Elevation of cartilage AGEs does not accelerate initiation of canine experimental osteoarthritis upon mild surgical damage

Abstract

Osteoarthritis is a highly prevalent disease, age being the main risk factor. The age-related accumulation of advancedglycation-endproducts (AGEs) adversely affects the mechanical and biochemical properties of cartilage. The hypothesis that accumulation of cartilage AGEs in combination with surgically induced damage predisposes to the development of osteoarthritis was tested in vivo in a canine model. To artificially increase cartilage AGEs, right knee joints of eight dogs were repeatedly injected with ribose/ threose (AGEd-joints). Left joints with vehicle alone served as control. Subsequently, minimal surgically applied cartilage damage was induced and loading restrained as much as possible. Thirty weeks after surgery, joint tissues of all dogs were analyzed for biochemical and histological features of OA. Cartilage pentosidine levels were $5-fold enhanced (p ¼ 0.001 vs. control-joints). On average, no statistically significant differences in joint degeneration were found between AGEd and control-joints. Enhanced cartilage pentosidine levels did correlate with less cartilage proteoglycan release (R ¼ À0.762 and R ¼ À0.810 for total and newly-formed proteoglycans, respectively; p ¼ 0.028 and 0.015 for both). The current data support the diminished cartilage turnover, but only a tendency towards enhanced cartilage damage in AGEd articular cartilage was observed. As such, elevated AGEs do not unambiguously accelerate the development of early canine OA upon minimal surgical damage. Keywords: osteoarthritis; non-enzymatic glycation; canine; pentosidine; proteoglycan Osteoarthritis (OA), with a high prevalence and increasing incidence due to the aging population, having a large impact on the patient's quality of life, is characterized by progressive cartilage damage, bone changes, and secondary synovial inflammation. 1 As yet, the pathogenesis of OA is largely unknown. Several factors have been reported to predispose to the development of OA, such as genetic background, overweight, joint laxity, and muscle weakness. 2 However, undisputedly, the most important risk factor for development of OA is age. 3 The incidence of OA increases strongly with age: >50% of the population over 60 years of age is affected. 4,5 However, there are still many uncertainties how age contributes to the onset and progression of OA. Age-related changes in the articular cartilage are suggested to play an important role in the susceptibility of cartilage to OA.One of the major age-related changes in articular cartilage is the spontaneous modification of proteins by non-enzymatic glycation resulting in the accumulation of advanced glycation endproducts (AGEs). Nonenzymatic glycation is a post-translational modification of proteins by reducing sugars. The spontaneous condensation of reducing sugars with free amino groups in lysine or arginine residues on proteins leads to the formation of AGEs. 6 Pentosidine, a fluorescent AGE formed between lysine and arginine residues, is frequently used as marker for AGEs. AGEs are formed in all pr...

Endoplasmic reticulum stress induces the expression of COX-2 through activation of eIF2α, p38-MAPK and NF-κB in advanced glycation end products stimulated human chondrocytes

“…This is likely due to the ongoing (ineffective) increased turnover of cartilage matrix protein even in end stage disease. Moreover, elevation of cartilage AGEs does not accelerate initiation of canine experimental OA upon mild surgical damage [43]. These data further support the diminished cartilage turnover in OA, but only a tendency towards enhanced cartilage damage in AGEs accumulated articular cartilage.…”

In vitro glycation of articular cartilage alters the biomechanical response of chondrocytes in a depth-dependent manner

“…However, these changes alone do not accelerate OA 20 . Although caution is warranted over the implications of our findings, AC aging may alter the mechanical signals that cells receive in the upper and deeper tissue zones.…”

“…Treatment of AC with sugars, such as ribose 11,14,15,19,20 and threose 13,19e21 , have been used to mimic the aging process to demonstrate that cross-linking can alter the mechanical properties of AC and possibly cause tissue dysfunction, degeneration and/or OA 3e9,13e15 . Although these treatments provide a faster means of inducing in vitro glycation, they may not completely mimic the age-related non-enzymatic products that form in vivo 22e25 .…”

Consequences of metabolic and oxidative modifications of cartilage tissue

“…72 Such in vitro data have been confirmed in animal studies, as the same array of post-translational modifications occurs on proteins following intra-articular injection of ribose and threose in models of surgically induced OA. 73 Likewise, conditions associated with prolonged oxidative stress, such as chronic infections and chronic inflammatory processes, are associated with early signs of cartilage degeneration, even when the joints are not the primary targets of the autoimmune or inflammatory process. 74 …”