Advanced glycation endproducts (AGEs) are a form of metabolic waste, sugary compounds that can interact harmfully with structures and cells in the body. A few forms of persistent AGE can form lasting cross-links in the extracellular matrix that change the structural properties of tissues, contributing to the loss of elasticity in skin and blood vessels, for example. Most AGEs are transient compounds, however, associated with the abnormal metabolism of diabetes and the chronic inflammation of aging. Dietary AGEs may also be influential on levels of AGEs in the body, though the size of this contribution is arguable - the body is quite capable of manufacturing significant amounts of AGEs even without a dietary component.
Transient AGEs cause chronic inflammation and harmful changes to cell behavior by interacting with the receptor for AGEs (RAGE). In today's open access research paper, researchers show that this contributes meaningfully to the progression of degenerative disc disease, impacting the maintenance of collagen in intervertebral discs. Inhibition of RAGE signaling is thus a potential target for therapies, though finding a way to suppress levels of AGEs - or address causes of rising amounts of AGEs - sounds like a better class of approach.
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
Aging and diabetes are identified as risk factors associated with increased intervertebral disk (IVD) degeneration degeneration and back pain. These associations may be attributed to chronic proinflammatory conditions, yet these associations are confounded by environmental and genetic factors, making causal relationships difficult to identify. A leading hypothesis for a relationship between diabetes and IVD degeneration is the formation and accumulation of advanced glycation end products (AGEs) in diabetic IVD tissue. AGEs are highly oxidant compounds that accumulate in aging and are implicated in diabetic complications that are known to cause structural and biological alterations to collagen and the extracellular matrix (ECM).
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, increased vertebral bone changes, and increased collagen degradation. 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.
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, highlighting the direct contributions that AGEs can make to IVD degeneration.
This two-part study used in vivo and ex vivo IVD model systems with wild type and RAGE-knockout (RAGE-KO) mice in order to investigate changes in AF collagen quality and degradation in response to AGE challenges. First, we used SHG imaging on thin sections with an in vivo dietary mouse model and determined that high-AGE (H-AGE) diets increased annulus fibrosus (AF) fibril disruption and collagen degradation resulting in decreased total collagen content, suggesting an early degenerative cascade. Next, we used in situ imaging with an ex vivo IVD organ culture model of AGE challenge on wild type and RAGE-knockout (RAGE-KO) mice and determined that early degenerative changes to collagen quality and degradation were RAGE dependent. We conclude that AGE accumulation leads to RAGE-dependent collagen disruption in the AF and can initiate molecular and tissue level collagen disruption.