Age-related accumulation of Maillard reaction products in human articular cartilage collagen

Abstract

Non-enzymic modification of tissue proteins by reducing sugars, the so-called Maillard reaction, is a prominent feature of aging. In articular cartilage, relatively high levels of the advanced glycation end product (AGE) pentosidine accumulate with age. Higher pentosidine levels have been associated with a stiffer collagen network in cartilage. However, even in cartilage, pentosidine levels themselves represent <1 cross-link per 20 collagen molecules, and as such cannot be expected to contribute substantially to the increase in collagen network stiffness. In the present study, we investigated a broad range of Maillard reaction products in cartilage collagen in order to determine whether pentosidine serves as an adequate marker for AGE levels. Not only did the well-characterized AGEs pentosidine, N(epsilon)-(carboxymethyl)lysine, and N(epsilon)-(carboxyethyl)lysine increase with age in cartilage collagen (all P<0.0001), but also general measures of AGE cross-linking, such as browning and fluorescence (both P<0.0001), increased. The levels of these AGEs are all higher in cartilage collagen than in skin collagen. As a functional measure of glycation the digestibility of articular collagen by bacterial collagenase was investigated; digestibility decreased linearly with age, proportional to the extent of glycation. Furthermore, the arginine content and the sum of the hydroxylysine and lysine content of cartilage collagen decrease significantly with age (P<0.0001 and P<0. 01 respectively), possibly due to modification by the Maillard reaction. The observed relationship between glycation and amino acid modification has not been reported previously in vivo. Our present results indicate that extensive accumulation of a variety of Maillard reaction products occurs in cartilage collagen with age. Altogether our results support the hypothesis that glycation contributes to stiffer and more brittle cartilage with advancing age.

Glycation cross-linking induced mechanical–enzymatic cleavage of microscale tendon fibers

“…Accumulation of collagen cross-links has been shown to increase resistance to collagenolytic digestion (Paik et al, 2006; Verzijl et al, 2002; Verzijl et al, 2000a), in agreement with these previous reports that cross-linking is protective, our unloaded fiber digestion tests (Results 2.2) showed that the ‘7-day cross-linked fibers’ are highly resistant to enzymatic degradation. However when cross-linked fibers were mechanically deformed with an applied tensile force they became increasingly susceptible to bacterial collagenase (Results 2.4).…”

“…The half-life for collagen has been reported on the order of decades in healthy tissues (Bank et al, 1999; Maroudas et al, 1992; Verzijl et al, 2000b). Due to the long protein half-life in vivo , collagen is one of the proteins that undergo spontaneous glycation and the formation of measurable amounts of Advanced Glycation End products (AGEs) during aging (Choudhary et al, 2011; Sell and Monnier, 2004; Verzijl et al, 2000a; Verzijl et al, 2000b). …”

“…AGE cross-linking results in changes in the mechanical properties of soft tissues, which include increased Young’s modulus, maximum failure load and toughness, while in mineralized tissue there are minimal changes in these properties after glycation (Reddy, 2003; Reddy et al, 2002). In addition AGE cross-linking has been implicated in a variety of pathological aging-related changes, including vascular (Aronson, 2003) and articular cartilage stiffening (Chen et al, 2002; Verzijl et al, 2000a) which might contribute to a arteriosclerosis and osteoarthritis, respectively.…”

Advanced glycation end-products and bone fractures

“…Post-translational modification of proteins by the process of non-enzymatic glycation (NEG) occurs in tissues with limited turnover such as cartilage and tendon (1–2). The slow turnover process exposes matrix proteins to the extracellular environment for extended times, leading to modifications by NEG.…”

Feasibility of Using Magnetic Resonance Elastography to Study the Effect of Aging on Shear Modulus of Skeletal Muscle

“…These cross-links result in increased tissue stiffness. Negative effects of this stiffening have been seen in numerous tissues, including cardiac muscle (Asif et al, 2000), bone (Vashishth et al, 2001), and articular cartilage (Verzijl et al, 2000). Cross-links have also been shown to accumulate in the skeletal muscle of aged rats (Gosselin et al, 1998).…”