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  2. Abstract


Osteoarthritis (OA) is one of the most prevalent and disabling chronic conditions affecting the elderly. Its etiology is largely unknown, but age is the most prominent risk factor. The current study was designed to test whether accumulation of advanced glycation end products (AGEs), which are known to adversely affect cartilage turnover and mechanical properties, provides a molecular mechanism by which aging contributes to the development of OA.


The hypothesis that elevated AGE levels predispose to the development of OA was tested in the canine anterior cruciate ligament transection (ACLT) model of experimental OA. Cartilage AGE levels were enhanced in young dogs by intraarticular injections of ribose. This mimics the accumulation of AGEs without the interference of other age-related changes. The severity of OA was then assessed 7 weeks after ACLT surgery in dogs with normal versus enhanced AGE levels.


Intraarticular injections of ribose enhanced cartilage AGE levels ∼5-fold, which is similar to the normal increase that is observed in old dogs. ACLT surgery resulted in more-pronounced OA in dogs with enhanced AGE levels. This was observed as increased collagen damage and enhanced release of proteoglycans. The attempt to repair the matrix damage was impaired; proteoglycan synthesis and retention were decreased at enhanced AGE levels. Mankin grading of histology sections also revealed more-severe OA in animals with enhanced AGE levels.


These findings demonstrate increased severity of OA at higher cartilage AGE levels and provide the first in vivo experimental evidence for a molecular mechanism by which aging may predispose to the development of OA.

The population of Western society is aging rapidly. Consequently, age-related diseases will increase greatly over the coming decades and will have a great impact on the quality of life of the elderly. Osteoarthritis (OA) is one of the most prevalent and disabling chronic conditions affecting the elderly and poses a significant public health problem (1). The most prominent feature of OA is the progressive destruction of articular cartilage, resulting in impaired joint motion, severe pain, and, ultimately, disability (2). As yet, the etiology of OA remains largely unknown. The incidence of OA increases with age: >50% of the population over 60 years of age is affected (3, 4). Although age is identified as the main risk factor for the development of OA, the mechanism by which aging is involved remains unclear. Age-related changes in the articular cartilage are expected to play an important role in the susceptibility of cartilage to OA.

Articular cartilage derives its mechanical properties from its extracellular matrix. This matrix is composed of type II collagen, which forms a 3-dimensional network that provides the cartilage with resistance to tensile forces (5). Highly negatively charged proteoglycans are embedded within this collagen network, and they generate a large swelling force that facilitates load support (the resilience of cartilage) (6, 7). One of the first characteristics of OA is damage to the collagen network, as reflected in increased swelling of the tissue and loss of proteoglycans (8–10). Both the collagen damage and the loss of proteoglycans adversely affect the mechanical properties of the cartilage. The chondrocytes within the cartilage are essential to maintaining the integrity of the tissue. They respond to tissue damage by increasing proteoglycan and collagen synthesis in an attempt to repair the damage (11, 12). If repair fails, damage will progress, leading to degeneration of the articular cartilage.

One of the major age-related changes in articular cartilage is the accumulation of advanced glycation end products (AGEs), which result from the spontaneous reaction of reducing sugars with proteins, or nonenzymatic glycation (NEG) (13, 14). The initial step in this reaction is the condensation of a sugar aldehyde with an ϵ-amino group of hydroxylysine or arginine residues in proteins. Subsequently, the initially formed Schiff base is stabilized by Amadori rearrangement. The Amadori product is further stabilized by oxidation and molecular rearrangements, ultimately generating a range of fluorophores and chromophores, which are collectively known as AGEs (14, 15). Most of these AGEs have not yet been isolated or characterized. Therefore, a few well-characterized AGEs are routinely used as markers for the process of NEG. Pentosidine, a fluorescent AGE formed by lysine and arginine residues, is often used for this purpose (16). AGEs are formed in all proteins, and since they can only be removed from the body when the protein is removed, AGEs accumulate in long-lived proteins such as collagens (17, 18). In human articular cartilage, a tissue with extremely slow turnover (half-life of type II collagen >100 years), pentosidine levels increase 50-fold from age 20 years to age 80 years (18–22).

