Sci. Aging Knowl. Environ., 21 July 2004
Vol. 2004, Issue 29, p. pe31
[DOI: 10.1126/sageke.2004.29.pe31]

PERSPECTIVES

Aging Cartilage and Osteoarthritis--What's the Link?

Richard F. Loeser Jr.

The author is in the Departments of Medicine and Biochemistry, Section of Rheumatology at Rush Medical College, Rush University Medical Center, Chicago, IL 60612, USA. E-mail: rloeser{at}rush.edu

http://sageke.sciencemag.org/cgi/content/full/2004/29/pe31

Key Words: cartilage • osteoarthritis • chondrocyte • extracellular matrix • catabolic pathways • oxidative stress

Introduction

The articular cartilage provides a smooth and slippery covering to the ends of the bones that form the various articulating joints in the body, producing a surface with a very low amount of friction that facilitates the normal smooth gliding motion of the joint. The cartilage must be able to withstand years of repeated mechanical loading. When the articular cartilage fails, joint motion is compromised and pain ensues. Because cartilage lacks a nerve supply, pain is likely to be a result of associated damage to local joint tissues, including neighboring bone, synovium, the joint capsule, and other soft tissues (Fig. 1). Progressive cartilage destruction is characteristic of osteoarthritis (OA). OA is the most common form of arthritis and affects over 20 million people in the United States (1). Although multiple factors such as obesity, previous joint injury, and genetics can lead to the development of OA, the primary risk factor is age (2). In fact, OA is the most common cause of chronic disability in older adults (1) (see "The Burden of Pain on the Shoulders of Aging").



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Fig. 1. Joint structure. Cartilage provides a smooth and slippery surface at the ends of articulating bones. The synovium is a thin membrane-like structure that lines the joint cavity and is surrounded by thicker fibrous tissue that forms the joint capsule. The pain of OA might be derived from damage to tissues in the region of the joint, including the bone, synovium, and joint capsule, as well as the muscle and ligament (not shown).

 
Over the past several years, our knowledge of the pathogenesis of OA has progressed beyond the overly simplified concept of arthritis being caused by "wear and tear." Although mechanical factors certainly play a key role in the development of this condition, they likely work to destroy the cartilage matrix through the activation of catabolic pathways in the articular chondrocytes themselves (3). Chondrocytes are the only cell type present within cartilage and are responsible for both the synthesis and the degradation of the very abundant extracellular matrix (ECM) present in this tissue (see Reed Perspective for a discussion of the ECM). They are responsive to mechanical stimuli, which under normal loading conditions help to maintain tissue homeostasis (4). When normal mechanics are altered and abnormal joint loading occurs, the chondrocyte can respond in such a way that matrix catabolism is favored over repair (5).

Chondrocyte metabolic activity is controlled by the local production of anabolic growth factors and catabolic cytokines. During the development of OA, an increase in both anabolic and catabolic activity has been observed to result from an increased abundance of a number of growth factors [including insulin-like growth factor-1 (IGF-1) and transforming growth factor-{beta} (TGF-{beta}) and cytokines [including interleukin-1{beta} (IL-1{beta}), tumor necrosis factor-{alpha}, and IL-6], with the balance being tipped toward the catabolic side (6). An increase in catabolic signaling results in increased expression and release of enzymes that degrade type II collagen and a large proteoglycan called aggrecan, the major matrix proteins in cartilage. These enzymes include several of the metalloproteinases, such as MMP-1 and MMP-13, that degrade collagen, and enzymes called aggrecanases that degrade aggrecan (7-9). The excessive enzymatic activity in OA results in degradation and loss of the cartilage matrix. Matrix loss is accompanied by both cell death and chondrocyte proliferation, the latter thought to be an attempt of the chondrocyte to repair the damaged matrix (Fig. 2).



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Fig. 2. Histological changes characteristic of OA. A toludine blue-stained section of knee articular cartilage demonstrates fibrillation and extensive loss of matrix staining in the surface zone associated with a loss of cells. In the deeper areas, clusters of proliferating chondrocytes are noted, which are thought be a response to lost matrix and an attempt at repair. Studies of these clusters have also noted the presence of apoptotic cells (34). There is duplication of the tidemark (the wavy line between the articular and calcified cartilage zones) in the calcified cartilage and thickening of the subchondral bone (that is, the bone beneath the cartilage).

 
Because OA is so closely associated with aging, it is important to understand how aging plays a role in the OA process. As discussed in more detail below, aging-associated changes have been observed in both cartilage ECM components and in the chondrocytes. Normally there is little turnover of the majority of the cartilage matrix in the adult, and there is little turnover of cells (10). Because adult articular cartilage does not appear to contain a supply of precursor cells to replace damaged or senescent chondrocytes and because very little to no cell division occurs in normal adult cartilage (11), the resident chondrocytes must maintain the tissue for the lifetime of the individual. The fact that chondrocytes are long-lived cells could play a central role in cartilage aging. Unlike tissues that have a regular turnover of cells, cartilage contains cells that must remain metabolically active for many years and therefore can potentially accumulate cellular damage over many years. This possibility makes cartilage a particularly interesting tissue to study from the viewpoint of understanding aging.

Aging and the Development of OA Are Closely Related

The structural changes of OA that appear on standard x-rays are narrowing of the joint space caused by cartilage loss, the formation of osteophytes (also called bony spurs) at the joint margins, and bony sclerosis (during which the bone becomes denser or thicker than usual) just underneath the articular cartilage. The joints most commonly affected include the distal joints of the hand, the first metatarsal joint of the feet, and joints in the cervical and lumbar spine, hips, and knees. The radiographic features of OA are very rare in adults before about the age of 40 years (12, 13), but by the age of 60 almost 80% of the population will exhibit changes in at least one joint (14). But not all of these people are symptomatic, and the mere presence of small osteophytes is often considered to be a feature of "normal aging."

