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Iowa Orthop J. 2001; 21: 1–7.
PMCID: PMC1888191

Roles of Articular Cartilage Aging and Chondrocyte Senescence in the Pathogenesis of Osteoarthritis


Osteoarthritis (OA), the disease characterized by joint pain and loss of joint form and function due to articular cartilage degeneration,68,13 is not an inevitable consequence of aging, but a strong association exists between age and increasing evidence of OA. Aging changes in articular cartilage that increase the risk of articular cartilage degeneration include fibrillation of the articular surface, decrease in the size and aggregation of proteoglycan aggrecans, increased collagen cross-linking and loss of tensile strength and stiffness. These alterations are most likely primarily the result of aging changes in chondrocyte function that decrease the ability of the cells to maintain the tissue including decreased synthetic activity, synthesis of smaller less uniform aggrecans and less functional link proteins and decreased responsiveness to anabolic growth factors. Our recent work suggests that the cause of the age-related loss of chondrocyte function may be progressive senescence of articular cartilage chondrocytes marked by a decline in mitotic activity, increased expression of the senescence-associated enzyme beta-galactosidase and erosion of telomere length. New efforts to prevent the development or progression of OA might include strategies that delay the onset of chondrocyte senescence or replace senescent cells.

The rapid increase in the mean age of the United States population, and the even more striking increase in the portion of the population over age 60, is profoundly changing the demands placed on our health care system. A wide variety of impairments and diseases have a close relationship to aging, and the prevalence and impact of these impairments and diseases are increasing as the population ages. Concern over the effects of aging on health has led physicians, scientists and the public to direct their attention toward improving understanding of age-related changes in tissues and organ systems and the role of these changes in causing disease and disability.2,14 Dramatic progress has been made in defining alterations in brain, bone and skeletal muscle that occur with age and in developing approaches to decrease the adverse effects of these changes. Far less attention has been paid to the age-related changes in articular cartilage that may lead to degeneration of this tissue and the pathological process consisting of gradual generally progressive loss of the tissue structure and function.2,68,14 Yet, no disease is more closely correlated with advancing age than osteoarthritis, and no disease causes more impairment of mobility.29,30


The strong correlations between increasing age and increasing incidence and prevalence of osteoarthritis2930 (Figure 1) have led to the widespread concept that osteoarthritis is an inevitable result of growing older, that is, with time and use joints wear out.17 This concept leads to the conclusion that preventing the development or progression of osteoarthritis is not possible and that the best approaches to management of the disease are symptomatic treatments for patients with mild or moderate disease and joint replacement for patients with severe disease. An alternative view is that the joint degeneration responsible for osteoarthritis is distinct from articular cartilage aging. The implications of this conclusion are that osteoarthritis is not an inevitable consequence of aging and that the potential exists to develop strategies that will decrease the risk or slow the progression of osteoarthritis. Determining which of these views is correct requires an understanding of relationships between osteoarthritis and articular cartilage aging.

Figure 1
Incidence of Symptomatic Knee Osteoarthritis vs Age


Osteoarthritis is the clinical syndrome manifested by joint pain and loss of joint form and function caused by the degeneration of articular cartilage.58 One of the first events in articular cartilage degeneration is disruption or alteration of the molecular structure and composition of the matrix. Some of the early matrix changes in articular cartilage degeneration include loss of proteoglycans and an increase in water concentration. The tissue damage stimulates a chondrocytic synthetic and proliferative response that may maintain or even restore the articular cartilage. This chondrocytic response may continue for years; however, in progressive joint degeneration the chondrocytic anabolic response eventually declines and the imbalance between chondrocyte synthetic activity and degradative activity leads to progressive thinning and loss of articular cartilage. Even in the early stages of joint degeneration, the stiffness of the articular cartilage declines and its permeability increases. These alterations in material properties may further accelerate the progression of the disease.

Articular cartilage degeneration does not progress relentlessly in all cases. The response of the synovial joint to articular cartilage degeneration can in some instances restore a form of cartilaginous surface.8,13 It is not clear how frequently this occurs, but studies of small groups of patients confirm that even in individuals with complete loss of articular cartilage the potential exists for spontaneous restoration of a cartilaginous surface that may function effectively for years.13 Thus far the characteristics of patients in whom this response occurs have not been defined, but this phenomenon deserves further study.


Articular cartilage undergoes significant structural, matrix composition, and mechanical changes with age.2,4,8,12,14,15,27,31 Although the structural, matrix and mechanical changes are almost certainly closely related to progressive change in cell function that is an age-related decline in the ability of the cells to maintain the tissue, this relationship has not been clearly defined.

Autopsy studies have documented increasing prevalence of articular surface fibrillation with age (Figures 2 and and3).3). This condition is more common in some joints than others, but appears to be a universal age-related process. The majority of patients with articular surface fibrillation do not develop joint pain or dysfunction. Thus, age-related articular cartilage fibrillation does not necessarily lead to the progressive articular cartilage degeneration responsible for osteoarthritis.

Figure 2
Prevalence of Humeral and Patellar Articular Surface Fibrillation versus Age
Figure 3
Prevalence of Ankle and Knee Articular Surface Fibrillation and Degeneration versus Age

Alterations in aggregating proteoglycans (molecules referred to as aggrecans that consist of central protein cores with multiple covalently bound chondroitin and keratan sulfate chains and that give articular cartilage its stiffness to compression, resilience and durability) are among the most striking articular cartilage matrix changes seen with aging.3,9,10,12,34 The size of proteoglycan aggregates (molecules formed by the non-covalent association of multiple aggrecans with a hyaluronan filament) decreases significantly with age (Figure 4), because the aggrecan molecules become shorter (Figure 5), as do their chondroitin sulfate chains, and because the mean number of aggrecans in each aggregate decreases (Figure 4). These age-related changes might be due to degradation of the proteoglycans in the matrix, alterations in proteoglycan synthesis, or both. Evidence from studies of bovine chondrocytes in vitro suggests that there is an age-related change in aggrecan synthesis that leads to the production of shorter, more variable aggrecan protein cores and chondroitin sulfate chains.3,12,33 Likewise, in vitro experiments show that aggregates assembled in cultures of older chondrocytes are smaller and more irregular than those assembled in cultures of younger chondrocytes.12 Some of these changes in aggregates may be caused by age-related alterations in link proteins (the small proteins that stabilize the association between aggrecans and hyaluronan).1,11,12,32 Other age-related changes in the molecular composition and structure of the articular cartilage matrix include increased collagen cross-linking and decreased water concentration.2,14

Figure 4
Electron micrographs of bovine articular cartilage proteoglycan aggregates12
Figure 5
Histogram showing the decrease in human proteoglycan aggrecan length with age12

Presumably as a result of changes in the molecular composition and organization of the matrix, the mechanical properties of articular cartilage deteriorate with age.1820,27,31 The best documented changes are declines in tensile stiffness and strength that may make the tissue more vulnerable to injury and development of progressive degeneration.

Recent studies of rat articular cartilage chondrocytes revealed an age-related decline in synthetic activity and in the anabolic response of the cells to insulin-dependent growth factor I (IGF-I).24,26 IGF-I appears to be one of the most important anabolic factors in articular cartilage and thus presumably has a critical role in maintaining the chondrocyte synthetic activity that preserves articular cartilage.24 The age-related decline in the anabolic response of articular cartilage chondrocytes to IGF-I may be associated with increased expression of insulin growth-factor binding proteins.26 An age-related increase in the production of these binding proteins could decrease the ability of the chondrocytes to maintain or repair articular cartilage matrix.

If articular cartilage aging and the articular cartilage degeneration responsible for osteoarthritis are distinct processes6,8 (Table 1), how can the striking increase in the incidence of articular cartilage degeneration with age be explained? The answer appears to be that the structural, molecular, cellular and mechanical aging changes in articular cartilage increase the vulnerability of the tissue to degeneration. Furthermore, the evidence that articular cartilage chondrocytes synthesize smaller, more irregular aggrecans and are less responsive to anabolic cytokines with increasing age suggests that older articular cartilage is less able to repair and restore itself.24,26 Thus, articular cartilage aging does not cause osteoarthritis, but aging changes in articular cartilage increase the risk of articular cartilage degeneration, and decrease the ability of joint tissues to prevent progression once degeneration begins. However, the apparent relationship between aging changes in chondrocyte function and the risk of developing osteoarthritis does not explain why the aging changes occur. Lack of such an explanation makes it difficult to develop new scientifically sound strategies for preventing the development of osteoarthritis or slowing its progression.

