Collagen Biomarkers for Arthritis Applications

Background The most common form of chronic arthritis is osteoarthritis (OA) with prevalence as high as 80% after age 75 (Arden and Nevitt, 2006). The incidence of OA is expected to increase as the population ages, increasing the socioeconomic burden of OA. Despite the signifi cant burden of this disease, no drug has been identifi ed that can effectively modify disease progression (Moskowitz and Hooper, 2005; Abadie et al. 2004). However, slowing disease progress and improvement in quality of life may be achieved by behavioral modifi cations, such as weight loss and exercise. Many patients with early OA will progress to disability and joint replacement. Physical examination and radiographic studies are relatively poor means for detecting disease early or predicting progression. Therefore, identifi cation of factors to facilitate early OA diagnosis and prognosis is a major focus of current OA research (Lohmander and Felson, 2004; Lohmander, 2004; Garnero and Delmas, 2003). Considerable intellectual and fi nancial resources are currently being invested into this biomarker development effort worldwide in the hope that biomarkers will help in the following ways: i) to diagnose OA prior to the stage when loss of articular cartilage can be measured on a radiograph, ii) to identify patients with increased risk of progression, iii) to monitor effectiveness of therapeutic interventions, and iv) to select patients for clinical trials of new drugs. To this end, numerous potential OA biomarkers have emerged over the last decade (Moskowitz and Hooper, 2005). These biomarkers comprise a diverse group of molecules derived from all components of the joint. Moreover, studies of these molecules have provided valuable insights into cartilage pathobiology (Poole, 2003). An imbalance in cartilage synthesis and degradation is central to the development of OA (Guilak et al. 2004; Lippiello et al. 1977; Malemud et al. 2003). Therefore, products of cartilage metabolism have been explored as potential candidate biomarkers for OA. Cartilage is composed of two major proteins, aggrecan, and type II collagen, in addition to many less abundant proteins such as decorin, fi bromodulin, cartilage oligomeric matrix protein (COMP), cartilage intermediate layer protein (CILP), proline arginine-rich end leucine-rich protein (PRELP), various minor collagens, link protein, fi bronectin, and the glycosaminoglycanhyaluronan (Saxne, 2006). Potential OA related biomarkers can originate both within and outside of joint tissues (Table 1). The focus of this review is type II collagen, the most abundant protein component of cartilage and a molecule that has yielded a wealth of potential OA-related biomarkers. Many different type II collagen epitopes have been described as potential OA biomarkers (Table 2). Interestingly, many of these epitopes can refl ect different biological processes even though they originate from the same molecule. For instance, collagen provides epitopes indicative of both degradative or catabolic events, and synthetic or anabolic events. Simultaneous assessment of both collagen degradation and synthesis in a patient is a particularly promising approach for diagnosing and determining risk of OA progression (Poole, 2003). Thus, type II collagen serves as a useful and instructive paradigm of the biomarker development process. In conjunction with the presentation of the human clinical evidence available for each of the collagen biomarkers, we make use of the newly proposed BIPED classifi cation scheme put forth by the Osteoarthritis Biomarkers Network (Bauer et al. 2006). The proposed algorithm classifi es markers into fi ve categories for the purpose of applying a common biomarker vocabulary across investigators, their laboratories and potentially across fi elds, and to facilitate the design of biomarker