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

Verzijl, Nicole; DeGroot, Jeroen; Zaken, Chaya Ben; Braun-Benjamin, Orit; Maroudas, Alice; Bank, Ruud A.; Mizrahi, J.; Schalkwijk, Casper G.; Thorpe, Suzanne R.; Baynes, John W.; Bijlsma, J. W. J.; Lafeber, Floris P. J. G.; TeKoppele, J.M.

doi:10.1002/1529-0131(200201)46:1<114::aid-art10025>3.0.co;2-p

Cited by 398 publications

(230 citation statements)

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“…Measurements of the effective Young's modulus of cartilage (stiffness) at several locations within a prescribed indentation matrix before and after l ‐threose incubation were performed. Our data indicated that incubation with l ‐threose as the reducing sugar results in stiffened cartilage matrix, which agrees with the findings of a previous study 22. Our micro‐indentation data illustrated that l ‐threose treatment under hyper‐osmolality enhances the formation of advanced glycation end‐products (Fig.…”

Section: Discussionsupporting

confidence: 92%

Non‐enzymatic cross‐linking of collagen type II fibrils is tuned via osmolality switch

Pouran

Moshtagh

Arbabi

et al. 2018

Journal Orthopaedic Research

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An important aspect in cartilage ageing is accumulation of advanced glycation end products (AGEs) after exposure to sugars. Advanced glycation results in cross‐links formation between the collagen fibrils in articular cartilage, hampering their flexibility and making cartilage more brittle. In the current study, we investigate whether collagen cross‐linking after exposure to sugars depends on the stretching condition of the collagen fibrils. Healthy equine cartilage specimens were exposed to l‐threose sugar and placed in hypo‐, iso‐, or hyper‐osmolal conditions that expanded or shrank the tissue and changed the 3D conformation of collagen fibrils. We applied micro‐indentation tests, contrast enhanced micro‐computed tomography, biochemical measurement of pentosidine cross‐links, and cartilage surface color analysis to assess the effects of advanced glycation cross‐linking under these different conditions. Swelling of extracellular matrix due to hypo‐osmolality made cartilage less susceptible to advanced glycation, namely, the increase in effective Young's modulus was approximately 80% lower in hypo‐osmolality compared to hyper‐osmolality and pentosidine content per collagen was 47% lower. These results indicate that healthy levels of glycosaminoglycans not only keep cartilage stiffness at appropriate levels by swelling and pre‐stressed collagen fibrils, but also protect collagen fibrils from adverse effects of advanced glycation. These findings highlight the fact that collagen fibrils and therefore cartilage can be protected from further advanced glycation (“ageing”) by maintaining the joint environment at sufficiently low osmolality. Understanding of mechanochemistry of collagen fibrils provided here might evoke potential ageing prohibiting strategies against cartilage deterioration. © 2018 The Authors. Journal of Orthopaedic Research Published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 36:1929–1936, 2018.

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Section: Discussionsupporting

confidence: 92%

Non‐enzymatic cross‐linking of collagen type II fibrils is tuned via osmolality switch

Pouran

Moshtagh

Arbabi

et al. 2018

Journal Orthopaedic Research

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“…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 agerelated 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.…”

Section: Discussionmentioning

confidence: 99%

“…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)(24)(25)(26)(27), and articular cartilage (20,28). Moreover, an increase in AGEs renders tissue increasingly brittle, and thus more prone to mechanical damage.…”

mentioning

confidence: 99%

Accumulation of advanced glycation end products as a molecular mechanism for aging as a risk factor in osteoarthritis

DeGroot¹,

Verzijl²,

Wijk

et al. 2004

Arthritis & Rheumatism

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177

110

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Objective. 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.Methods. 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.Results. Intraarticular injections of ribose enhanced cartilage AGE levels ϳ5-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.Conclusion. 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: Ͼ50% 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).

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“…On a molar basis, ascorbate is 70-fold more active than glucose in crosslinking lens proteins (crystallins) in vitro (34) and may be the primary glycating agent in aging normal lenses (35). Moreover, threose, a metabolite of ascorbic acid (36), increases collagen crosslinking (AGEs) within the extracellular matrix of cartilage (37). These crosslinks are hypothesized to increase cartilage susceptibility to OA (38).…”

Section: Discussionmentioning

confidence: 99%

Ascorbic acid increases the severity of spontaneous knee osteoarthritis in a guinea pig model

Kraus

Huebner

Stäbler

et al. 2004

Arthritis & Rheumatism

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Objective. To determine whether ascorbic acid might be of benefit for the treatment of spontaneous osteoarthritis (OA) when administered over a long period of time.Methods. We investigated the effects of 8 months' exposure to low, medium, and high doses of ascorbic acid on the in vivo development of histologic knee OA in the male Hartley guinea pig. The low dose represented the minimum amount needed to prevent scurvy. The medium dose was the amount present in standard laboratory guinea pig chow and resulted in plasma levels comparable with those achieved in a person consuming 200 mg/day (5 fruits and vegetables daily). The high dose was the amount shown in a previous study of the guinea pig to slow the progression of surgically induced OA.Results. We found an association between ascorbic acid supplementation and increased cartilage collagen content but, in contrast to findings in a previous study of surgically induced OA in the guinea pig, ascorbic acid worsened the severity of spontaneous OA. Active transforming growth factor ␤ (TGF␤) was expressed in marginal osteophytes, whose size and number were significantly increased with increasing intake of ascorbic acid. Synovial fluid levels of cartilage oligomeric matrix protein, a biomarker of cartilage turnover, corroborated the histologic findings.Conclusion. Ascorbic acid has been shown to activate latent TGF␤. Prolonged intraarticular exposure to TGF␤ has been shown to cause OA-like changes. We found expression of active TGF␤ in osteophytes, a prominent feature of the joint histology seen in association with ascorbic acid treatment. Thus, the deleterious effects of prolonged ascorbic acid exposure may be mediated in part by TGF␤. This worsening of OA with ascorbic acid supplementation suggests that ascorbic acid intake should not be supplemented above the currently recommended dietary allowance (90 mg/day for men and 75 mg/day for women).

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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

Cited by 398 publications

References 48 publications

Non‐enzymatic cross‐linking of collagen type II fibrils is tuned via osmolality switch

Non‐enzymatic cross‐linking of collagen type II fibrils is tuned via osmolality switch

Accumulation of advanced glycation end products as a molecular mechanism for aging as a risk factor in osteoarthritis

Ascorbic acid increases the severity of spontaneous knee osteoarthritis in a guinea pig model

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