OA in the knee joint accounts for a large proportion of pain and disability from this condition, affecting approximately 10% of the population over the age of 60 years (1). The incidence of knee OA continues to rise until at least age 80 (13). However, it appears that the incidence of disease may level off in the older age groups. In centenarians, the prevalence of symptomatic OA of the hip, knee, shoulder, or spine was found to be only 54% (15). These findings suggest that OA is not an inevitable consequence of aging. Clearly, aging-associated changes in joint tissues, as well as in tissues that support joint function such as muscle, play an important role in the development of OA, but additional factors contribute to when, how severely, and which joints will be affected. These additional factors (OA factors) include systemic factors such as sex, race, genetics, obesity, and nutrition, as well as local factors such as joint injury, alignment, anatomy, and muscle strength (2, 16). The relation between aging and OA factors is summarized in Fig. 3. This model suggests that aging-related changes in joint tissues do not directly cause OA but rather increase the susceptibility of older adults to developing OA when other factors are present.



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Fig. 3. Theoretical relation between aging and the development of OA. Changes that occur in musculoskeletal tissues as a result of aging do not directly lead to the development of OA but rather contribute to an increased susceptibility to OA. Additional factors (OA factors) combine with the aging-associated changes and result in the development of OA in specific joints. Proprioception refers to the mechanism that regulates movement and posture. [Adapted from (39)]

 
OA affects multiple joint tissues, as described above, including not only the articular cartilage but also neighboring bone, ligaments, tendons, menisci, synovium, and the joint capsule. There is even some debate as to whether OA might be a primary disease of bone rather than cartilage (17). This possibility might be true for some individuals; however, the destruction and loss of the articular cartilage are central features of OA. Recent work has suggested that the rate of cartilage loss predicts the subsequent need for joint replacement surgery, a procedure necessary for management of advanced cases of OA (18). The aging-associated changes that make older adults more susceptible to OA have been best studied in the articular cartilage and will be the focus of the rest of this discussion.

Aging-Associated Changes in the Cartilage ECM

Cartilage is mostly composed of water and ECM proteins, with cells making up less than 2% of the volume of the tissue (19). It appears that age-related changes in the ECM of cartilage result in a tissue that is less able to handle mechanical stress. The major matrix proteins in cartilage are the proteoglycans, which are responsible for the resiliency of the tissue, and type II collagen, which provides the tensile strength. Aggrecan, the major cartilage proteoglycan, becomes smaller with age and is altered structurally as the result of proteolytic modification in the core protein as well as changes in the length and abundance of the attached glycosaminoglycan chains (20). The negatively charged sulfate groups on the glycosaminoglycan chains are hydrophilic and are responsible for maintaining the water content of cartilage, which decreases with age; a change that contributes to a decrease in resiliency (21).

Perhaps the most striking age-related change in articular cartilage is the accumulation of advanced glycation end products (AGEs) (see Monnier Perspective and "Aging Research Grows Up"). Because collagen has such a long half-life (estimated to be over 100 years for type II collagen in cartilage), it is particularly susceptible to progressive accumulation of AGEs (22). The AGEs that have been best characterized in cartilage are pentosidine and carboxymethyllysine (23). Studies have shown that the amount of pentosidine found in collagen directly increases with donor age in human cartilage (22, 24). Pentosidine formation, which can cross-link collagen molecules, might be an important factor in the increase in collagen stiffness and altered cartilage biomechanics observed with aging (23, 25, 26). As discussed below, pentosidine formation in cartilage has been associated with reduced chondrocyte anabolic activity (24), suggesting that AGE accumulation might affect chondrocyte function in addition to cartilage biomechanics.

The prevalence of cartilage calcification (chondrocalcinosis) increases with age (27, 28). An increase in the formation of crystals in cartilage that lead to calcification might be the result of an increase in transglutaminase activity, which contributes to crystal formation (29), and/or an increase in inorganic pyrophosphate formation in response to TGF-{beta} (30). In addition, recent work in guinea pigs that develop spontaneous OA with aging suggests that age-associated progressive adenosine triphosphate (ATP) depletion resulting in increased nucleotide pyrophosphatase/phosphodiesterase activity might also contribute to aging-related chondrocalcinosis (31).

Additionally, there is some degree of cartilage thinning with age, particularly in the femoral cartilage. The volume of such cartilage was found to be reduced by about 21% in women and 13% in men in normal people aged 50 to 78 years as compared to those 20 to 30 years of age in a study using quantitative magnetic resonance imaging (32). This change might be partly the result of an age-related decrease in cartilage hydration but is unlikely to be due to significant cell death. A decline in cell numbers in cartilage with aging has been noted, but the magnitude of such cell loss is debated. A study of cell death during aging in knee cartilage found less than 5% cell loss (11), whereas a study of hip cartilage from people without apparent arthritis revealed a 30% decrease in cell density between the ages of 30 and 70 years (33). Although the connection between cell death and aging is not clear, there is relatively good evidence that cell death plays a role in the development of OA (34). Death of a chondrocyte is of particular importance because dead chondrocytes are unlikely to be replaced. Chondrocyte proliferation is rare in normal adult cartilage (11), and the proliferative capacity of the cells appears to decrease with aging, perhaps as a consequence of a reduced mitogenic response to growth factor stimulation (30, 35). Whether this change is related to replicative senescence of chondrocytes is not known, although recent work has suggested this possibility, with evidence of telomere shortening in chondrocytes from older adults (36). Telomere shortening, a phenomenon that occurs as a result of DNA replication, is the primary cause of senescence in cultured human cells (see Hornsby Perspective). Studies have suggested that oxidative damage can also promote telomere erosion (37, 38) providing a potential mechanism for telomere shortening in cartilage that does not require cell proliferation. The role of oxidative stress in cartilage aging is further discussed below. Changes in cartilage matrix and chondrocyte function with aging are summarized in Fig. 4.



