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

Abstract

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).

Matrix cross-linking–mediated mechanotransduction promotes posttraumatic osteoarthritis

“…Aging processes have been implicated in elevating ECM stiffness in various tissues (9). In particular, advanced glycation end-products (AGEs) are regarded as a major factor in driving nonenzymatic collagen cross-linking, thereby increasing ECM stiffness (10). Examination of AGE levels in cartilage of young and aged mice revealed significant accumulation of AGEs in aging cartilage (Fig.…”

What is Intervertebral Disc Degeneration, and What Causes It?

“…28 In addition, reactions between collagen and glucose lead to "nonenzymatic glycation" (extra cross-links that give old discs their characteristic yellowbrown appearance). 38 Increased cross-linking inhibits matrix turnover and repair in old discs, encouraging the retention of damaged macromolecules 32 and probably leading to reduced tissue strength.…”

Pioglitazone Inhibits Advanced Glycation End Product-Induced TNF-E and MMP-13 Expression via the Antagonism of NF-TB Activation in Chondrocytes

“…In vivo, the generation of AGEs is an inevitable process. In OA, the concentration of AGEs in synovial fluid and cartilage is up to 56.6 ± 28.7 nmol/l, which is 5 times the concentration found in normal synovial fluid [10,11]. AGEs are known to affect the physical and chemical properties of proteins.…”