AGEs are known to affect the physical and chemical properties of proteins. In particular, tissue strength is dependent upon the number of crosslinks present (15). Accumulation of AGEs is correlated with increased tissue stiffness in arteries, lenses, skin, tendons (23–27), and articular cartilage (20, 28). Moreover, an increase in AGEs renders tissue increasingly brittle, and thus more prone to mechanical damage. This effect has been shown in human lens capsules, cortical bone (25, 29), and articular cartilage (30). In addition to affecting the mechanical properties of tissue, AGEs interfere with cellular processes, such as adhesion of cells to the extracellular matrix, proliferation, and gene expression (31–33). Articular cartilage chondrocytes show decreased proteoglycan and collagen synthesis at increased AGE levels (21, 34). Degradation of AGE-modified collagen by matrix metalloproteinases is impaired as compared with that of unmodified collagen (34, 35).

The age-related accumulation of AGEs in articular cartilage increases tissue stiffness and decreases the capacity of the chondrocytes to remodel their extracellular matrix. Together, these effects render tissue more prone to damage and provide the molecular mechanism by which age-related accumulation of AGEs may eventually lead to the development of OA. In the present study, the hypothesis that the accumulation of AGEs predisposes to the development of OA was tested in the established canine anterior cruciate ligament transection (ACLT) model of OA (36–37).


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  2. Abstract

Experimental design.

Fifteen female beagle dogs obtained from the animal laboratory of Utrecht University (∼1 year old, weighing 8–10 kg) were randomly divided into 3 treatment groups of 5 dogs each. After 1 week of acclimatization, dogs in the first group (phosphate buffered saline [PBS]/ACLT group) received intraarticular injections of PBS into the right knee joint (twice weekly for 7 weeks). Dogs in the other 2 groups (AGE/ACLT and AGE/control) received injections of 2.5 ml 350 mM D-(–)-ribose (Sigma, St. Louis, MO) in PBS to enhance cartilage AGE levels. All intraarticular injections were performed under medetomidine/atipamezole (Pfizer Animal Health, New York, NY) sedation. After the last intraarticular injection, the dogs were allowed to recover for 2 weeks, after which joint instability was induced by ACLT in the right knee joint of dogs in the PBS/ACLT and AGE/ACLT groups, as described below. The AGE/control group had enhanced AGE levels but no surgery. Seven weeks after the ACLT surgery, dogs were killed by intravenous injection of sodium pentobarbitone, both hind legs were removed, and cartilage, synovium, and synovial fluid (SF) were processed as described below.

During the entire study, dogs were housed in groups of 5 and were fed a standard commercial diet and provided with water ad libitum. The weight of the animals was monitored during the study and did not change. The study was approved by the Ethics Committee on Animal Experiments of Utrecht University.

Induction of joint instability and ACLT.

ACLT surgery was performed on the right knee joint, as previously described; the other joint was left intact and served as a control (38–40). The dogs were anesthetized with halothane in a mixture of oxygen and nitrous oxide, administered endotracheally. To view the ACL, a small anterolateral incision (<2 cm) paralleling the ligamentum patellae was made. The ACL was lifted and transected with care so as not to damage other joint structures. A positive anterior drawer sign confirmed the completeness of the transection. The incision was sutured subcutaneously and cutaneously. The dogs received analgesics (buprenorphine hydrochloride 0.01 mg/kg) and antibiotics (amoxicillin 400 mg/kg) during the first 3 days after surgery. Exercise (twice daily for >30 minutes, 5 days/week) was started 2 days after surgery and continued until death (37).

Cartilage processing and AGE levels.

Cartilage was obtained from the femoral condyles of control and experimental knee joints of all dogs according to standardized procedures (41). Within 1 hour after dissection, full-thickness cartilage slices (excluding the subchondral bone) were cut into square pieces (3–10 mg) and processed for histologic and biochemical analyses (40). Tissue pentosidine levels (2 cartilage samples per dog per joint) were determined by reverse-phase high-performance liquid chromatography after acid hydrolysis, as previously described (21, 42). In addition, pentosidine levels were determined in stored cartilage samples (−20°C; remnants from unrelated studies) of young (mean ± SEM 1.5 ± 0.2 years; n = 20) and old (4.0 ± 0.9 years; n = 8) dogs. Pentosidine levels were expressed per collagen triple helix, assuming 300 residues of hydroxyproline per collagen molecule.

Collagen damage.

Damage to the collagen network was assessed by selective proteolysis (by α-chymotrypsin) of denatured collagen, as previously described (43). The α-chymotrypsin only cleaves off damaged, denatured collagen and leaves the intact triple-helical collagen behind. Cartilage samples (2 samples per joint) were extracted twice with 4M guanidinium chloride to remove proteoglycans. After washing, denatured collagen was digested overnight at 37°C with α-chymotrypsin. The supernatant was quantitatively separated from the insoluble collagen, and hydroxyproline levels were determined colorimetrically in both fractions after acid hydrolysis (44). The percentage of collagen denaturation was calculated as (hydroxyproline in supernatant)/(total hydroxyproline) × 100%.

