Original full length articleBone's responses to mechanical loading are impaired in type 1 diabetes
Introduction
Obesity and diabetes are epidemic health problems associated with sedentary life-style and high-fat diets. According to the Center for Disease Control and Prevention's 2005–2008 National Health and Nutrition Examination Survey, 14% of adults between ages 45–64 and 27% of adults older than 65 are diabetic. Diabetes causes serious health complications including heart disease, neuropathy, blindness, kidney failure, and lower-extremity amputations. It is the seventh leading cause of death in the United States (www.cdc.gov). However, the negative impacts of diabetes on bone health have not been well recognized until recently. In 2007, two meta-analyses of 13–16 large clinical trials showed a startling elevation in bone fracture risk for diabetic patients compared with normal population, which was a 7-fold increase in type 1 diabetes (T1D, formerly called juvenile-onset diabetes) and a 1.4-fold increase in type 2 diabetes (T2D, formerly called adult-onset diabetes) [1], [2]. Since nearly 1 in 6 patients with hip fracture died within one year [3], bone fractures can be life threatening. The risk is especially high for diabetic patients, whose impaired vasculature and wound healing capability contribute to increased mortality [4].
The mechanisms underlying the observed elevation in fracture risk among diabetics are not fully understood, although human and animal studies have documented bone defects such as retarded bone accrual and reduced bone size [5], [6], [7] (for T1D) and/or altered bone matrix [8], [9] and increased cortical porosities [10], [11], [12] (for T2D) [11], [12]. The fragile bone phenotypes have been recapitulated in various diabetic animal models [13], [14], [15], [16]. On the cellular and molecular levels, hyperglycemia and hormonal disturbances, present in both T1D and T2D [17], [18], were found to i) inhibit the proliferation and differentiation of bone marrow mesenchymal stem cells into bone-forming osteoblasts [19], ii) suppress osteoblast's functions [20], [21], and iii) increase nonenzymatic glycation of collagen (the major organic constitute of bone matrix) [8], [9], [15]. Paradoxically, long-term use of some diabetes treatments such as thiazolidinediones, a class of insulin-sensitizing drug including rosiglitazone and pioglitazone, was recently found to stimulate adipogenesis and inhibit osteogenesis, leading to even more bone deterioration [11], [22]. Thus, there is a great need to improve bone health in diabetics using non-pharmaceutical interventions.
Mechanical stimulation associated with exercise and physical activities is long recognized as a potent anabolic factor in promoting bone health [23], [24], [25]. The beneficial effects of mechanical stimulation can be best demonstrated in the stronger bone seen in the accrual of bone mass in the dominant arms of professional tennis players, in contract with the rapid bone loss seen in astronauts and bed-rest patients as their skeletons are deprived from mechanical stimulation [26], [27]. During these bone adaptation processes, osteocytes, the most abundant cells in bone, play a central role. Dispersed in bone matrix and being well-connected with each other as well as the cells lining the bone surfaces, osteocytes serve not only as the primary sensors that detect external mechanical stimuli, but also as a paracrine regulator of osteoblasts and osteoclasts via signaling molecules such as PGE2, RANKL, OPG and sclerostin/SOST [28], [29], [30], [31]. However, the efficacy of applying mechanical stimulation in rescuing diabetic bone diseases is not known and whether diabetic hyperglycemia impairs osteocyte's mechanosensing has yet to be determined.
The objective of the present study was to test the hypothesis that bone's response to anabolic mechanical loading is attenuated in diabetes due to, at least partially, impaired mechanosensing in osteocytes. We first investigated bone's acute responses to exogenously applied ulnar loading in T1D female and male mice as well as their age- and gender-matched normal controls. We then further studied how hyperglycemia associated with severe diabetes affected the responses of osteocytic MLO-Y4 cells to fluid flow stimulation. Our results demonstrated that in vivo bone formation was impaired in severe diabetic T1D mouse and hyperglycemia inhibited osteocyte's sensitivity or responses to mechanical stimulation in vitro. This study suggests the use of proper glycemic control to restore bone's response to mechanical signals and to improve bone health in diabetic patients.
Section snippets
Animals
To test whether hyperglycemia negatively affect in vivo bone responses to loading, we used heterozygous C57BL/6-Ins2Akita/J (Akita) male and female mice and their age matched wild-type (WT) C57BL/6J controls (7-month-old, N = 5–7 mice/group, Jackson Laboratory, Bar Harbor, Maine). Due to the spontaneous Akita mutation that impairs the normal folding and secretion of insulin, Akita male mice develop T1D diabetes at the age of 5 weeks, manifesting severe hyperglycemia, hypoinsulinemia, polydipsia,
Basic metabolic parameters
Akita female mice showed no significant difference in body weight compared with WT mice (25.43 ± 1.40 vs. 26 ± 1.87 g), but a 44% elevation in fasting blood glucose level (216.14 ± 35.19 vs. 150.40 ± 6.69 mg/dL, p = 0.002) (Table 1). Akita males, however, showed a more severe level of diabetes with a 28.5% decrease in body weight (23.40 ± 1.52 vs. 32.71 ± 2.69 g, p < 0.0001) and 227% elevation in fasting blood glucose level (574.80 ± 21.39 vs. 175.57 ± 18.23 mg/dL, p < 0.0001, Table 1).