Table 1
Differences Between Articular Cartilage Aging and Articular Cartilage Degeneration Responsible for Osteoarthritis


A recently formulated hypothesis suggests that an intrinsic genetic "clock" regulates cell aging and that erosion of telomeres (DNA sequences at the ends of chromosomes that are necessary for chromosomal replication) as a result of cell divisions marks the advancement of this "clock." Chromosomes from young, normal somatic cells show relatively long telomeres of >9 kilobase pairs (kbp) but these are eroded at the rate of 100-200 base pairs (bp) with each cell division cycle. Erosion beyond the minimum length necessary for DNA replication (5-7.6 kbp) results in cell cycle arrest, a condition referred to as replicative senescence.

Most cell types reach cell cycle arrest after a characteristic number of population doublings. This fundamental barrier to unbridled growth, termed the Hayflick limit, is common to somatic cells that lack telomerase, an enzyme responsible for replacing telomere sequences. The Hayflick limit for human fibroblasts has been estimated at ~60 population doublings while the estimated limit for human chondrocytes is ~35 doublings. In contrast, germ cell lines and cancer cell lines, in which the "telomerase" enzyme is active, are virtually immortal. In telomerase-negative cells, telomere length can be viewed as cumulative history of preceding cell division as well as a predictor of future capacity to divide.

Cell function may begin to deteriorate before cells reach cell cycle arrest. Declining protein synthesis, altered growth factor responses, and longer population doubling times are senescence changes that begin to appear in continuously grown somatic cell cultures long before Hayflick limits are reached. This suggests that cell populations begin to drift toward senescence relatively early in their replicative lifespans, before telomeres have eroded to critical lengths.

The role of chondrocyte turnover in cartilage aging and disease has not been systematically studied due in part to the difficulty of assessing the in vivo replicative history of chondrocytes. Terminal restriction fragment length analysis of telomeres offers a simple means to overcome this problem as cell-turnover should be detectable as an age-related decline in average telomere length. If telomere erosion is an indication of cell senescence, telomere length should correlate with phenotypic measures of senescence. Based on these rationales, we hypothesized that telomere length in human articular cartilage chondrocytes declines as a funtion of age as phenotypic measures of senescence (loss of DNA synthetic activity and increasing expression of senescence-associated beta-galactosidase activity) increase.

To test this hypothesis, we measured senescence markers in human articular cartilage chondrocytes from 27 donors ranging in age from one to 87 years.25 The markers included expression of the senescence-associated enzyme beta-galactosidase, mitotic activity measured by 3H-thymidine incorporation, and telomere length. Betagalactosidase expression increased with age (r=.84, p=.0001) while mitotic activity and mean telomere length declined (r=-.77, p=.001 and r=-.71, p=.0004 respectively). Decreasing telomere length was strongly correlated with increasing expression of beta-galactosidase and decreasing mitotic activity. These findings help explain the previously reported age-related changes in aggrecan synthesis and declines in chondrocyte synthetic activity and responsiveness to anabolic growth factors3,9,10,12,14,22,23,26,33,34 and indicate that in vivo articular cartilage chondrocyte senescence is responsible, at least in part, for the age-related increased incidence of osteoarthritis (Figure 6).

Figure 6
Graph showing how the incidence of knee osteoarthritis and erosion of articular cartilage chondrocyte telomere length (a marker of cell senescence) increase with age25, 28

Although telomere erosion and senescence-associated phenotypic changes were correlated with donor age, these data must be interpreted with caution. First, the apparent linear relations we found between senescence markers and donor age may be due in part to the uneven age distribution of the donors. Relatively few young and middle aged donors were analyzed and the resulting clustering of points at very young and old ages could lead to a false impression of linearity over the entire age range. Second, other processes such as oxidative stress, and damage to DNA may induce senescence. Thus, some of the senescence we observed in chondrocyte strains, particularly those harvested from osteoarthritic donors following inflammatory episodes, may have been due to processes other than telomere erosion. Third, beta-galactosidase activity at pH 6.0 is a controversial senescence marker. Although our results with articular chondrocytes are similar to findings for vascular smooth muscle cells, which appear to exhibit the same strong correlation between age and activity, investigators studying human fibroblasts have been unable to observe a relationship between activity and donor age. This suggests that senescent cells accumulate in different tissues at different rates. Moreover, although beta-galactosidase activity is strongly associated with replicative senescence, it is also present in quiescent cells which may be common in some cartilage samples. Lastly, the apparent age-related changes we observed might have been due to other ongoing disease processes in osteoarthritic donors which were clustered in the old age range.