Proteoglycan release.

Cartilage degradation was assessed by colorimetric assessment of glycosaminoglycan (GAG) release over 3 days into the culture medium of the cartilage samples, which were also assessed for retention of newly synthesized proteoglycans (see below) (45). GAGs were precipitated and stained with Alcian blue (Sigma). Staining was quantified photometrically by the change in absorbance at 620 nm (Vitalab 10; Vital Scientific, Dieren, The Netherlands). Shark cartilage chondroitin sulfate (Sigma) served as a standard. GAG release was normalized to the wet weight of the cartilage samples (46).

Proteoglycan synthesis.

Cartilage samples (3–10 mg) were individually cultured in 96-well tissue culture plates in 200 μl Dulbecco's modified Eagle's medium (DMEM) supplemented with 0.85 mM ascorbic acid, 2 mM glutamine, 100 IU/ml sodium benzylpenicillin, 100 IU/ml streptomycin sulfate, and 10% (volume/volume) heat-inactivated pooled beagle serum (37°C, 5% CO2 in air) (40). Following 1 hour of preculture, ex vivo proteoglycan synthesis was measured as the rate of sulfate incorporation (6 explants per joint per dog) by adding 10 μl DMEM containing 2 μCi carrier-free Na235SO4 (DuPont NEN, Boston, MA) during 4 hours of culture. After this 4-hour labeling, cartilage was briefly washed, digested with papain (Sigma), and GAGs were precipitated using cetylpyridinium chloride (Sigma). Incorporation of 35SO42− (DuPont NEN) into the GAGs was analyzed by liquid scintillation counting. Proteoglycan synthesis was calculated from the 35SO42− incorporation and the specific activity of the culture medium, normalized to the initial wet weight of the explant, and expressed as nanomoles of 35SO42− incorporated per hour per gram wet weight of tissue (21, 40).

Proteoglycan retention.

Cartilage samples (6 explants from each joint) were labeled ex vivo for 4 hours using carrier-free 35SO42− in a procedure identical to the one described above for proteoglycan synthesis, but using different samples. Following labeling, cartilage samples were extensively washed to remove unincorporated 35SO42− and chased for 3 days to assess the retention of newly synthesized proteoglycans. The release of radiolabeled proteoglycans into the culture medium was measured by Alcian blue precipitation and liquid scintillation counting. Released proteoglycans were normalized to the remaining radiolabeled proteoglycans in the cartilage explant (measured by Alcian blue precipitation after papain digestion) (40).

Metalloproteinase activity.

SF was obtained from control and experimental knees by aspiration using 21-gauge needles. Typically, 25–50 μl of SF was collected from control joints and >150 μl from experimental knees. Metalloproteinase activity in SF (final dilution 1:20 in 50 mM Tris [pH 7.5], 5 mM CaCl2, 150 mM NaCl, 1 μM ZnCl2, 0.01% Brij-35, 0.02% NaN3) was determined with fluorogenic substrate TNO211-F (5 μM) in the presence of an EDTA-free general proteinase inhibitor (Complete; Roche, Indianapolis, IN) (47, 48). This assay is considered to represent overall metalloproteinase activity.

Cartilage and synovium histology.

When the dogs were killed, cartilage (2 samples per joint) was removed, fixed in 4% formaldehyde (containing 2% sucrose), embedded in paraffin, and sectioned into 3-μm slices. Histologic grading of the extent of cartilage degeneration was carried out blinded (FPJGL and MJGWvW) in random order by light microscopy according to the slightly modified criteria of Mankin, on Safranin O–stained sections (40). Synovium samples (3 infrapatellar samples per joint) were fixed in 4% formaldehyde, embedded in paraffin, and sectioned into 3-μm slices. Synovial inflammation was quantified on hematoxylin and eosin–stained tissue sections using the Goldenberg-Cohen score as modified by Pelletier (synovial lining cell hyperplasia, villous hyperplasia, and cell influx) (49, 50).

Statistical analysis.

Statistical evaluation was performed using SPSS software, version 10.0 (SPSS, Chicago, IL). Data are presented as the mean ± SEM. Differences between contralateral control knees of the 3 groups were analyzed by analysis of variance. Two-sided Student's t-tests were performed for the comparison of control versus experimental knees (paired t-test), young versus old animals (unpaired t-test), and PBS- versus ribose-injected experimental knees (unpaired t-test). P values less than 0.05 were considered significant.


