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 4

Short-term T2D has modest deleterious effects on bone biomechanical strength and material properties.

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Short-term T2D has modest deleterious effects on bone biomechanical stre...
(A) Schematic of the study design depicting male C57BL/6 mice 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, HFD/VEH, HFD/STZ (n = 10/group). Comparisons among the groups at study endpoint (7 months of age) of bone biomechanical properties (assessed by compression testing) at the lumbar vertebrae, including (B) stiffness (N/mm), (C) ultimate load (N), and (D) ultimate stress (MPa). Endpoint comparisons of bone biomechanical properties (assessed by 3-point bending) at the femur midshaft, including (E) stiffness (N/mm), (F) ultimate load (N), and (G) failure energy (N). Endpoint comparisons of bone material properties (assessed by nanoindentation) at the lumbar vertebrae, including (H) modulus (GPa) and (I) hardness (GPa). Endpoint comparisons of indices of bone material properties (assessed by reference point microindentation [RPI]) at the femur diaphysis, including (J) total indentation distance (TID) and (K) average loading slope (avLS). For all analyses, n = 10/group. Data represent mean ± SEM (error bars). ns, P ≥ 0.10; *P < 0.05 (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.