Matrix metalloproteinase-3 inhibitor retards treadmill running-induced cartilage degradation in rats

Abstract

IntroductionThe effect of intra-articular injection of matrix metalloproteinase (MMP)-3 inhibitor was investigated in a rat model to understand the role of MMP-3 in cartilage degradation induced by excessive loading from running.MethodsA total of 24 male Wistar rats were randomly assigned into groups of sedentary control (SED), high-intensity running (HIR), HIR + low dosage of MMP-3 Inhibitor I (HIRI1), and HIR + high dosage of MMP-3 Inhibitor I (HIRI2). Rats in the HIR, HIRI1 and HIRI2 groups were intensively trained for six weeks on the treadmill. Those in HIRI1 and HIRI2 groups were provided bilateral intra-articular injections of 80 μL of 0.2 mM and 2 mM MMP-3 Inhibitor I in knee joints once a week, respectively. Blood samples were collected to measure serum MMP-3 level using ELISA. Femoral condyles were collected to observe cartilage characteristics by histochemistry, and MMP-3 as well as collagen II was measured by immunohistochemistry. In addition, cartilage samples were obtained to assess MMP-3 mRNA expression by RT-PCR.ResultsHistological examination showed osteoarthritic changes in rats after six weeks of high intensity running. In comparison to the SED group, significant decreases in glycosaminoglycans (GAG) and collagen content were found in the HIR group, which corresponded to significant increase in serum MMP-3 level, cartilage MMP-3 activity and gene expression. However, such a degradative process was considerably retarded by intra-articular injection of MMP-3 inhibitor at higher dosage. Statistical differences were found between the HIR and HIRI2 groups with regard to GAG and collagen II content, serum MMP-3 level, cartilage MMP-3 activity and gene expression.ConclusionsHigh-intensity running for six weeks may lead to cartilage degradation in a rat model. It was shown that the chrondroprotective effect was offered by the use of intra-articular injection of MMP-3 inhibitor. MMP-3 acts as the key mediator of this catabolic change under such mechanical condition. The results also showed that MMP-3 selective inhibitor may be an effective option for retarding such osteoarthritic changes.

Effect of Running on Inclined Treadmill on the Occurrence of Knee Joint Osteoarthritis in the Male and Female Wistar Rats

“…Ding et al, specified that body and bone size had significant effects on this difference, which was in agreement with some speculations, suggesting that cartilage volume had a direct relationship with bone size (12,32,33); consequently, males have a thicker cartilage than females (3,34,35).…”

“…Moreover, it is among the most common weight -bearing exercises (2,3). One common concern related to running is the possible long -term effect on the body.…”

Osteoarthritis biomarker responses and cartilage adaptation to exercise: A review of animal and human models

“…It has been shown that 6 weeks of running at 25 m/min (45 km) initiates structural changes in the cartilage surface and depletion of the cartilage matrix. 53 These changes were accompanied by a significant increase in both cartilage and serum levels MMP-3 activity suggesting excessive cartilage breakdown (Figure 3). 53 Interestingly, Franciozi et al confirmed that 6 weeks of running at 25 m/min induces chondrocyte death, matrix depletion, and subsequent local inflammation.…”

“…53 These changes were accompanied by a significant increase in both cartilage and serum levels MMP-3 activity suggesting excessive cartilage breakdown (Figure 3). 53 Interestingly, Franciozi et al confirmed that 6 weeks of running at 25 m/min induces chondrocyte death, matrix depletion, and subsequent local inflammation. 54 Two studies from 2007 and 2008 showed that a speed of 20 m/min for 6 weeks was also sufficient to induce OA-accompanied by histological changes after 30 km of running.…”

Targeting TGFβ signaling in subchondral bone and articular cartilage homeostasis

“…Vigorous cyclic loading leads to cartilage matrix damage such as collagen fiber broken and proteoglycan depletion possibly due to increased MMP-3 132 . Although intermittent articular loading seems to be necessary for normal cartilage metabolism, abnormal loading patterns likely activate TGFβ irregularly which further induce progressive cartilage degeneration 133 . Therefore, the fluctuation of subchondral bone mechanical property inevitably influences its capacity to dissipate the mechanical stimuli from the joint surface and consequently leads to cartilage degeneration in OA.…”