Static bone histomorphometry
For females, after five sessions
Discussion
Our in vivo ulnar loading study, for the first time, revealed that untreated severe type 1 diabetic bone showed much reduced responses to anabolic mechanical loading in contrast to the normoglycemic controls. This important finding implies that proper diabetic control may be essential to maximize the beneficial effects of exercise on skeletal health. As expected, the normoglycemic WT males and females both responded to the current loading regimen (~ 3500 με, 2 Hz, 3 min/day for 5 days) with robust
Conflicts of Interest
All authors state that they have no conflicts of interest.
Acknowledgments
The authors thank Dr. Ryan Pohlig in the College of Health Sciences of the University of Delaware for his advice on the statistical analysis in this study. The study was supported by the following funds: NIH AR054385 (LW), NIH P30GM103333 (LW), DOD PR120788 (XLL) and NSERC 341704 (LY). Author contributions: study design—LW, XLL and LY; data collection—AP, XL, XG, SP and CP for the in vivo ulnar loading; and WL and XLL for the in vitro studies; data and statistical analysis—all authors; data
References (67)
Increasing duration of type 1 diabetes perturbs the strength–structure relationship and increases brittleness of bone
Bone
(2011)- et al.
Connective tissue and joint disease in diabetes mellitus
Endocrinol. Metab. Clin. N. Am.
(1996) Type 2 diabetic mice demonstrate slender long bones with increased fragility secondary to increased osteoclastogenesis
Bone
(2009)- et al.
Physical activity and bone mass: exercises in futility?
Bone Miner.
(1993) - et al.
Strain rate as a controlling influence on adaptive modeling in response to dynamic loading of the ulna in growing male rats
Bone
(1998) Recovery of spaceflight-induced bone loss: bone mineral density after long-duration missions as fitted with an exponential function
Bone
(2007)Mechanical stimulation of bone in vivo reduces osteocyte expression of SOST/sclerostin
J. Biol. Chem.
(2008)Targeted ablation of osteocytes induces osteoporosis with defective mechanotransduction
Cell Metab.
(2007)- et al.
A model for the excitation of osteocytes by mechanical loading-induced bone fluid shear stresses
J. Biomech.
(1994) Osteocytes as mechanosensors in the inhibition of bone resorption due to mechanical loading
Bone
(2008)
Modulation of appositional and longitudinal bone growth in the rat ulna by applied static and dynamic force
Bone
The P2X7 nucleotide receptor mediates skeletal mechanotransduction
J. Biol. Chem.
Mechanotransduction in bone: genetic effects on mechanosensitivity in mice
Bone
Glucose-induced inhibition of in vitro bone mineralization
Bone
Mechanosensation and transduction in osteocytes
Bone
Intracellular Ca2 + stores and extracellular Ca2 + are required in the real-time Ca2 + response of bone cells experiencing fluid flow
J. Biomech.
Calcium response in osteocytic networks under steady and oscillatory fluid flow
Bone
Oscillatory fluid flow-induced shear stress decreases osteoclastogenesis through RANKL and OPG signaling
Bone
Osteocyte apoptosis regulates osteoclast precursor adhesion via osteocytic IL-6 secretion and endothelial ICAM-1 expression
Bone
Bone densities and bone size at the distal radius in healthy children and adolescents: a study using peripheral quantitative computed tomography
Bone
Extracellular NO signalling from a mechanically stimulated osteocyte
J. Biomech.
Pulsating fluid flow increases prostaglandin production by cultured chicken osteocytes—a cytoskeleton-dependent process
Biochem. Biophys. Res. Commun.
Dentin matrix protein 1 gene cis-regulation: use in osteocytes to characterize local responses to mechanical loading in vitro and in vivo
J. Biol. Chem.
The effect of insulin therapy on biomechanical deterioration of bone in streptozotocin (STZ)-induced type 1 diabetes mellitus in rats
Diabetes Res. Clin. Pract.
Long-term, high-fat-sucrose diet alters rat femoral neck and vertebral morphology, bone mineral content, and mechanical properties
Bone
Systematic review of type 1 and type 2 diabetes mellitus and risk of fracture
Am. J. