Preclinical osteoarthritis (OA) models are often employed in studies investigating disease-modifying

Preclinical osteoarthritis (OA) models are often employed in studies investigating disease-modifying OA drugs (DMOADs). density analysis, and biochemical analysis of type II collagen breakdown using the CTX II biomarker. Expression of hypertrophic chondrocyte markers was also assessed in articular cartilage. Cartilage degradation, subchondral changes, and subchondral bone loss were observed as early as 2 weeks after surgery, with considerable correlation to that seen in human OA. We found excellent correlation between histologic changes and micro-CT analysis of underlying bone, which reflected properties of human OA, and recognized additional molecular changes that enhance our understanding of OA pathogenesis. Interestingly, forced mobilization exercise accelerated OA progression. Minor OA activity was also observed in the contralateral joint, LBH589 manufacturer including proteoglycan loss. Finally, we observed increased chondrocyte hypertrophy during pathogenesis. We conclude that forced mobilization accelerates OA damage in the destabilized LBH589 manufacturer joint. This surgical model of OA with forced mobilization is suitable for longitudinal preclinical studies, and it is well adapted for investigation of both early and late stages of OA. The time course of OA progression can be modulated through the use of forced mobilization. Introduction Osteoarthritis (OA) is usually a complex degenerative disease [1-3] that causes structural changes to articular cartilage and subchondral bone of synovial joints [4-7]. An understanding of OA etiopathology, however, has proven to be elusive [2]. Coupled with the fact that OA affects nearly 70% of all people SKP1 at some point in their lives, LBH589 manufacturer OA has major economic and interpersonal impacts on patients and health care systems [8-10]. Consequently, there is a pressing need to develop disease-modifying OA drugs (DMOADs). Before a DMOAD can reach clinical trials, it must first be successful in preclinical trials. This requires animal models of OA in which specific aspects of drug efficacy in articular cartilage, subchondral bone and other affected tissues may be examined, as may potential side effects in other organs [11]. Large animals such as dogs or sheep are sometimes favored for these purposes because they provide sufficient amounts of tissue for analysis [12]. However, large animal studies incur high costs (for instance, housing), which make them impractical for large-scale screens of multiple compounds. In contrast, small animals (such as rodents) are more cost-effective than large ones, and they are well suited to longitudinal preclinical OA studies. Among these, rats and mice are particularly encouraging because of advanced annotation of their genomes and the amazing genetic, anatomic, and physiologic similarities between humans and rodents [13]. Rodent models of OA were first developed in the late 1970s in mice and rats [14-17]. Initially, experiments employed models in which OA was induced in the temporomandibular joint [18-20], but subsequently these models were developed to involve other synovial joints, including the knee [14]. Either a chemical method (intra-articular injection of, for instance, papain [21] or sodium iodoacetate [22]) or a surgical method (structural alteration to the tendons, muscle mass, or ligaments [23-25]) was used. A review by Shwartz [26], published in 1987, summarizes these early developments. Other models developed since then rely on genetic predisposition or engineering to stimulate OA pathology. However, a long time may be required for OA to develop in genetic models, and there is often considerable variability between animals (for example, in the temporal dynamics of OA progression). Disease progression in surgical models is faster and more consistent. Moreover, these models reflect post-traumatic (secondary) OA, because they rely on changes in excess weight bearing and unnatural joint articulation for OA etiopathology [27,28]. It is advantageous to develop surgical models in rats LBH589 manufacturer or mice because genetic studies are possible in these animals [29-31]. Rat models are of interest because their larger size (compared with mice) provides more tissue for biochemical and gene expression analysis, and permits cross-disciplinary studies (for example, genomics, cell biology, electrophysiology, and em in vivo /em small animal imaging) [32]. Models developed in the rat include.