Osteoarthritis Early-, Mid- and Late-Stage Progression in the Rat Medial Meniscus Transection Model

Abstract

Osteoarthritis is a degenerative disease of synovial joints affecting all tissues, including the articular cartilage and underlying subchondral bone. Osteoarthritis animal models can recapitulate aspects of human disease progression and are commonly used to test the development of drugs, biomaterials, and cell therapies for treatment. The rat medial meniscus transection (MMT) model is a surgically induced post-traumatic osteoarthritis model and is one of the most commonly used models for therapeutic development; however, it is typically used to evaluate the efficacy of therapies to prevent disease development rather than testing the treatment of disease progression in already established disease. We describe herein, the qualitative and quantitative changes to articular cartilage, subchondral bone, and formation of osteophytes in rats at early-(3-weeks post-surgery), mid-(6-weeks post-surgery) and late-(12-weeks post-surgery) stages of osteoarthritis progression. Tibiae of MMT-operated animals showed loss of proteoglycan and fibrillation formation on articular cartilage surfaces as early as 3-weeks post-surgery. Using a contrast-enhanced CT technique, quantitative, 3-dimensional analysis of the tibiae showed that the articular cartilage initially thickened at 3- and 6-weeks post-surgery and then decreased at 12-weeks post-surgery. This decrease in cartilage thickness corresponded with increased lesions in the articular cartilage, including fully degraded surfaces down to the subchondral bone layer. In this rat MMT model, subchondral bone thickening was significant at 6-weeks post-surgery and seem to follow cartilage damage. Osteophytes were found at 3-weeks post-surgery, which coincided with articular cartilage degradation. Cartilaginous osteophytes preceded mineralization suggesting that these marginal tissue growths most likely occurred through endochondral ossification. The use of the rat MMT model has predominantly been used out to 3-weeks, and most studies determine the effect of therapies to delay or prevent the onset of osteoarthritis. We provide evidence that an extension of the rat MMT model out to 6 and 12 weeks resembled more severe phenotypes of human osteoarthritis. The mid- to late-stages of rat MMT model can be used to evaluate the therapeutic efficacy of novel treatments to treat the progression of established disease -- since patients typically present in the clinic when the disease is established and becomes symptomatic, thus evaluating the efficacy of new treatments at the late stage will be important for eventual clinical translation.