OA is a multifactorial condition but the pathological changes seen in osteoarthritic joints have common features no matter what the cause(s) of the condition in a given individual. These features include degradation of the articular cartilage starting at the joint surface and progressing to full thickness loss, thickening of the subchondral bone with accumulation of poorly mineralized matrix, osteophyte formation at the margins of joint surfaces, variable degrees of synovial inflammation with limited pannus formation, degeneration of ligaments and, in the knee the menisci, with eventual ligamentous rupture and meniscal extrusion, and hypertrophy of the joint capsule contributing to joint enlargement (). In some individuals, increased subchondral bone remodeling results in bone marrow lesions detected on MRI and, in many older adults, calcification in the articular cartilage and/or the menisci is seen on plain radiographs. In the articular cartilage, the earliest changes at the joint surface occur in the areas that receive the greatest mechanical forces. As OA progresses, the loss of the articular cartilage affects joint movement due to the loss of a smooth lubricated surface responsible for the normal gliding motion of the joint. The pathological changes noted in the other joint tissues also contribute to the loss of normal joint function and, because unlike the cartilage they contain pain fibers, these tissues are responsible for the pain experienced by people with OA.
There are reasons to believe that although OA has common pathological features seen once the disease becomes advanced, it may start with selected features that are dependent on the initiating factors in a given individual. For example, in an individual with post-traumatic OA resulting from rupture of the anterior cruciate ligament the condition likely started with a period of acute joint inflammation with synovitis and cartilage matrix destruction followed later by development of bony changes while in an individual with OA related to obesity it may have started with increased bone formation followed by articular cartilage matrix destruction and secondary synovial inflammation stimulated by release of cartilage matrix fragments. The early stages of OA have been difficult to study. Most people do not develop symptoms until significant joint damage has occurred, commonly after age 50-60 years, but there is radiographic evidence for OA in a significant percent of women beginning in the early 40's10
. Researchers are attempting to develop biomarkers and advanced imaging techniques that could detect early stage disease but given the slowly progressive nature of OA it will be some time before sufficient information is available to determine the predictive power of these techniques.
At the cell and tissue level, cartilage in OA is characterized by an imbalance in matrix synthesis and matrix degradation. The chondrocyte is the only cell type present in articular cartilage and therefore is responsible for both the synthesis and the breakdown of the cartilaginous extracellular matrix11
. Signals generated by cytokines, growth factors, and the matrix regulate chondrocyte metabolic activity. In the early stages of OA, there is evidence of increased matrix synthesis, although not all the matrix proteins produced are the same as those made by normal adult articular chondrocytes. There is increased expression of the fetal form of type II collagen (type IIA)12
and of type III collagen and fibronectin13, 14
as well as proteoglycans with altered sulfation patterns15
. Progressively, excessive matrix degradation overwhelms matrix synthesis and this appears to be due to inflammatory and catabolic signals that are present in excess of the anti-inflammatory and anabolic signals (). Pro-inflammatory cytokines found in OA cartilage include IL-1, IL-6, IL-7, IL-8, and TNF-α to name just a few. The presence of a large number of inflammatory mediators within the articular cartilage indicates that OA is much more inflammatory than previously thought. The excess of inflammatory signals inhibits matrix synthesis and promotes increased production of matrix degrading enzymes, including matrix metalloproteinases (MMPs), aggrecanases, and other proteases that degrade the cartilage matrix. As OA develops, chondrocytes can assume a hypertrophic phenotype characterized by production of type X collagen, alkaline phosphatase, and matrix metalloproteinase (MMP)-13 (collagenase-3)13
Catabolic and anabolic factors that regulate chondrocyte function
Chondrocyte death has been observed during the development of OA but whether this is an early or late event is not clear16, 17
. Because cartilage lacks an abundant supply of stem or progenitor cells, the loss of chondrocytes to cell death results in a decline in cell numbers. This is most apparent in the superficial region of the articular cartilage. Although normally adult articular chondrocytes rarely divide, there is evidence for cell proliferation during the development of OA resulting in clusters of chondrocytes being present. However, these cells are unable to maintain the matrix which may be due at least in part to a reduced ability to respond to growth factor stimulation further contributing to an imbalance in matrix synthesis and degradation.
In contrast to matrix loss in the articular cartilage, the subchondral bone undergoes increased matrix production resulting in a thickening of this region. Older theories of OA suggested that the increased subchondral bone resulted in increased stiffness that contributed to the degradation of the overlying cartilage by increasing local stresses18, 19
. However, later studies found that the subchondral bone in OA was poorly mineralized and perhaps less stiff than normal bone18-20
. More recently, studies have focused on inflammatory mediators produced by subchondral bone cells that could diffuse through the calcified cartilage zone or enter through cracks in the calcified cartilage and negatively affect the overlying articular cartilage21
. The presence of localized areas of increased bone remodeling detected by bone scans or by MRI has been noted in areas of cartilage loss and is associated with pain in OA22
. The correlation of these lesions in the knee with the location of excessive loading, i.e., medial bone lesions in association with varus alignment and lateral lesions with valgus alignment, suggest they are mechanically mediated23
The degree of synovitis present in OA is variable. In people with OA severe enough to require knee replacement, about a third of patients had marked synovitis, one third moderate synovitis, and one third little to no synovitis24
. This suggests that synovitis may be important in a subset of people with OA but it is not required to progress to end-stage disease. However, an arthroscopic study of people with early OA did find an association between the presence of synovitis and progression of cartilage lesions measured a year later25
. Studies of OA synovial fluid have revealed the presence of inflammatory cytokines that could be involved in stimulating cartilage destruction as well as destruction of other joint tissues such as the meniscus and ligaments. The growth factor TGF-β, although an important contributor to cartilage matrix production, may be responsible for the stimulation of synovial hypertrophy as well as osteophyte formation26
Although the synovium is involved in OA, the extent of inflammation is usually less than that found in rheumatoid arthritis (RA) where pannus formation is much more extensive and appears to be directly responsible for joint tissue destruction. The extent of synovial inflammation as well as higher systemic levels of inflammatory mediators has been used to classify RA as inflammatory arthritis and OA as “non-inflammatory”. However, as noted above, inflammatory mediators are responsible for joint tissue destruction in OA and elevated serum levels of CRP27
and cytokines including IL-628
in people with OA indicate that inflammation plays a role in OA as well as RA.