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Fig. 4. Summary of aging-related changes observed in cartilage cells and matrix and their relation to aging processes (genomic, oxidative, and endocrine) and subsequent changes in cartilage function (reduced repair capacity and increased susceptibility to catabolic stimuli).

 
Aging-Associated Changes in Chondrocyte Function

Like changes in the ECM, aging-related changes in chondrocyte function can occur over many years because of the normally low turnover of chondrocytes. The ability of the chondrocyte to maintain cartilage homeostasis declines with aging and this decline appears to be primarily the result of decreased anabolic activity (39). As introduced above, chondrocyte metabolic activity is regulated by the integration of signals generated from (i) biomechanical stimulation (for example, intermittent compression); (ii) ECM proteins (for example, matrix glycoproteins, collagens, and proteoglycans); and (iii) soluble factors including growth factors [for example, IGF-1 and osteogenic protein-1 (OP-1)], cytokines (for example, IL-1 and IL-6), lipid mediators (for example, prostaglandins), and even gases (for example, nitric oxide and oxygen) [reviewed in (3, 6, 10)]. Anabolic factors, including IGF-1, can be anticatabolic (40, 41), and catabolic factors, including IL-1 and IL-6, can be antianabolic (42, 43). There is a lack of data on how age-related changes in biomechanical stimulation might affect chondrocyte function. The available data, which are minimal, on the effect of age on the catabolic response to cytokines such as IL-1 suggest that it does not appear to go down with age (44). In addition, the antianabolic effects of IL-1 do not differ in young and old mice, whereas the ability of TGF-{beta} to counteract the inhibitory effects of IL-1 is lost in cartilage from old mice (45).

The majority of the work has been done on the response to anabolic factors, which shows a decline with aging. Several studies have focused on age-related changes in the chondrocyte response to IGF-1. This factor is unique among the endogenous cartilage growth factors studied to date in that it stimulates matrix synthesis and cell survival and has anticatabolic activity. In experiments using bovine explant cultures (representative of young adult cartilage), IGF-1 has been shown to be the major stimulator of proteoglycan synthesis present in synovial fluid and in fetal calf serum (46, 47). The anabolic response to IGF-1 is reduced with age in rat (48, 49) and monkey cartilage (50), and we have recently found that the anabolic and survival effects of IGF-1 are reduced in human cartilage from aged versus young individuals (51). Recent data also demonstrate that proteoglycan synthesis stimulated by another cartilage anabolic factor, bone morphogenetic protein 6 (BMP-6), declines with age in human cartilage (52). Although there are no data to suggest that the anabolic response to OP-1 (also known as BMP-7) declines with age, there are data to suggest that endogenous production of OP-1 decreases with age, a change that could also contribute to a decline in anabolic activity in the cartilage (53).

The mechanism responsible for an age-related decline in growth factor response is not clear. It could theoretically occur as a result of a reduced number of growth factor receptors, an alteration in the cell signaling response to stimulation, or an altered response at the level of transcription or translation. Very little work has been done in this area, particularly in human cartilage. An age-related change in the number of IGF-1 receptors was not seen in rat cartilage (48) or in senescent fibroblasts (54), and several studies of cartilage affected by OA have noted increased rather than decreased expression of IGF-1 receptors (55, 56), suggesting that decreased receptor numbers is unlikely to be responsible for the decline in the response to growth factors. A study in rat cartilage noted an increased abundance of an IGF-1 binding protein (IGFBP-3) in older versus younger rats, which was hypothesized to limit the IGF-1 response (48). However, available data on IGFBP-3 in cartilage indicate that it might not inhibit IGF activity. For example, IGFBP-3 enhances IGF-1-stimulated proteoglycan synthesis by OA explants (57), and we have shown that estrogen replacement in ovarectomized monkeys increases the abundance of IGFBP-3 in cartilage (58) and yet decreases the amount of OA-like change (59). Also, our previous studies in monkey cartilage demonstrated an age-related decrease in the response to des(1-3)IGF-1, a form of IGF-1 that has a similar affinity for the IGF-1 receptor but more than 500 times less affinity for IGFBP-2 and about 20- times less affinity for IGFBP-3 as compared to intact IGF-1 (50). These studies suggest that the reduced response is caused by altered cell signaling. This idea is supported by a recent study of aging rat cartilage, in which IGF-1 displayed a reduced ability to stimulate production of cyclic adenosine monophosphate and activation of protein kinase C (49).

It is also possible that other age-related changes in the ECM could affect chondrocyte function via a feedback mechanism. As noted above, probably the most dramatic change in the aging versus young ECM is the accumulation of AGEs. A significant negative correlation was found between the amount of pentosidine and the level of proteoglycan synthesis in human articular cartilage explants cultured in medium containing 10% serum (24). Whether AGEs directly interfere with the ability of growth factors to stimulate their receptors or have some indirect affect on growth factor activity is not known. Cells can express receptors capable of binding AGEs that might generate signals that modulate growth factor signaling. The best characterized AGE receptor is called RAGE (receptor for AGEs). RAGE signaling has been shown to induce oxidative stress and activate mitogen-activated protein kinase signaling that leads downstream to increased activity of the nuclear factor {kappa}B (NF-{kappa}B) transcription factor (60, 61). Activation of NF-{kappa}B could create a proinflammatory state in chondrocytes affecting the cells response to growth factors and cytokines. We have found that chondrocytes express RAGE (51) and are determining whether activation of RAGE signaling interferes with the response to IGF-1.

