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 5

Effects of T2D on skeletal histomorphometry parameters, bone turnover markers, and bone gene expression markers.

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Effects of T2D on skeletal histomorphometry parameters, bone turnover ma...
(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/STZ (n = 10/group). Histomorphometric quantification at the tibia endocortical (Ec.) surface of (B) osteoclast numbers per bone perimeter (N.Oc/B.Pm; /mm), (C) osteoblast numbers per bone perimeter (N.Ob/B.Pm; /mm), (D) mineral apposition rate (MAR; mcm/d), and (E) bone formation rate per bone surface (BFR/BS; mcm3/mcm2/d). Quantification of circulating serum bone turnover makers, including (F) the bone resorption marker, cross-linked C-telopeptide of type I collagen (CTx; ng/mL), and (G) the bone formation marker, amino-terminal propeptide of type I collagen (P1NP; ng/mL). rt-qPCR mRNA gene expression analyses of (H) osteoblast marker genes, (I) osteocyte genes, (J) osteoprotegerin (Tnfrsf11b, Opg), and (K) tumor necrosis factor ligand superfamily member 11 (Tnfsf11, Rankl) in bone samples. Data represent mean ± SEM (error bars). ns, P ≥ 0.10; *P < 0.05; **P < 0.01 (independent samples t test or Wilcoxon’s rank-sum test, as appropriate). HFD, high-fat diet; STZ, streptozotocin; T2D, type 2 diabetes; LFD, low-fat diet; VEH, vehicle; Ec, endocortical.