Molecular mechanisms of cartilage destruction: Mechanics, inflammatory mediators, and aging collide (2006)

Destruction and loss of articular cartilage is a central feature in most forms of arthritis including the most common form, osteoarthritis (OA). The pathobiologic differences among the various types of arthritis relate, at least in part, to differences in mechanisms driving cartilage destruction. Often forms of arthritis are divided into “inflammatory” and “noninflammatory,” where “inflammatory” arthritis is meant to indicate cellular inflammation resulting from an influx of various activated leukocytes into the joint which mediate destruction, while “noninflammatory” arthritis indicates a lack of significant inflammatory cell invasion and is often described as “degenerative arthritis.” However, as we discover more about the basic mechanisms behind “noninflammatory” or “degenerative arthritis,” it is becoming clear that these are misnomers.

Although cartilage destruction is a central feature in OA, pain and disability result from processes that affect multiple tissues that contribute to joint structure and function, not just the articular cartilage. A recent editorial in Arthritis & Rheumatism has addressed the importance of bone in the development of OA (1). Although synovial inflammation in OA is not as extensive as that observed in the classic inflammatory forms of arthritis such as rheumatoid arthritis (RA), there is mounting evidence that synovitis plays a role at least in a subset of patients with OA (2,3). Magnetic resonance imaging studies are also revealing a high frequency of meniscal lesions in OA joints, and meniscal damage as well as ligament damage are clear risk factors for development of OA (4,5). Pathology in the menisci and ligaments most likely contributes to the development of OA through altered biomechanics, and it is certain that mechanical forces play an essential role in the development of OA. The altered mechanical forces, factors released from subchondral bone, and in some cases inflammatory mediators released from the synovium all can contribute to the cartilage pathology in OA (Figure 1).



Figure 1

Factors acting on articular cartilage during the development of osteoarthritis (OA). The image of OA tissue is from a toluidine blue–stained section and demonstrates classic OA features including loss of matrix staining and loss of cells in the ...



So, other than in the subset of patients who exhibit some degree of synovitis, where is the inflammation in OA? There is mounting evidence that the cartilage destruction in OA is the result of cartilage inflammation at the molecular level (for review, see refs. 6 and 7). Abnormal mechanical forces appear to awaken the adult chondrocyte from a state of low metabolic activity (8) and stimulate the cell to produce a host of inflammatory mediators, many of which are normally produced by macrophages during responses to injury or infection (7). These include cytokines and chemokines (such as interleukin-1 [IL-1], IL-6, IL-8, IL-17, IL-18, monocyte chemoattractant protein 1, leukemia inhibitory factor, growth-related oncogene, and oncostatin M) as well as reactive oxygen species (ROS; such as nitric oxide [NO], superoxide, hydrogen peroxide, and peroxynitrite). These various factors, along with lipid-derived inflammatory mediators (such as prostaglandins and leukotrienes), serve to increase the catabolic activity of the chondrocyte, which results in the release of proteolytic enzymes, including aggrecanases and matrix metalloproteinases, that cause destruction of the cartilage matrix. Cartilage destruction in OA may be, at least in part, an overzealous attempt of the chondrocyte to remove a damaged matrix so that it can be replaced with new material.

Nature has produced a series of checks and balances in tissues such that, if everything were in order, once the damaged matrix proteins were removed, the proteolytic process would be turned off and the chondrocyte would work to replace the lost matrix. Chondrocytes produce a host of growth factors (such as bone morphogenetic protein 2 [BMP-2], BMP-7, cartilage-derived morphogenetic proteins, insulin-like growth factor 1, and transforming growth factor β [TGFβ]) that serve to stimulate matrix production and to inhibit production of proteolytic enzymes. Many of these are stored in the cartilage bound to matrix proteins and are released when the matrix is degraded so that they can act locally to shut down the degradation. In the OA joint, it would appear that this phase of matrix remodeling is insufficient or defective. But why?

