Induction and rescue of skeletal fragility in a high-fat diet mouse model of type 2 diabetes: An in vivo and in vitro approach

Techniques for advanced glycation end product measurements for diabetic bone disease: pitfalls and future directions

“…The fAGEs measured in bone matrix using this technique have proved to be significant predictors of bone fragility [14,26]. Removal of fAGEs from aging and diabetic bone has been shown to rescue skeletal fragility [15,27], indicating their causal relationship with bone fracture and potential use as a therapeutic target. The fAGE measurement ’in bulk’ is currently the most direct and convenient method to estimate the collective accumulation of a large number of fluorescent AGEs/ AGOEs without specifically identifying them.…”

“…CML is of considerable importance to various oxidative stress-related diseases as in-vivo formation of this AGE is also connected with cellular oxidative/carbonyl metabolism [11,12,13 ▪ ]. This nonfluorescent AGE has been shown to accumulate at high levels in human bone [19] and correlate with bone fracture properties [14,15], hip [55] and diabetic fractures [56 ▪▪ ]. Thomas et al [19] determined that CML in bone is 40–100 times greater than pentosidine, the current most commonly used marker of AGEs in bone.…”

“…The Amadori products undergo a variety of irreversible dehydration and rearrangement reactions, which at the end, result in the formation of hundreds of chemical species. Glycation reactions are highly accelerated in hyperglycemia [10,11] and oxidative stress [10,12,13 ▪ ] and lead to, for example, diabetic complications [13 ▪ ,14,15] and premature tissue aging [16,17].…”

Crosstalk Between Senescent Bone Cells and the Bone Tissue Microenvironment Influences Bone Fragility During Chronological Age and in Diabetes

“…Pre-clinical studies in animal models of diabetes have demonstrated AGEs accumulation in bone ( Rubin et al, 2016 ; Acevedo et al, 2018 ). In diabetic male mice fed on a high fat diet, increased levels of total fAGEs, pentosidine and carboxymethyl-lysine (CML) were found in bone, while ex vivo treatment of femurs obtained from these mice with phenacyl thiazolium chloride (PTC) for in vitro removal of glycation products increased bone toughness, a parameter of mechanical strength ( LLabre et al, 2021 ). Glycation of the trabecular bone similarly affects its mechanical properties, notably the damage fraction, post-yield strain energy and energy dissipation, suggesting a higher susceptibility to brittle fracture ( Tang et al, 2007 ).…”

Collagen cross-link profiles and mineral are different between the mandible and femur with site specific response to perturbed collagen

“…While numerous AGEs have been detected in bone collagen, pentosidine (PEN) is the predominantly reported AGE in ( Saito et al, 2006 ; Wang et al, 2002 ; Katayama et al, 1996 ; Kawamura et al, 2019 ; Saito et al, 2010 ; Saito et al, 2006 ; Viguet-Carrin et al, 2006 ; Chavarry et al, 2019 ; Odetti et al, 2005 ; Vaculík et al, 2016 ; Kida et al, 2019 ; Hunt et al, 2018 ; Hunt et al, 2019 ; Heveran et al, 2019 ), yet present in low quantities compared to other AGEs ( Thomas et al, 2018 ). CML is of recent interest ( Thomas et al, 2018 ; Creecy et al, 2021 ; Arakawa et al, 2020 ; Sroga and Vashishth, 2021 ; LLabre et al, 2022 ) but direct quantification of CML between anatomical sites remains a critical knowledge gap. For enzymatic cross-links, LH and LOX control tissue-specific patterning ( Hanson and Eyre, 1996 ; Knott and Bailey, 1998 ).…”