Could Oxidative Stress Contribute to Cartilage Aging and the Development of OA?

The free radical theory of aging suggests that the chronic production of endogenous reactive oxygen species (ROS) and subsequent cellular damage from these species could mediate many of the changes that are associated with cellular aging (62, 63) (see "The Two Faces of Oxygen" and Praticò Review). There is extensive evidence that supports an important role for oxidative stress and oxidant-mediated damage in aging and age-related disease, ranging from cataract formation to atherosclerosis and neurodegeneration (63). The major ROS produced by cells are superoxide anions (O2), hydroxyl radicals (·OH), and hydrogen peroxide (H2O2). Although they are technically "reactive nitrogen species," nitric oxide (NO) and products formed by the reaction of NO with ROS such as peroxynitrite (ONOO) are also considered to be important ROS. All of these ROS have been found to be produced by chondrocytes (64-66). However, little is known about the potential role of oxidative stress in cartilage aging despite evidence that ROS might be involved in cartilage degradation [reviewed in (67)].

Enhanced production of ROS, including NO, can decrease chondrocyte synthesis of proteoglycan (68-70) and hyaluronic acid (a high-molecular-weight polymer in the ECM) (71). NO has been specifically shown to reduce IGF-1-stimulated proteoglycan synthesis (72-74), but it is not known whether this effect is caused by NO by itself or by NO reacting with ROS to produce ONOO, which also inhibits proteoglycan synthesis (69, 70). There is evidence that NO suppresses proteoglycan synthesis, at least in part, through disruption of integrin signaling (72), reduced phosphorylation of the IGF-1 receptor (74), stimulation of cyclic guanosine monophosphate production (75), and depression of mitochondrial oxidative phosphorylation (76). It is not known which, if any, of these mechanisms are responsible for the age-related reduction in IGF-1-stimulated proteoglycan synthesis.

The production of ROS is normally balanced by the presence of an antioxidant defense system that maintains the normal redox state within the cell (see Sampayo Perspective). This system includes enzymatic scavengers such as catalase (CAT), superoxide dismutases (SOD1 and SOD2), and glutathione peroxidase. Important nonenzymatic scavengers include glutathione, peroxiredoxins, ascorbate, pyruvate, flavonoids, and carotenoids (63). Oxidative stress occurs when the balance of ROS and antioxidant defenses favors ROS. We have recently discovered evidence for age-related oxidative stress and damage in cartilage. The first evidence came from a study using antibodies that recognize 3-nitrotyrsosine, a marker for oxidative damage in cartilage (77). 3-nitrotyrosine can form by the reaction of peroxynitrite with protein tyrosine residues. We found evidence for nitrotyrosine formation in adult monkey and human articular cartilage that increased with age and was particularly prominent in OA cartilage (77).

In a second study, we measured concentrations of reduced and oxidized glutathione in chondrocytes isolated from human cartilage obtained from donors of different ages. The concentration of total glutathione was over three times higher in chondrocytes from older versus younger donors, mainly as a result of an increase in the concentration of oxidized glutathione, which is a sign of oxidative stress (78). When glutathione concentrations were expressed as a ratio of oxidized to reduced glutathione, there was a significant age-related increase in the glutathione ratio (Fig. 5). It was also noted that reduced glutathione was important in protecting chondrocytes from oxidant-mediated cell death. Chondrocytes from older adults, which had higher concentrations of oxidized glutathione, were more susceptible to oxidant-mediated cell death (78).



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Fig. 5. Increased ratio of oxidized to reduced glutathione (GSSG/GSH) with aging in articular chondrocytes. Concentrations of oxidized and reduced glutathione were measured in chondrocytes isolated from normal ankle cartilage obtained from tissue donors. Data are from (78) and plotted using donor age as a continuous variable. The increased ratio of oxidized to reduced glutathione is evidence for oxidative stress in chondrocytes with aging.

 
In support of a role for ROS in the development of age-related OA, the use of several antioxidant vitamins along with the antioxidant selenium was recently shown to reduce the development of OA in a mouse model (79). Furthermore, a low intake of antioxidant vitamins has been associated with OA progression in humans (80). There is still much to learn about ROS and oxidative stress in aging and OA in order to define more specific targets for interventions that might help prevent OA. Studies directed at the aspects of this disease that are specific to aging, rather than just to the disease itself, should provide a novel and perhaps more preventative approach to the management of OA.


