Monosodium iodoacetate induced osteoarthritis in the knee joint of growing rats: effects on bone as measured by micro-computed tomography

Abstract

Purpose: Several experimental animal models in various species have been developed for human osteoarthritis (OA) and used to study the preclinical efficacy of disease and symptom modifying OA drug candidates. One of these models is induced chemically by an intra-articular injection of monosodium iodoacetate (MIA) into rat knee. Intra-articular MIA disrupts chondrocyte glycolysis through the inhibition of glyceraldehyde-3-phosphate dehydrogenase. This results in chondrocyte death and damage in the entire joint space, and leads to OA symptoms including joint pain similar to those observed in human patients. Previously, we have characterized the effects of intra-articular MIA on knee joint discomfort and pain, and on articular cartilage, synovium and bone in the knee joint of young adult rats. In this study, we characterized the effects of intra-articular MIA injection on bone in more detailed by high-resolution micro-computed tomography (micro-CT) both in the tibiofemoral and patellofemoral joints of growing rats. Methods: The study was conducted using growing male Sprague-Dawley rats. Unilateral OA was induced in their knee joints at the age of 6 weeks (150–183 g) by the intra-articular injection of MIA at the dose of 2 mg. The effects of MIA injection on body weight and bone in knee joint were followed during the study. Rats were terminated at 4 weeks after the MIA injection and their hind limbs were harvested for analyses. Knee joints were fixed and representative images were obtained by micro-CT (Skyscan 1276, Bruker microCT), from the entire knee joint including the distal end of femur, the proximal end of tibia and patella. In reconstructed micro-CT images, the entire epiphyses of tibia and femur and patella were separated, and tibial and femoral epiphyses were divided into medial and lateral compartments. Bone parameters in entire epiphyses, medial and lateral compartments and patella were analyzed by Bruker CTAn analysis software. This experimental protocol was approved by National Animal Experiment Board, Regional State Administrative Agency for Southern Finland, Hameenlinna, Finland. Results: Intra-articular MIA injection did not affect body weight gain in growing rats after 4 weeks post-injection. Representative micro-CT images demonstrated apparent tissue damage both in the tibiofemoral and patellofemoral joints of MIA-injected knee. The MIA injection decreased total bone volume in the entire epiphyses of tibia and femur similarly, namely by 44% in tibia and 47% in femur. However, total bone volume in the entire patella remained unchanged in MIA-injected knee. In weight-bearing region, the intra-articular MIA injection decreased bone volume by 44% in medial tibial plateau, 40% in lateral tibial plateau, 34% in medial femoral condyle, and by 29% in lateral femoral condyle. This suggested that bone in medial compartment was affected by MIA slightly more than bone in lateral compartment. These reductions in epiphyseal bone volume were associated with decreased number and thickness of individual trabeculae in epiphyseal marrow cavity. Conclusions: The present study characterized the effects of intra-articular MIA injection on bone in rat knee including both tibiofemoral and patellofemoral joints in the rat MIA model used widely in the preclinical efficacy studies of OA. In this study, the amount of MIA was higher and rats were younger than used in our previous studies. With these experimental settings, intra-articular MIA injection induced significant tissue damage and decreased bone volume in tibiofemoral joint. In patellofemoral joint, clear erosion was observed on articular surface without changes in total bone volume. High-resolution micro-CT demonstrated to be a useful tool to measure changes in bone and can be used when testing the preclinical efficacy of OA drug candidates in the rat MIA model. The follow-up of treatment effects by high-resolution in vivo micro-CT both on articular cartilage and bone would improve the analysis of preclinical efficacy in the rodent models of human OA.