Contributions of material properties and structure to increased bonefragility for a given bone mass in the UCD-T2DM rat model of type 2diabetes

摘要

Adults with type 2 diabetes (T2D) have a higher fracture risk for a given bone quantity, but the mechanisms remain unclear. Using a rat model of polygenic obese T2D, we demonstrate that diabetes significantly reduces whole-bone strength for a given bone mass (micro-CT-derived BMC), and we quantify the roles of T2D-induced deficits in material properties versus bone structure, i.e., geometry and microarchitecture. Lumbar vertebrae and ulnae were harvested from 6-month-old lean Sprague-Dawley rats, obese Sprague-Dawley rats, and diabetic obese UCD-T2DM rats (diabetic for 69 ± 7 days; blood glucose >200 mg/dl). Both obese rats and those with diabetes had reduced whole-bone strength for a given BMC. In obese rats, this was attributable to structural deficits, whereas in UCD-T2DM rats, this was attributable to structural deficits and to deficits in tissue material properties. For the vertebra, deficits in bone structure included thinner and more rod-like trabeculae; for the ulnae, inefficient distribution of bone mass to resist bending. Deficits in ulnar material properties in UCD-T2DM rats were associated with increased non-enzymatic crosslinking and impaired collagen fibril deformation. Specifically, small angle X-ray scattering revealed thatdiabetes reduced collagen fibril ultimate strain by 40%, and those changescoincided with significant reductions in the elastic, yield, and ultimatetensile properties of the bone tissue. Importantly, the biomechanical effects ofthese material property deficits were substantial. Prescribing diabetes-specifictissue yield strains in high-resolution finite element models reduced whole-bonestrength by a similar amount (and in some cases a 3.4-fold greater amount) asthe structural deficits. These findings provide insight into factors thatincrease bone fragility for a given bone mass in T2D; not only does diabetesassociate with less biomechanically efficient bone structure, but diabetes alsoreduces tissue ductility by limiting collagen fibril deformation, and in doingso, reduces the maximum load capacity of the bone.