 per animal weight administered in our experiments is lower. Our previous reports (Hayashi et al 2008;Sekiya et al 2009) and this study indicate that repetitive intraarticular injections of a small amount of BMP-7 represent an effective method to inhibit cartilage degeneration without remarkable side-effects.…”

“…Based on our past reports (Sekiya et al 2009) and our preliminary experiments, three kinds of doses varying between 10 and 1000 ng per joint were chosen in this experiment. We found no obvious ectopic bone or cartilage formation in the rat knee joint in the BMP-7-treated group microscopically or macroscopically.…”

“…It also regulates cartilage metabolism and promotes the synthesis of extracellular matrix in vitro (Chubinskaya et al 2008;Saas et al 2006) and in vivo (Chubinskaya et al 2007b). Recent studies have demonstrated that the weekly local administration of BMP-7 inhibits the progression of osteoarthritis in vivo (Hayashi et al 2008;Sekiya et al 2009). In addition, the administration of BMP-7 promotes the healing of experimental inflammatory intestinal disease (Maric et al 2003) and also reduces the severity of injury after ischemic acute renal failure in rat (Vukicevic et al 1998).…”

Off-Label Use of Bone Morphogenetic Proteins in the United States Using Administrative Data

“…20,21 Even as pilot data suggest that the complication rates following BMP use in posterior cervical fusion will likely be lower than those for anterior cervical fusion, 21 there is concern that BMPs may cause an inflammatory response, resulting in a higher incidence of posterior cervical wound complications compared to those receiving iliac crest bone graft. 20 In addition to the off-label use of BMP in spine fusion surgeries, other nonfusion applications of BMP have also been investigated, including periodic injections to delay the progression of cartilage degeneration 34 and disc degeneration, 35 healing of segmental bone defects, 36 treatment of symptomatic osteonecrosis of the femoral head, 37 and bone graft substitutes for total joint arthroplasty. 38 As more scientific evidence emerges, additional clinical applications may arise and affect the national utilization of BMP.…”

The Role of Synovial Macrophages and Macrophage-Produced Mediators in Driving Inflammatory and Destructive Responses in Osteoarthritis

“…This growth factor also has anti-catabolic actions, including MMP and aggrecanase inhibition (Badlani et al, 2008). It has been investigated in various animal models of OA with positive results: injected intra-articularly, it inhibited cartilage degeneration and the progression of OA (Sekiya et al, 2009). A Phase I clinical trial of intra-articular recombinant OP-1 (Stryker), assessing safety and effect on signs and symptoms, with dose escalation over 24 weeks, has been completed (Hellio le Graverand-Gastineau, 2010).…”