Low bone toughness in the TallyHO model of juvenile type 2 diabetes does not worsen with age

Abstract

Fracture risk increases as type 2 diabetes (T2D) progresses. With the rising incidence of T2D, in particular early-onset T2D, a representative pre-clinical model is needed to study mechanisms for treating or preventing diabetic bone disease. Towards that goal, we hypothesized that fracture resistance of bone from diabetic TallyHO mice decreases as the duration of diabetes increases. Femurs and lumbar vertebrae were harvested from male, TallyHO mice and male, non-diabetic SWR/J mice at 16weeks (n≥12 per strain) and 34weeks (n≥13 per strain) of age. As is characteristic of this model of juvenile T2D, the TallyHO mice were obese and hyperglycemic at an early age (5weeks and 10weeks of age, respectively). The femur mid-shaft of TallyHO mice had higher tissue mineral density and larger cortical area, as determined by micro-computed tomography, compared to the femur mid-shaft of SWR/J mice, irrespective of age. As such, the diabetic rodent bone was structurally stronger than the non-diabetic rodent bone, but the higher peak force endured by the diaphysis during three-point (3pt) bending was not independent of the difference in body weight. Upon accounting for the structure of the femur diaphysis, the estimated toughness at 16weeks and 34weeks was lower for the diabetic mice than for non-diabetic controls, but neither toughness nor estimated material strength and resistance to crack growth (3pt bending of contralateral notched femur) decreased as the duration of hyperglycemia increased. With respect to trabecular bone, there were no differences in the compressive strength of the L6 vertebral strength between diabetic and non-diabetic mice at both ages despite a lower trabecular bone volume for the TallyHO than for the SWR/J mice at 34weeks. Amide I sub-peak ratios as determined by Raman Spectroscopy analysis of the femur diaphysis suggested a difference in collagen structure between diabetic and non-diabetic mice, although there was not a significant difference in matrix pentosidine between the groups. Overall, the fracture resistance of bone in the TallyHO model of T2D did not progressively decrease with increasing duration of hyperglycemia. However, given the variability in hyperglycemia in this model, there were correlations between blood glucose levels and certain structural properties including peak force.

Bone Tissue Composition in Postmenopausal Women Varies With Glycemic Control From Normal Glucose Tolerance to Type 2 Diabetes Mellitus

“…For example, overexpression of lysyl hydroxylases—which regulate the organization of enzymatic cross‐links in type 1 collagen—can change the molecular packing of collagen fibrils and lead to abnormal nucleation of hydroxyapatite crystals, ( 55 ) whereas inhibition of lysyl oxidase in rats decreased the concentration of mature collagen cross‐links by ~45% decreased femoral bending strength by 26% compared with controls. ( 58 ) Although the KKay mouse, ( 59 ) TallyHo mouse, ( 60 ) and ZDSD rat ( 61 ) similarly exhibit greater tissue mineral content (in contrast to mice fed a high‐fat diet ( 62 ) ), these models have limited ability to inform how progressive glycemic derangement alters tissue‐level and structural properties in bone because no rodent model captures (i) all of the observed changes in compositional properties, as reviewed recently ( 63 ) or (ii) the complexity of human T2DM (eg, longer duration, later onset). Together, the compositional differences identified here highlight several possible areas for future studies of the mechanisms of altered skeletal integrity with impaired glucose control and T2DM.…”

Assessing matrix quality by Raman spectroscopy helps predict fracture toughness of human cortical bone

“…Raman sub-peaks of the Amide I band of bone are also sensitive to the disruption of collagen enzymatic crosslinking 46 , tissue aging 47 , degree of mineralization 48 , ionizing radiation 49,50 , and hydration 45 . More recently, the ~I 1670 /I 1640 ratio was found to be higher in diabetic mouse bone with lower toughness compared to non-diabetic mice bone with higher toughness 51 , implying it could be sensitive to advanced glycated end-products (AGEs), although fluorescence AGEs and pentosidine, an AGE crosslink, were not different between the groups. The ~I 1670 /I 1640 ratio was also recently reported to be sensitive to in vitro glycation of human cortical bone as well 52 .…”

Update on the impact of type 2 diabetes mellitus on bone metabolism and material properties

“…In animal models of T2DM, some studies have reported increased AGE content in the bone tissue (48, 49), while other studies have reported no difference in AGEs but alterations in the collagen structure (50) and increased collagen maturity (51). Since levels of AGEs in the bone tissue cannot be measured noninvasively in patients, surrogates, such as serum or urine levels, are typically used.…”