Galectin‐3 and RAGE differentially control advanced glycation endproduct‐induced collagen damage in murine intervertebral disc organ culture

Abstract

Background Back and neck pain are leading causes of global disability that are associated with intervertebral disc (IVD) degeneration. Causes of IVD degeneration are multifactorial, and diet, age, and diabetes have all been linked to IVD degeneration. Advanced glycation endproducts (AGEs) accumulate in the IVD as a result of aging, diet, and diabetes, and AGE accumulation in the IVD has been shown to induce oxidative stress and catabolic activity that result in collagen damage. An association between AGE accumulation and IVD degeneration is emerging, yet mechanism behind this association remains unclear. The Receptor for AGEs (RAGE) is thought to induce catabolic responses in the IVD, and the AGE receptor Galectin 3 (Gal3) had a protective effect in other tissue systems but has not been evaluated in the IVD. Methods This study used an IVD organ culture model with genetically modified mice to analyze the roles of RAGE and Gal3 in an AGE challenge. Results Gal3 was protective against an AGE challenge in the murine IVD ex vivo, limiting collagen damage and biomechanical property changes. Gal3 receptor levels in the AF significantly decreased upon an AGE challenge. RAGE was necessary for AGE‐induced collagen damage in the IVD, and RAGE receptor levels in the AF significantly increased upon AGE challenge. Discussion These findings suggest both RAGE and Gal3 are important in the IVD response to AGEs and highlight Gal3 as an important receptor with protective effects on collagen damage. This research improves understanding the mechanisms of AGE‐induced IVD degeneration and suggests Gal3 receptor modulation as a potential target for preventative and therapeutic treatment for IVD degeneration.

From hyperglycemia to intervertebral disc damage: exploring diabetic-induced disc degeneration

“…After ACG activation, Gal3 and RAGE can act as receptors of ACG to affect collagen, in which Gal3 has a protective effect on AGE attack, limiting collagen damage and biomechanical changes. RAGE is an essential receptor for collagen injury induced by AGEs ( 74 ). MRI image analysis showed that oral treatment with the AGE inhibitor PM could reduce NP dehydration after needle injury.…”

Role of Galectin-3 in intervertebral disc degeneration: an experimental study

“…Furthermore, the expression of Galectin-3 is upregulated in nucleus pulposus cells and inhibition of Galectin-3 can alleviate spinal cord injury and intervertebral disc degeneration [ 22 ]. It has also been suggested that Galectin-3 may have a protective effect on cells and tissues involved in intervertebral disc degeneration, limiting collagen damage and changes in biomechanical properties [ 23 ]. However, there is no study on the expression and role of Galectin-3 in the cartilage endplate of the intervertebral disc.…”

Collagen integrity of the annulus fibrosus in degenerative disc disease individuals quantified with collagen hybridizing peptide

“…Recently, a Collagen Hybridizing Peptide (CHP) has been reported as being able to identify and quantify collagen damage in IVDs and other connective tissues at the molecular level. 9 , 14 , 21 , 22 , 23 , 24 , 25 Briefly, CHP binds selectively to the dissociated triple helix structure in the degraded collagens through a unique helix hybridization process, 12 , 21 mimicking the triple‐helical molecular structure of natural collagen, where it binds to the glycine (G)‐proline (P)‐hydroxyproline (O) amino acid repeat chains in the fibrillar triple helical domain. 12 Through hydrogen bonding, a stable homotrimeric triple helix is formed.…”

“…Their study showed that collagen denaturation was associated with the onset of mechanical damage. To date, only a few studies have examined the use of CHP to detect collagen damage in the AF, 9 , 14 , 23 , 25 of which only two use human AF. 9 , 23 However, the focus of those studies was on various murine models whereas human samples were not examined in detail.…”

“…Additionally, previous studies have usually examined samples from a single lumbar level or combined samples from various lumbar levels. 9 , 14 , 23 , 25 However, the different lumbar levels operate in a distinct and unique mechanical environment, 32 , 33 degenerating at different rates, 34 thus suggesting further study of structural differences of different lumbar levels.…”