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  2. Abstract

Cartilage AGE levels.

In vivo, AGE levels increased in articular cartilage with age after skeletal maturity had been reached. In humans, we found a 5-fold increase in cartilage pentosidine between ages 30 and 80 years (21). Similarly, in dogs, a 5-fold increase in cartilage pentosidine levels was observed between ages 1.5 and 4 years (P < 0.01) (Figure 1). Absolute levels in mature dogs (∼0.5 mmoles/mole of collagen at 4 years of age) were lower than in adult humans (∼8 mmoles/mole of collagen at 80 years of age).

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Figure 1. Cartilage advanced glycation end product (AGE) levels. Pentosidine levels were increased 5-fold in the femoral cartilage of old (mean ± SEM 4.0 ± 0.9 years; n = 8) versus young (1.5 ± 0.2 years; n = 20) dogs. A similar 5-fold increase in pentosidine levels was achieved by 14 injections with ribose (AGE/anterior cruciate ligament transection [ACLT]; n = 5), compared with control dogs, which received phosphate buffered saline (PBS) injections (PBS/ACLT; n = 5). Open bars represent control (uninjected) knees; solid bars represent injected knees. Values are the mean and SEM. NS = not significant.

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To study the effect of cartilage AGEs on the susceptibility to mechanically induced OA, it is essential to exclude the interference of other age-related changes besides AGE accumulation. For this purpose, 5 young dogs received 14 consecutive intraarticular injections of ribose in 1 knee joint (in 7 weeks) to enhance cartilage AGE levels, without other aging effects present. Five other dogs received control injections of PBS. The ribose injections induced a 5-fold increase in cartilage pentosidine levels compared with PBS injections (P < 0.05) (Figure 1). The increase in pentosidine was restricted to the injected joint; no changes in pentosidine levels were observed in the untreated contralateral control joint. Cartilage AGE levels upon ribose injections were comparable to levels found in normally aged animals (Figure 1).

Since synovial inflammation is regarded as a secondary process in OA, care was taken to minimize the synovial damage from the repeated injections. Histologic assessment of joint inflammation indicated that such damage was successfully prevented. Synovial tissue samples from 5 dogs that received 14 intraarticular ribose injections but no ACLT surgery showed no signs of inflammation. The modified Goldenberg-Cohen score for synovium inflammation was a mean ± SEM of 0.6 ± 0.4 in uninjected joints versus 1.7 ± 0.5 in ribose-injected joints (P > 0.1; maximum score 10).

Characterization of the test model: PBS/ACLT group.

In our study design, the control group should have showed limited cartilage degeneration to allow a window for studying the aggravating effects of increased AGE levels. Induction of joint instability by ACLT induced mild OA features in the PBS-injected animals 7 weeks postsurgery. Collagen damage, one of the first signs of OA, increased from 6% to 7% (∼20% increase) in the ACLT joint compared with the control joint (Figure 2). Consistent with the decreased matrix integrity, the release of GAGs was increased ∼30% in experimental knees (Figure 3A). In an attempt to restore tissue integrity, the chondrocyte repair mechanism was activated, as indicated by the increase in proteoglycan synthesis (∼70% increase) (Figure 3B). This repair was clearly not effective, since the newly synthesized proteoglycans were poorly retained in the matrix. The release of these newly produced molecules was increased by ∼30% in the ACLT joint compared with the control joint (Figure 3C). Consequently, the level of GAGs in the matrix was ∼14% reduced in the ACLT joint (mean ± SEM 31.4 ± 1.8 μg/mg cartilage in experimental knees versus 36.5 ± 1.1 μg/mg in control knees; P not significant). In addition, minor synovial inflammation was observed (Goldenberg-Cohen score 0.5 ± 0.3 in control knees versus 2.5 ± 0.4 in experimental knees, maximum score 10; P < 0.02). The activity of metalloproteinases (proteinases involved in the destruction of cartilage tissue in OA) in SF was increased in experimental knees (Figure 4). All these biochemical changes of OA were consistent with an ∼50% increase in the histologic Mankin score for OA (Figure 5). Together, these data indicate that a mild form of OA had developed in PBS-injected knees after ACLT surgery. As expected, due to the short followup (7 weeks), some of the above parameters did not reach statistical significance. This mild degree of OA in the PBS/ACLT group is consistent with the findings of previous studies (37, 51, 52) and was essential for testing our hypothesis that an increased AGE level will increase the susceptibility for OA.

