Identification of meniscus damage biomarker: implications for the future treatment of knee injury

Abstract

Knee pain is associated with a spectrum of various injuries and/or degradative states, which may be treated more specifically with regard to their particular etiologies. It is well established that knee injury leads to an increased risk of post-traumatic osteoarthritis and chronic knee pain [1–5]. However, joint pain from a specific injury may be a distinct entity from chronic, nontraumatic osteoarthritic pain. Furthermore, the biomolecular milieu of each specific injury resulting in knee pain may be more distinct from each other than usually appreciated (e.g., anterior cruciate ligament injury vs meniscal damage) [6,7]. Teasing out the characteristics of these various injuries is crucial, not only in diagnosis, but also in advancing our understanding of targeted treatment modalities. Whereas the symptoms, such as pain, may be similar across various knee injuries, the specific biomolecular environment and sequence of events may, in fact, be unique. To date, treatment of posttraumatic knee pain remains generalized, with practices focused on general suppression of inflammation (i.e., rest, ice, nonsteroidal antiinflammatory drugs and steroid injections). However, it is possible that the inflammatory milieu initiating pain may have subtle but consistent variables in each distinct pathology that offer targeted treatment opportunities. Presently, the diagnosis of intrinsic knee pathology relies heavily on imaging studies. For years, MRI has been the mainstay of diagnosis and subsequent treatment of symptomatic meniscal injury. However, the extent to which current imaging modalities provide targeted treatment is inherently limited. MRI generally has over 93% sensitivity and specificity for meniscal tears when compared with arthroscopy (the gold standard in diagnosis) [8]. Nonetheless, meniscal injury can be detected in up to 76% of asymptomatic patients by MRI [8–10]. Thus, as not all meniscal injuries are painful, its presence does not mandate treatment. It is important to distinguish between meniscal injury and painful meniscal injury. It is unclear at this time why some patients who sustain meniscal injury experience pain and others do not. Furthermore, it is unclear why some patients with knee injuries progress to develop chronic pain consistent with post-traumatic osteoarthritis. Recently, there has been an exponential increase in the number of studies evaluating these very subtleties, with an emphasis on the inflammatory component. Several studies have investigated inf lammatory markers in knee pain. Specific to meniscal damage, cytokines have been the primary focus, with IL-1, IL-6, TNF-a, IFN-g, MCP-1 and MIP-1b most frequently identified. Matrix metalloproteinases (MMPs) have also been extensively investigated, with studies suggesting that MMPs inhibit IL-1 activity and the meniscal response to healing [11]. Similarly, Lawrence et al. discuss the chondroprotective effect of inhibition of IL-1 and TNF-a, and potential modulation of the molecular environment after acute meniscal damage, in an effort to decrease the risks of post-traumatic osteoarthritis due to cartilage breakdown [12]. It is our belief that cytokine modulation after acute injury is key to regulating the inflammatory environment that sets the stage for post-traumatic osteoarthritis and pain. Particular cytokines may be involved in the genesis of pain and inflammation. While it is tempting to presume that blockade of these cytokines will alleviate pain and, maybe, the development of arthritis, further studies are needed to further delineate the roles of cytokines, growth factors and generalized inflammation, not only in pain generation but also in the processes of