July 21, 2004
  1. R. C. Lawrence, C. G. Helmick, F. C. Arnett, R. A. Deyo, D. T. Felson, E. H. Giannini, S. P. Heyse, R. Hirsch, M. C. Hochberg, G. G. Hunder, et al., Estimates of the prevalence of arthritis and selected musculoskeletal disorders in the United States. Arthritis Rheum. 41, 778-799 (1998).[CrossRef][Medline]
  2. D. T. Felson, Y. Zhang, An update on the epidemiology of knee and hip osteoarthritis with a view to prevention. Arthritis Rheum. 41, 1343-1355 (1998).[CrossRef][Medline]
  3. M. B. Goldring, The role of the chondrocyte in osteoarthritis. Arthritis Rheum. 43, 1916-1926 (2000).[CrossRef][Medline]
  4. J. P. Urban, The chondrocyte: a cell under pressure. Br. J. Rheumatol. 33, 901-908 (1994).[Abstract/Free Full Text]
  5. T. P. Andriacchi, A. Mundermann, R. L. Smith, E. J. Alexander, C. O. Dyrby, S. Koo, A framework for the in vivo pathomechanics of osteoarthritis at the knee. Ann. Biomed. Eng. 32, 447-457 (2004).[CrossRef][Medline]
  6. J. P. Pelletier, J. Martel-Pelletier, S. B. Abramson, Osteoarthritis, an inflammatory disease: potential implication for the selection of new therapeutic targets. Arthritis Rheum. 44, 1237-1247 (2001).[CrossRef][Medline]
  7. B. Caterson, C. R. Flannery, C. E. Hughes, C. B. Little, Mechanisms involved in cartilage proteoglycan catabolism. Matrix Biol. 19, 333-344 (2000).[CrossRef][Medline]
  8. J. A. Mengshol, K. S. Mix, C. E. Brinckerhoff, Matrix metalloproteinases as therapeutic targets in arthritic diseases: bull's-eye or missing the mark? Arthritis Rheum. 46, 13-20 (2002).[CrossRef][Medline]
  9. B. Bau, P. M. Gebhard, J. Haag, T. Knorr, E. Bartnik, T. Aigner, Relative messenger RNA expression profiling of collagenases and aggrecanases in human articular chondrocytes in vivo and in vitro. Arthritis Rheum. 46, 2648-2657 (2002).[CrossRef][Medline]
  10. H. Muir, The chondrocyte, architect of cartilage. Biomechanics, structure, function and molecular biology of cartilage matrix macromolecules. Bioessays 17, 1039-1048 (1995).[CrossRef][Medline]
  11. T. Aigner, M. Hemmel, D. Neureiter, P. M. Gebhard, G. Zeiler, T. Kirchner, L. McKenna, Apoptotic cell death is not a widespread phenomenon in normal aging and osteoarthritis human articular knee cartilage: A study of proliferation, programmed cell death (apoptosis), and viability of chondrocytes in normal and osteoarthritic human knee cartilage. Arthritis Rheum. 44, 1304-1312 (2001).[CrossRef][Medline]
  12. M. Sowers, L. Lachance, M. Hochberg, D. Jamadar, Radiographically defined osteoarthritis of the hand and knee in young and middle-aged African American and Caucasian women. Osteoarthritis Cartilage 8, 69-77 (2000).[CrossRef][Medline]
  13. S. A. Oliveria, D. T. Felson, J. I. Reed, P. A. Cirillo, A. M. Walker, Incidence of symptomatic hand, hip, and knee osteoarthritis among patients in a health maintenance organization. Arthritis Rheum. 38, 1134-1141 (1995).[CrossRef][Medline]
  14. J. S. Lawrence, J. M. Bremner, F. Bier, Osteo-arthrosis. Prevalence in the population and relationship between symptoms and x-ray changes. Ann. Rheum. Dis. 25, 1-24 (1966).[Free Full Text]
  15. K. Andersen-Ranberg, M. Schroll, B. Jeune, Healthy centenarians do not exist, but autonomous centenarians do: a population-based study of morbidity among Danish centenarians. J. Am. Geriatr. Soc. 49, 900-908 (2001).[CrossRef][Medline]
  16. L. Sharma, J. Song, D. T. Felson, S. Cahue, E. Shamiyeh, D. D. Dunlop, The role of knee alignment in disease progression and functional decline in knee osteoarthritis. JAMA 286, 188-195 (2001).[CrossRef][Medline]
  17. D. T. Felson, T. Neogi, Osteoarthritis: is it a disease of cartilage or of bone? Arthritis Rheum. 50, 341-344 (2004).[CrossRef][Medline]
  18. F. M. Cicuttini, G. Jones, A. Forbes, A. E. Wluka, Rate of cartilage loss at two years predicts subsequent total knee arthroplasty: A prospective study. Ann. Rheum. Dis. 28 April 2004 [e-pub ahead of print]. [Abstract] [Full Text]
  19. E. B. Hunziker, T. M. Quinn, H. J. Hauselmann, Quantitative structural organization of normal adult human articular cartilage. Osteoarthritis Cartilage 10, 564-572 (2002).[CrossRef][Medline]
  20. T. Wells, C. Davidson, M. Morgelin, J. L. Bird, M. T. Bayliss, J. Dudhia, Age-related changes in the composition, the molecular stoichiometry and the stability of proteoglycan aggregates extracted from human articular cartilage. Biochem. J. 370, 69-79 (2003).[CrossRef][Medline]
  21. G. Grushko, R. Schneiderman, A. Maroudas, Some biochemical and biophysical parameters for the study of the pathogenesis of osteoarthritis: a comparison between the processes of ageing and degeneration in human hip cartilage. Connect. Tissue Res. 19, 149-176 (1989).[CrossRef][Medline]