This is most likely where aging comes into play. Development of OA is strongly associated with age. Besides changes that occur in the matrix, such as accumulation of advanced glycation end products that make the tissue more brittle (9), the age-related changes in the chondrocyte result in a cell that is less responsive to growth factor stimulation (for review, see ref. 10). If sufficient growth factor activity is not present in aged cartilage, then the tissue will not generate the signals necessary to turn off production of catabolic factors and turn on matrix synthesis (Figure 2). This could result in a continued cycle of unchecked matrix degradation in response to mechanical forces and continued damage to the matrix.



Figure 2

Theoretical model for pathways involved in cartilage destruction during the development of osteoarthritis. Excessive mechanical forces stimulate the chondrocyte directly or indirectly through signals generated by matrix damage, including generation of ...



In addition to the more obvious genetic defects that result in production of abnormal cartilage matrix structure, genetic factors also could contribute to insufficient repair of matrix damage. For example, in a Japanese population with knee OA, a polymorphism in the gene that codes for a small leucine-rich proteoglycan named asporin results in production of a protein that appears to have a greater affinity for TGFβ and that could therefore inhibit the ability of TGFβ to adequately stimulate the chondrocyte (11). Polymorphisms in other genes associated with OA, such as the FRZB gene and CALM1, could also act to disrupt the normal balance of anabolic–catabolic signaling in cartilage (for review, see ref. 12).

Therefore, to better understand mechanisms responsible for cartilage destruction, at least that which is mediated by the chondrocyte itself (sometimes called chondrocytic chondrolysis), it is necessary to study the molecular mechanisms responsible for creating an imbalance in chondrocyte catabolic and anabolic activity. Since at some point in the cartilage destruction process chondrocytes are lost due to cell death, it is also important to know if these factors contribute to cell death as well.

In this issue of Arthritis & Rheumatism, Green et al (13) add to the growing body of literature which suggests that production of ROS plays a role in events occurring after mechanical injury to cartilage. Previous studies have demonstrated that mechanical stimulation can increase chondrocyte production of ROS that depolymerize hyaluronic acid (14) and kill chondrocytes (15). Green et al used a blunt-trauma model to acutely injure the cartilage and determined that the observed cell death could be inhibited by blocking NO synthase with NG-monomethyl-L-arginine. Since NO by itself is unlikely to cause chondrocyte death (16), the findings suggest that excess NO had combined with increased production of other ROS that react with NO to form highly reactive and toxic compounds such as peroxynitrite.

In addition, Green et al demonstrated that the injured cartilage was more susceptible to further injury mediated by leukocytes. The injured chondrocytes increased expression of intercellular adhesion molecule 1, which serves as an adhesion receptor for leukocytes. Adhesion of leukocytes to the injured chondrocytes resulted in death of additional cells due either to stimulation of further production of toxic ROS by the chondrocytes or to release of ROS from leukocytes. It is unlikely that this observation has any relevance to chondrocyte death in OA, where the presence of leukocytes within the joint with access to cartilage would be expected to be quite low, but it may be relevant to acute trauma when it is severe enough to cause blood to enter the joint, or in RA, where greater numbers of leukocytes would be present.

If the abnormal mechanical loading that is observed in OA is found to be sufficient to stimulate a chronic excess production of ROS, this could be an important mechanism that ties mechanical forces and aging changes in cartilage to the creation of a proinflammatory state and an imbalance in anabolic–catabolic activity. There is evidence for oxidative damage with aging and in OA cartilage, and there are data to suggest that ROS can mediate processes involved in cartilage destruction, including an imbalance in metabolic activity (for review, see ref. 17).

The effects of chronic ROS production go beyond just simply causing direct damage to the cell and matrix. Altering the intracellular redox state could alter the activity of specific redox-sensitive signaling proteins that may be important in controlling anabolic and catabolic pathways (18). If correcting abnormal mechanics is not possible in particular patients, then targeting the pathways by which abnormal mechanics result in destruction of joint tissues could have obvious therapeutic value. More work is needed to further define the signaling pathways activated by excessive mechanical forces, including the role of ROS. These studies should help to further elucidate the basic molecular mechanisms that link mechanics, cartilage inflammation, and aging to the development of OA.