Accelerated osteocyte senescence and skeletal fragility in mice with type 2 diabetes
Brittany A. Eckhardt, Jennifer L. Rowsey, Brianne S. Thicke, Daniel G. Fraser, Katherine L. O’Grady, Olga P. Bondar, Jolaine M. Hines, Ravinder J. Singh, Andrew R. Thoreson, Kuntol Rakshit, Anthony B. Lagnado, João F. Passos, Adrian Vella, Aleksey V. Matveyenko, Sundeep Khosla, David G. Monroe, Joshua N. Farr
Brittany A. Eckhardt, Jennifer L. Rowsey, Brianne S. Thicke, Daniel G. Fraser, Katherine L. O’Grady, Olga P. Bondar, Jolaine M. Hines, Ravinder J. Singh, Andrew R. Thoreson, Kuntol Rakshit, Anthony B. Lagnado, João F. Passos, Adrian Vella, Aleksey V. Matveyenko, Sundeep Khosla, David G. Monroe, Joshua N. Farr
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Research Article Bone biology

Accelerated osteocyte senescence and skeletal fragility in mice with type 2 diabetes

Abstract

The worldwide prevalence of type 2 diabetes (T2D) is increasing. Despite normal to higher bone density, patients with T2D paradoxically have elevated fracture risk resulting, in part, from poor bone quality. Advanced glycation endproducts (AGEs) and inflammation as a consequence of enhanced receptor for AGE (RAGE) signaling are hypothesized culprits, although the exact mechanisms underlying skeletal dysfunction in T2D are unclear. Lack of inducible models that permit environmental (in obesity) and temporal (after skeletal maturity) control of T2D onset has hampered progress. Here, we show in C57BL/6 mice that a onetime pharmacological intervention (streptozotocin, STZ) initiated in adulthood combined with high-fat diet–induced (HFD-induced) obesity caused hallmark features of human adult-onset T2D, including prolonged hyperglycemia, insulin resistance, and pancreatic β cell dysfunction, but not complete destruction. In addition, HFD/STZ (i.e., T2D) resulted in several changes in bone quality that closely mirror those observed in humans, including compromised bone microarchitecture, reduced biomechanical strength, impaired bone material properties, altered bone turnover, and elevated levels of the AGE CML in bone and blood. Furthermore, T2D led to the premature accumulation of senescent osteocytes with a unique proinflammatory signature. These findings highlight the RAGE pathway and senescent cells as potential targets to treat diabetic skeletal fragility.

Authors

Brittany A. Eckhardt, Jennifer L. Rowsey, Brianne S. Thicke, Daniel G. Fraser, Katherine L. O’Grady, Olga P. Bondar, Jolaine M. Hines, Ravinder J. Singh, Andrew R. Thoreson, Kuntol Rakshit, Anthony B. Lagnado, João F. Passos, Adrian Vella, Aleksey V. Matveyenko, Sundeep Khosla, David G. Monroe, Joshua N. Farr

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Figure 2

Effects of HFD/STZ on metabolic and pancreatic β cell parameters.

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Effects of HFD/STZ on metabolic and pancreatic β cell parameters. (A) Sc...
(A) Schematic of the study design depicting male C57BL/6 mice (n = 10/group) randomized to either LFD (10% kcal from fat) or HFD (60% kcal from fat) for 1 month (lead-in phase) followed by treatment (at baseline) with either VEH or STZ and follow-up for 3 months (experimental phase) out to 7 months of age (endpoint): LFD/VEH, LFD/STZ, HFD/VEH, HFD/STZ (n = 10/group). (B) Compared with each of the 3 other groups, HFD/STZ mice exhibited significantly higher nonfasted glucose levels (taken weekly from tail blood) 2 weeks after receiving STZ that were maintained throughout the remainder of the study. (C) Comparisons of median glucose concentrations (weeks 2–12) among the 4 groups. (D) Compared with each of the 3 other groups, HFD/STZ mice exhibited significantly higher nonfasted HbA1c levels (taken from tail blood) at midpoint and endpoint of the experimental phase. (E) Mice fed HFD alone (HFD/VEH) can significantly increase their circulating insulin concentrations, whereas HFD/STZ mice cannot activate this compensatory mechanism in order to maintain their blood glucose levels in the physiological range due to functional β cell deterioration. (F) Immunohistochemical analyses of pancreatic β cells with the overlay of insulin (shown in green) and DAPI-positive nuclei (shown in blue) demonstrate that mice fed HFD alone (HFD/VEH) exhibit significantly greater β cell masses and insulin-positive areas, whereas HFD/STZ mice exhibit loss of β cell function and mass, consistent with a model of T2D. (G) Quantification of comparisons of β cell area among the 4 groups. For all analyses, n = 10/group. Data represent mean ± SEM (error bars). ns, P ≥ 0.10; *P < 0.05; ***P < 0.001 (1-way ANOVA with post hoc Tukey’s correction for multiple comparisons); ‡P < 0.001 versus each of the 3 other groups (1-way ANOVA with post hoc Tukey’s correction for multiple comparisons). HFD, high-fat diet; STZ, streptozotocin; T2D, type 2 diabetes; LFD, low-fat diet; VEH, vehicle.