  22. N. Verzijl, J. DeGroot, S. R. Thorpe, R. A. Bank, J. N. Shaw, T. J. Lyons, J. W. Bijlsma, F. P. Lafeber, J. W. Baynes, J. M. TeKoppele, Effect of collagen turnover on the accumulation of advanced glycation endproducts. J. Biol. Chem. 275, 39027-39031 (2000).[Abstract/Free Full Text]
  23. N. Verzijl, R. A. Bank, J. M. TeKoppele, J. DeGroot, AGEing and osteoarthritis: a different perspective. Curr. Opin. Rheumatol. 15, 616-622 (2003).[CrossRef][Medline]
  24. J. DeGroot, N. Verzijl, R. A. Bank, F. P. Lafeber, J. W. Bijlsma, J. M. TeKoppele, Age-related decrease in proteoglycan synthesis of human articular chondrocytes: the role of nonenzymatic glycation. Arthritis Rheum. 42, 1003-1009 (1999).[CrossRef][Medline]
  25. R. A. Bank, M. T. Bayliss, F. P. Lafeber, A. Maroudas, J. M. Tekoppele, Ageing and zonal variation in post-translational modification of collagen in normal human articular cartilage. The age-related increase in non-enzymatic glycation affects biomechanical properties of cartilage. Biochem. J. 330, 345-351 (1998).
  26. N. Verzijl, J. DeGroot, Z.C . Ben, O. Brau-Benjamin, A. Maroudas, R. A. Bank, J. Mizrahi, C. G. Schalkwijk, S. R. Thorpe, J.W. Baynes, et al., Crosslinking by advanced glycation end products increases the stiffness of the collagen network in human articular cartilage: a possible mechanism through which age is a risk factor for osteoarthritis. Arthritis Rheum. 46, 114-123 (2002).[CrossRef][Medline]
  27. E. Wilkins, P. Dieppe, P. Maddison, G. Evison, Osteoarthritis and articular chondrocalcinosis in the elderly. Ann. Rheum. Dis. 42, 280-284 (1983).[Abstract/Free Full Text]
  28. D. T. Felson, J. J. Anderson, A. Naimark, W. Kannel, R. F. Meenan, The prevalence of chondrocalcinosis in the elderly and its association with knee osteoarthritis: the Framingham Study. J. Rheumatol. 16, 1241-1245 (1989).[Medline]
  29. A. K. Rosenthal, B. A. Derfus, L. A. Henry, Transglutaminase activity in aging articular chondrocytes and articular cartilage vesicles. Arthritis Rheum. 40, 966-970 (1997).[CrossRef][Medline]
  30. F. Rosen, G. McCabe, J. Quach, J. Solan, R. Terkeltaub, J. E. Seegmiller, M. Lotz, Differential effects of aging on human chondrocyte responses to transforming growth factor beta: increased pyrophosphate production and decreased cell proliferation. Arthritis Rheum. 40, 1275-1281 (1997).[Medline]
  31. K. Johnson, C. I. Svensson, D. V. Etten, S. S. Ghosh, A. N. Murphy, H. C. Powell, R. Terkeltaub, Mediation of spontaneous knee osteoarthritis by progressive chondrocyte ATP depletion in Hartley guinea pigs. Arthritis Rheum. 50, 1216-1225 (2004).[CrossRef][Medline]
  32. M. Hudelmaier, C. Glaser, J. Hohe, K. H. Englmeier, M. Reiser, R. Putz, F. Eckstein, Age-related changes in the morphology and deformational behavior of knee joint cartilage. Arthritis Rheum. 44, 2556-2561 (2001).[CrossRef][Medline]
  33. E. Vignon, M. Arlot, L. M. Patricot, G. Vignon, The cell density of human femoral head cartilage. Clin. Orthop. 121, 303-308 (1976).
  34. S. Hashimoto, R. L. Ochs, S. Komiya, M. Lotz, Linkage of chondrocyte apoptosis and cartilage degradation in human osteoarthritis. Arthritis Rheum. 41, 1632-1638 (1998).[CrossRef][Medline]
  35. P. A. Guerne, F. Blanco, A. Kaelin, A. Desgeorges, M. Lotz, Growth factor responsiveness of human articular chondrocytes in aging and development. Arthritis Rheum. 38, 960-968 (1995).[CrossRef][Medline]
  36. J. A. Martin, J. A. Buckwalter, Telomere erosion and senescence in human articular cartilage chondrocytes. J. Gerontol. A Biol. Sci. Med. Sci. 56, B172-B179 (2001).[Abstract/Free Full Text]
  37. M. H. Goyns, Genes, telomeres and mammalian ageing. Mech. Ageing Dev. 123, 791-799 (2002).[CrossRef][Medline]
  38. L. Liu, J. R. Trimarchi, P. Navarro, M. A. Blasco, D. L. Keefe, Oxidative stress contributes to arsenic-induced telomere attrition, chromosome instability and apoptosis. J. Biol. Chem. 278, 31998-32004 (2003).[Abstract/Free Full Text]
  39. R. F. Loeser, N. Shakoor, Aging or osteoarthritis: which is the problem? Rheum. Dis. Clin. North Am. 29, 653-673 (2003).[CrossRef][Medline]
  40. J. A. Tyler, Insulin-like growth factor 1 can decrease degradation and promote synthesis of proteoglycan in cartilage exposed to cytokines. Biochem. J. 260, 543-548 (1989).[Abstract/Free Full Text]
  41. H. J. Im, C. Pacione, S. Chubinskaya, A. J. Van Wijnen, Y. Sun, R. F. Loeser, Inhibitory effects of insulin-like growth factor-1 and osteogenic protein-1 on fibronectin fragment- and interleukin-1beta-stimulated matrix metalloproteinase-13 expression in human chondrocytes. J. Biol. Chem. 278, 25386-25394 (2003).[Abstract/Free Full Text]
  42. J. A. Tyler, Articular cartilage cultured with catabolin (pig interleukin 1) synthesizes a decreased number of normal proteoglycan molecules. Biochem. J. 227, 869-878 (1985).[Abstract/Free Full Text]
