Accelerated osteocyte senescence and skeletal fragility in mice with type 2 diabetes
Brittany A. Eckhardt, … , David G. Monroe, Joshua N. Farr
Brittany A. Eckhardt, … , David G. Monroe, Joshua N. Farr
Published April 8, 2020
Citation Information: JCI Insight. 2020;5(9):e135236. https://doi.org/10.1172/jci.insight.135236.
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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 1

Body composition of the HFD/STZ mouse model of T2D.

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Body composition of the HFD/STZ mouse model of T2D. (A) Schematic of the...
(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 control mice fed LFD (LFD/VEH group), mice fed an HFD (and subsequently treated with either VEH or STZ) exhibited significant gains in body weight over the course of 4 months. (C) Body weight comparisons among the 4 groups at endpoint (age 7 months). (D) Comparisons of fat mass at baseline after 1 month of diet (lead-in phase). (E) Fat mass comparisons among the 4 groups at endpoint (age 7 months). (F) Comparisons of lean mass at baseline after 1 month of diet (lead-in phase). (G) Lean mass comparisons among the 4 groups at endpoint (age 7 months). For all analyses, n = 10/group. Data represent mean ± SEM (error bars). ns, P ≥ 0.10; †P < 0.10; *P < 0.05; **P < 0.01; ***P < 0.001 (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.