Dietary advanced glycation end-product consumption leads to mechanical stiffening of murine intervertebral discs

Abstract

Back pain is a leading cause of disability and is strongly associated with intervertebral disc (IVD) degeneration. Reducing structural disruption and catabolism in IVD degeneration remains an important clinical challenge. Pro-oxidant and structure-modifying advanced glycation end-products (AGEs) contribute to obesity and diabetes, which are associated with increased back pain, and accumulate in tissues due to hyperglycemia or ingestion of foods processed at high heat. Collagen-rich IVDs are particularly susceptible to AGE accumulation due to their slow metabolic rates, yet it is unclear whether dietary AGEs can cross the endplates to accumulate in IVDs. A dietary mouse model was used to test the hypothesis that chronic consumption of high AGE diets results in sex-specific IVD structural disruption and functional changes. High AGE diet resulted in AGE accumulation in IVDs and increased IVD compressive stiffness, torque range and failure torque, particularly for females. These biomechanical changes were likely caused by significantly increased AGE crosslinking in the annulus fibrosus, measured by multiphoton imaging. Increased collagen damage measured with collagen hybridizing peptide did not appear to influence biomechanical properties and may be a risk factor as these animals age. The greater influence of high AGE diet on females is an important area of future investigation that may involve AGE receptors known to interact with estrogen. We conclude that high AGE diets can be a source for IVD crosslinking and collagen damage known to be important in IVD degeneration. Dietary modifications and interventions that reduce AGEs warrant further investigation and may be particularly important for diabetics, in whom AGEs accumulate more rapidly.

Matrix modification for enhancing the transport properties of the human cartilage endplate to improve disc nutrition

“…An important finding of this study is that solute uptake in both treated and untreated CEPs was lowest in tissues with high AGE concentrations (Fig 4, S5 Fig). AGEs are formed through non-enzymatic glycation of the free amino groups of proteins by reducing sugars, and AGE accumulation in low-turnover proteins of the disc increases with ageing [41] and is accelerated by metabolic disease [42–44] and with AGE-rich diets [45]. High AGE concentrations could negatively impact solute uptake in several ways.…”

Advanced glycation end products cause RAGE‐dependent annulus fibrosus collagen disruption and loss identified using in situ second harmonic generation imaging in mice intervertebral disk in vivo and in organ culture models

“…The specific structural changes to the IVD ECM due to AGE exposure in the presence of RAGE are not well‐understood and we believe this is partly due to limitations in the methods used to identify early degenerative changes to the ECM that mark the initiation of a degenerative cascade. Recently, we demonstrated that dietary accumulation of AGEs in the IVD increased levels of molecular level collagen degradation, 15 highlighting the direct contributions that AGEs can make to IVD degeneration. We believe that an improved understanding of the factors that cause early degenerative changes and the events that are subsequent to initiation of these changes may inform methods to detect and prevent such contributors to IVD degeneration.…”

“…There is mounting evidence for a causal relationship between IVD degeneration and AGEs. AGEs can accumulate in spinal tissues from aging, high‐AGE (H‐AGE) diets (eg, highly processed western diets) and diabetes, and are associated with structural changes in the IVD including decreased glycosaminoglycan content, 13‐15 increased vertebral bone changes, 16 and increased collagen degradation 15 . In addition, the receptor for AGEs (RAGE) has been observed to initiate an NF‐kB mediated inflammatory response in both human and mice IVD tissue exposed to AGEs 17,18 …”

“…We first hypothesized that loss of SHG intensity and collagen degradation due to H‐AGE diet will result in AF collagen fibril disruption and a loss of overall collagen. To test this hypothesis we utilized a dietary mouse model, validated previous SHG Intensity and collagen‐hybridizing peptide (CHP) results, 15 and performed new SHG image analysis to measure changes to fibril disruption and collagen quantity. The second hypothesis was that this early degenerative cascade is a result of resident IVD cell activity via the recognition of AGE ligands through RAGE, leading to degradation of the surrounding collagen.…”

Leptin signaling and the intervertebral disc: Sex dependent effects of leptin receptor deficiency and Western diet on the spine in a type 2 diabetes mouse model

“…The testing protocol was adopted from our previous studies [43][44][45]. In brief, on the day of testing, after 10 mins in PBS for thawing and hydrating, the motion segment specimens were loaded into parallel-platens of an axial loading machine (Bose ElectroForce 3220; TA Instruments, New Castle, DE, USA) using a custom-designed fixture with a fluid bath of PBS for axial testing.…”