  43. J. J. Nietfeld, B. Wilbrink, M. Helle, J. L. van Roy, W. den Otter, A. J. Swaak, O. Huber-Bruning, Interleukin-1-induced interleukin-6 is required for the inhibition of proteoglycan synthesis by interleukin-1 in human articular cartilage. Arthritis Rheum. 33, 1695-1701 (1990).[CrossRef][Medline]
  44. B. Dozin, M. Malpeli, L. Camardella, R. Cancedda, A. Pietrangelo, Response of young, aged and osteoarthritic human articular chondrocytes to inflammatory cytokines: molecular and cellular aspects. Matrix Biol. 21, 449-459 (2002).[CrossRef][Medline]
  45. A. Scharstuhl, H. M. van Beuningen, E. L. Vitters, P. M. van der Kraan, W. B. van den Berg, Loss of transforming growth factor counteraction on interleukin 1 mediated effects in cartilage of old mice. Ann. Rheum. Dis. 61, 1095-1098 (2002).[Abstract/Free Full Text]
  46. D. J. McQuillan, C. J. Handley, M. A. Campbell, S. Bolis, V. E. Milway, A.C. Herington, Stimulation of proteoglycan biosynthesis by serum and insulin-like growth factor-I in cultured bovine articular cartilage. Biochem. J. 240, 423-430 (1986).[Abstract/Free Full Text]
  47. J. Schalkwijk, L. A. Joosten, W. B. van den Berg, J. J. van Wyk, L. B. van de Putte, Insulin-like growth factor stimulation of chondrocyte proteoglycan synthesis by human synovial fluid. Arthritis Rheum. 32, 66-71 (1989).[CrossRef][Medline]
  48. J. A. Martin, S. M. Ellerbroek, J. A. Buckwalter, Age-related decline in chondrocyte response to insulin-like growth factor-I: the role of growth factor binding proteins. J. Orthop. Res. 15, 491-498 (1997).[CrossRef][Medline]
  49. H. Messai, Y. Duchossoy, A. Khatib, A. Panasyuk, D. R. Mitrovic, Articular chondrocytes from aging rats respond poorly to insulin-like growth factor-1: an altered signaling pathway. Mech. Ageing Dev. 115, 21-37 (2000).[CrossRef][Medline]
  50. R. F. Loeser, G. Shanker, C. S. Carlson, J. F. Gardin, B. J. Shelton, W. E. Sonntag, Reduction in the chondrocyte response to insulin-like growth factor 1 in aging and osteoarthritis: studies in a non-human primate model of naturally occurring disease. Arthritis Rheum. 43, 2110-2120 (2000).[CrossRef][Medline]
  51. Richard F. Loeser Jr., unpublished results.
  52. K. Bobacz, R. Gruber, A. Soleiman, L. Erlacher, J. S. Smolen, W. B. Graninger, Expression of bone morphogenetic protein 6 in healthy and osteoarthritic human articular chondrocytes and stimulation of matrix synthesis in vitro. Arthritis Rheum. 48, 2501-2508 (2003).[CrossRef][Medline]
  53. S. Chubinskaya, B. Kumar, C. Merrihew, K. Heretis, D. C. Rueger, K. E. Kuettner, Age-related changes in cartilage endogenous osteogenic protein-1 (OP-1). Biochim. Biophys. Acta 1588, 126-134 (2002).[CrossRef][Medline]
  54. C. Sell, A. Ptasznik, C. D. Chang, J. Swantek, V. J. Cristofalo, R. Baserga, IGF-1 receptor levels and the proliferation of young and senescent human fibroblasts. Biochem. Biophys. Res. Commun. 194, 259-265 (1993).[CrossRef][Medline]
  55. S. Dore, J. P. Pelletier, J. A. DiBattista, G. Tardif, P. Brazeau, J. Martel-Pelletier, Human osteoarthritic chondrocytes possess an increased number of insulin-like growth factor 1 binding sites but are unresponsive to its stimulation. Possible role of IGF-1-binding proteins. Arthritis Rheum. 37, 253-263 (1994).[CrossRef][Medline]
  56. J. Wang, P. Verdonk, D. Elewaut, E. M. Veys, G. Verbruggen, Homeostasis of the extracellular matrix of normal and osteoarthritic human articular cartilage chondrocytes in vitro. Osteoarthritis Cartilage 11, 801-809 (2003).[CrossRef][Medline]
  57. X. Chevalier, J. A. Tyler, Production of binding proteins and role of the insulin-like growth factor I binding protein 3 in human articular cartilage explants. Br. J. Rheumatol. 35, 515-522 (1996).[Abstract/Free Full Text]
  58. K. D. Ham, T. R. Oegema, R. F. Loeser, C. S. Carlson, Effects of long-term estrogen replacement therapy on articular cartilage IGFBP-2, IGFBP-3, collagen and proteoglycan levels in ovariectomized cynomolgus monkeys. Osteoarthritis Cartilage 12, 160-168 (2004).[CrossRef][Medline]
  59. K. D. Ham, R. F. Loeser, B. R. Lindgren, C. S. Carlson, Effects of long-term estrogen replacement therapy on osteoarthritis severity in cynomolgus monkeys. Arthritis Rheum. 46, 1956-1964 (2002).[CrossRef][Medline]
  60. S. D. Yan, A. M. Schmidt, G. M. Anderson, J. Zhang, J. Brett, Y. S. Zou, D. Pinsky, D. Stern, Enhanced cellular oxidant stress by the interaction of advanced glycation end products with their receptors/binding proteins. J. Biol. Chem. 269, 9889-9897 (1994).[Abstract/Free Full Text]
  61. H. M. Lander, J. M. Tauras, J. S. Ogiste, O. Hori, R. Moss, A. M. Schmidt, Activation of the receptor for advanced glycation end products triggers a p21(ras)-dependent mitogen-activated protein kinase pathway regulated by oxidant stress. J. Biol. Chem. 272, 17810-17814 (1997).[Abstract/Free Full Text]