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Figure 2. Effect of ACLT on cartilage collagen damage at low and high AGE levels. Collagen damage was increased in experimental knees 7 weeks after surgery (∼20% and ∼40% increase for PBS/ACLT and AGE/ACLT groups, respectively). Open bars represent control (uninjected) knees; solid bars represent injected knees. Values are the mean and SEM. See Figure 1 for definitions.

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Figure 3. Effect of ACLT on cartilage proteoglycan metabolism at low and high AGE levels. Induction of joint instability increased glycosaminoglycan (GAG) release (μg GAG/mg cartilage) (A), proteoglycan synthesis (nmoles of 35SO42−/mg of cartilage per hour) (B), and the release of newly synthesized proteoglycans (nmoles of 35SO42−/mg of cartilage in 3 days) (C). With increased AGE levels, GAG release was further increased (A), the repair response was decreased (B), and the incorporation of new proteoglycans into the matrix was reduced (C) (compare solid bars of the PBS/ACLT and AGE/ACLT groups). Open bars represent control (uninjected) knees; solid bars represent injected knees. Values are the mean and SEM. See Figure 1 for other definitions.

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Figure 4. Effect of ACLT on synovial fluid metalloproteinase activity at low and high AGE levels. Proteolytic activity in the synovial fluid was increased upon induction of joint instability but did not differ between experimental knees in the PBS/ACLT versus the AGE/ACLT group. Open bars represent control (uninjected) knees; solid bars represent injected knees. Values are the mean and SEM. RFU = relative fluorescence units. See Figure 1 for other definitions.

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Figure 5. Effect of ACLT on cartilage degeneration at low and high AGE levels. Induction of joint instability induced osteoarthritic changes in the articular cartilage, quantified according to the modified Mankin criteria. Cartilage degeneration was statistically significantly more severe at increased AGE levels. Open bars represent control (uninjected) knees; solid bars represent injected knees. Values are the mean and SEM. See Figure 1 for definitions.

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OA at enhanced AGE levels: AGE/ACLT group.

In animals with ribose-induced enhanced AGE levels, all parameters of OA were statistically significantly increased compared with the control knee (Figures 2–5). Collagen damage in AGE/ACLT animals increased 1.4-fold (from 5.5% to 7.5%) in the ACLT joint compared with the control joint (Figure 2). Release of GAGs more than doubled (2.2-fold higher) in the ACLT knee versus the contralateral control knee (Figure 3A). The chondrocyte repair mechanism was induced, and proteoglycan synthesis increased by ∼60% (Figure 3B). Matrix repair was not effective, since the release of the newly synthesized proteoglycans was almost doubled (190%) in experimental knees compared with contralateral control knees (Figure 3C). The combined matrix damage and ineffective repair response resulted in an ∼13% decrease in the level of GAGs in the matrix (mean ± SEM 31.0 ± 1.7 μg/mg cartilage in experimental knees versus 35.5 ± 1.8 in control joints; P < 0.05). ACLT surgery resulted in a minor secondary synovial inflammation (Goldenberg-Cohen score 0.3 ± 0.2 in control knees versus 3.5 ± 0.4 in experimental knees; P < 0.01), which was reflected by the concomitant increase in metalloproteinase activity in the experimental knee (Figure 4). The biochemical data were supported by a tripling of the histologic (Mankin) score for cartilage damage (Figure 5).

Effect of AGE levels on OA: PBS/ACLT versus AGE/ACLT.

The outcome parameters revealed that the grade of cartilage damage was more severe in the ribose-injected group than in the PBS-injected animals (compare solid bars in Figures 2–4). A 20% increase in collagen damage due to the joint instability (i.e., control versus experimental knee) was observed in the PBS/ACLT animals, whereas a 40% increase in damage was found in the AGE/ACLT group (Figure 2). Similarly, the release of GAGs from the matrix was 4-fold higher at high AGE levels (120% versus 30% increase; P < 0.05) (Figure 3A). The repair response in the AGE/ACLT group was less effective than that in the PBS/ACLT group; proteoglycan synthesis was significantly lower in the AGE/ACLT group (P < 0.02) (Figure 3B). Moreover, retention of these newly synthesized proteoglycans was impaired at high AGE levels compared with PBS-injected animals (P < 0.05) (Figure 3C). Overall, this resulted in more-severe OA in the AGE/ACLT group than in the PBS/ACLT group, as is underscored histologically by a significant increase in cartilage degeneration (P < 0.02) (Figure 5). These effects were not due to differences in synovial inflammation since both groups displayed only mild, not significantly different, histologic inflammation (mean ± SEM 2.5 ± 0.4 in PBS/ACLT versus 3.5 ± 0.4 in AGE/ACLT, maximum score 10; P not significant). In addition, no differences were observed in the levels of SF metalloproteinase activity, which in this model likely reflects the mild synovial inflammation (Figure 4).