The relationships between articular cartilage chondrocyte senescence and osteoarthritis are undoubtedly complex. Potentially relevant disease processes include chondrocyte "cloning," a classic histologic feature of the articular cartilage degeneration responsible for osteoarthritis that refers to isolated clusters of chondrocytes formed by clonal expansion of a single cell. Cells within such clusters show accelerated mitotic activity suggesting a cause for rapid telomere erosion. Thus, the rapid decline in mitotic activity and matrix synthesis typical of end-stage osteoarthritic chondrocytes may reflect replicative senescence brought on by cloning, a hypothesis which might explain why osteoarthritic samples typically showed shorter telomeres than non-osteoarthritic samples. Although this hypothesis indicates that chondrocyte senescence is a result rather than a cause of osteoarthritis, it also implies that the phenomenon plays an important role in the progression from early to end-stage articular cartilage degeneration.

The relevance of telomeres to cartilage aging and disease rests on proof that in vivo chondrocyte turnover rates are sufficient to cause telomere erosion. Short-term DNA labeling studies indicate that chondrocyte mitoses are relatively rare in normal cartilage. Although this apparent rate of turnover is too slow to result in significant telomere erosion over the short term, decades of turnover might well be sufficient. Furthermore, mitotic activity increases several-fold following cartilage injury, therefore repetitive joint injury could accelerate telomere erosion. Increased mitotic activity during cartilage degeneration may also speed up the accumulation of senescent, growth-arrested chondrocytes in end-stage osteoarthritis. These observations suggest that, in many cases, in vivo chondrocyte turnover is sufficient to result in biologically significant telomere erosion.

These results demonstrate that chondrocyte telomeres erode in vivo in parallel with phenotypic changes associated with senescence. How these processes contribute to degenerative joint disease is not yet clear, however, our data strongly suggest that cell senescence contributes to either the development or progression of osteoarthritis (Figure 6). Some of the variability in the risk of developing osteoarthritis among individuals may be due to differences in onset of chondrocyte senescence, possibly related to genetically determined differences or to differences in exposure to environmental factors, such as stress and injury, that increase the rate of chondrocyte turnover. Furthermore, in vivo chondrocyte senescence may adversely affect the results of chondrocyte transplantation procedures performed to restore damaged articular surfaces in older patients. Future efforts to prevent and treat osteoarthritis might include strategies that delay the onset of chondrocyte senescence or replace senescent cells.


Articular cartilage undergoes age-related changes that increase the risk of the articular cartilage degeneration that causes the clinical syndrome of osteoarthritis. In addition, these changes may adversely affect the outcomes of attempts to repair or regenerate articular cartilage. Perhaps the most important of these age changes involve alterations in chondrocyte synthesis of proteoglycans and the responsiveness of chondrocytes to anabolic growth factors. It is possible to slow, or temporarily reverse at least, some of the age-related changes in articular cartilage that increase the probability of joint degeneration? Once degenerative changes have developed, can they be stabilized or reversed? Will it be possible to develop methods that predictably produce functional durable cartilaginous articular surfaces for middle-aged and older people with joint injuries and joint degeneration? Further study will definitively answer these questions. However, the investigation of articular cartilage aging is only beginning and the observations developed thus far strongly suggest that better understanding of the aging changes in articular cartilage and how these changes influence the ability of the tissue to maintain and regenerate itself will lead to improved methods of preserving and restoring articular surfaces for middle-aged and older individuals. In particular, new efforts to prevent the development or progression of OA might include strategies that delay the onset of chondrocyte senescence or replace senescent cells.


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Articles from The Iowa Orthopaedic Journal are provided here courtesy of The University of Iowa
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