  62. D. Harman, Aging: A theory based on free radical and radiation chemistry. J. Gerontol. 11, 298-300 (1956).[Free Full Text]
  63. T. Finkel, N. J. Holbrook, Oxidants, oxidative stress and the biology of ageing. Nature 408, 239-247 (2000).[CrossRef][Medline]
  64. R. Studer, D. Jaffurs, M. Stefanovic-Racic, P. D. Robbins, C. Evans, Nitric oxide in osteoarthritis. Osteoarthritis Cartilage 7, 377-379 (1999).[CrossRef][Medline]
  65. T. S. Hiran, P. J. Moulton, J. T. Hancock, Detection of superoxide and NADPH oxidase in porcine articular chondrocytes. Free Radic. Biol. Med. 23, 736-743 (1997).[CrossRef][Medline]
  66. M. L. Tiku, R. Shah, G. T. Allison, Evidence linking chondrocyte lipid peroxidation to cartilage matrix protein degradation: Possible role in cartilage aging and the pathogenesis of osteoarthritis. J. Biol. Chem. 275, 20069-20076 (2000).[Abstract/Free Full Text]
  67. Y. E. Henrotin, P. Bruckner, J. P. Pujol, The role of reactive oxygen species in homeostasis and degradation of cartilage. Osteoarthritis Cartilage 11, 747-755 (2003).[CrossRef][Medline]
  68. M. S. Baker, J. Feigan, D. A. Lowther, Chondrocyte antioxidant defences: the roles of catalase and glutathione peroxidase in protection against H2O2 dependent inhibition of proteoglycan biosynthesis. J. Rheumatol. 15, 670-677 (1988).[Medline]
  69. M. Oh, K. Fukuda, S. Asada, Y. Yasuda, S. Tanaka, Concurrent generation of nitric oxide and superoxide inhibits proteoglycan synthesis in bovine articular chondrocytes: involvement of peroxynitrite. J. Rheumatol. 25, 2169-2174 (1998).[Medline]
  70. M. Del Carlo Jr., R. F. Loeser, Nitric oxide-mediated chondrocyte cell death requires the generation of additional reactive oxygen species. Arthritis Rheum. 46, 394-403 (2002).[CrossRef][Medline]
  71. E. J. Bates, D. A. Lowther, C. C. Johnson, Hyaluronic acid synthesis in articular cartilage: an inhibition by hydrogen peroxide. Biochem. Biophys. Res. Commun. 132, 714-720 (1985).[CrossRef][Medline]
  72. R. M. Clancy, J. Rediske, X. Tang, N. Nijher, S. Frenkel, M. Philips, S. B. Abramson, Outside-in signaling in the chondrocyte. Nitric oxide disrupts fibronectin-induced assembly of a subplasmalemmal actin/rho A/focal adhesion kinase signaling complex. J. Clin. Invest. 100, 1789-1796 (1997).[CrossRef][Medline]
  73. W. B. van den Berg, F. van de Loo, L. A. Joosten, O. J. Arntz, Animal models of arthritis in NOS2-deficient mice. Osteoarthritis Cartilage 7, 413-415 (1999).[CrossRef][Medline]
  74. R. K. Studer, E. Levicoff, H. Georgescu, L. Miller, D. Jaffurs, C. H. Evans, Nitric oxide inhibits chondrocyte response to IGF-I: inhibition of IGF-IRbeta tyrosine phosphorylation. Am. J. Physiol. Cell Physiol. 279, C961-C969 (2000).[Abstract/Free Full Text]
  75. R. K. Studer, K. Decker, S. Melhem, H. Georgescu, Nitric oxide inhibition of IGF-1 stimulated proteoglycan synthesis: role of cGMP. J. Orthop. Res. 21, 914-921 (2003).[CrossRef][Medline]
  76. K. Johnson, A. Jung, A. Murphy, A. Andreyev, J. Dykens, R. Terkeltaub, Mitochondrial oxidative phosphorylation is a downstream regulator of nitric oxide effects on chondrocyte matrix synthesis and mineralization. Arthritis Rheum. 43, 1560-1570 (2000).[CrossRef][Medline]
  77. R. F. Loeser, C. S. Carlson, M. D. Carlo, A. Cole, Detection of nitrotyrosine in aging and osteoarthritic cartilage: Correlation of oxidative damage with the presence of interleukin-1beta and with chondrocyte resistance to insulin-like growth factor 1. Arthritis Rheum. 46, 2349-2357 (2002).[CrossRef][Medline]
  78. M. Del Carlo Jr., R .F. Loeser, Increased oxidative stress with aging reduces chondrocyte survival: Correlation with intracellular glutathione levels. Arthritis Rheum. 48, 3419-3430 (2003).[CrossRef][Medline]
  79. B. Kurz, B. Jost, M. Schunke, Dietary vitamins and selenium diminish the development of mechanically induced osteoarthritis and increase the expression of antioxidative enzymes in the knee joint of STR/1N mice. Osteoarthritis Cartilage 10, 119-126 (2002).[CrossRef][Medline]
  80. T. E. McAlindon, P. Jacques, Y. Zhang, M. T. Hannan, P. Aliabadi, B. Weissman, D. Rush, D. Levy, D. T. Felson, Do antioxidant micronutrients protect against the development and progression of knee osteoarthritis? Arthritis Rheum. 39, 648-656 (1996).[Medline]
  81. Richard F. Loeser Jr. is The Robert S. Katz, MD--Joan and Paul Rubschlager Presidential Professor of Osteoarthritis Research.
Citation: R. F. Loeser, Aging Cartilage and Osteoarthritis--What's the Link? Sci. Aging Knowl. Environ. 2004 (29), pe31 (2004).








Science of Aging Knowledge Environment. ISSN 1539-6150