Appropriate study controls.

To ensure that the observed increase in OA severity was not caused by direct effects of the ribose injections, all the OA parameters were also determined in control animals receiving only ribose injections but no ACLT surgery (AGE/control group). In this group, AGE levels were enhanced 5-fold (P < 0.05, control versus experimental joint), similar to the AGE/ACLT group (Figure 1). In the AGE/control group, none of the outcome parameters was significantly different from untreated contralateral control knees, indicating that repeated injections with ribose did not induce cartilage degeneration in our model.

In addition, comparison of the severity of OA in 2 independent groups of animals (PBS/ACLT versus AGE/ACLT) required that the contralateral control joints of the animals in these 2 groups did not differ. Indeed, no statistically significant changes were observed between the contralateral control knees of the PBS/ACLT versus the AGE/ACLT groups or between these 2 groups and the contralateral control knees of the AGE/control group (P not significant for all parameters tested).


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  2. Abstract

Age is by far the most important risk factor for the development of OA (1). By which mechanism aging is involved in the development of this debilitating disease remains largely unknown. Fatigue failure of the cartilage collagen network due to repetitive loading has long been recognized as one of the mechanisms involved in the development of OA (53, 54). With increasing age, the strength of the collagen matrix to withstand loading diminishes. Therefore, age-related changes in articular cartilage that influence the composition and strength of the cartilage matrix are very likely involved in the development of OA (55). One such change, the age-related accumulation of AGEs, has previously been shown to increase tissue stiffness, decrease extracellular matrix turnover (synthesis and degradation), and affect many cellular processes (13, 14, 20, 21, 28, 34, 47, 56). In the present study, we demonstrated in an in vivo model that this process of NEG is indeed causally involved in the age-related increase in susceptibility to OA.

Our study was designed such that, by selectively increasing the AGE levels in the cartilage matrix, only the effect of NEG on the susceptibility to OA could be studied, without the effects of other age-related changes. This approach clearly demonstrated that increased AGE levels predispose to the development of OA. As such, the spontaneous process of NEG is the first molecular mechanism described to date that is capable of explaining, at least in part, the strong age dependency of OA incidence. Furthermore, the present data suggest that the rate of a generally occurring aging process (i.e., AGE formation occurs in all tissue but is especially important in tissue with slow turnover, such as articular cartilage [18]) may predispose to the development of an age-related pathology such as OA. These data are consistent with the observations of Sell et al (57, 58), who showed an inverse relationship between the rate of glycation and the longevity of a species, which further supports the idea that AGE accumulation is an important process in aging and age-related diseases.

The involvement of AGE accumulation in OA emphasizes the dual nature of sugars: they are essential for life as building blocks and as a cellular energy source, and they initiate the formation of potentially detrimental AGEs. The recognition of NEG as a molecular mechanism that contributes to the development of OA provides new opportunities for therapies directed at the prevention of OA by inhibiting or reversing AGE formation. Inhibition of AGE formation by prophylactic treatment with compounds such as aminoguanidine, pyridoxamine, tenilsetam, or simple amino acids (e.g., lysine or arginine) has been shown to prevent AGE-related pathologies such as vascular stiffening, heart collagen accumulation, and protein crosslinking (59–63). Alternatively, AGE-directed therapy can consist of so-called AGE-breakers (64). Thiazolium compounds such as N-phenacylthiazolium bromide and phenyl-4,5-dimethylthiazolium chloride, which have been reported to break dicarbonyl-containing AGEs, showed efficacy in reversing AGE-related tendon crosslinking and cardiac stiffness (65, 66). Despite the fact that these therapies are relatively new, they provide proof that inhibition or reversal of AGE formation can have beneficial effects in AGE-mediated pathologies.

The involvement of AGEs in the etiology of OA, as demonstrated by our data, in combination with the emerging possibilities for AGE-directed therapies, provides possible tools for preventing or postponing the development of OA. This is an important development, since adequate therapy for OA is lacking, while the number of people with this debilitating disease is increasing because of the aging population.


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  2. Abstract
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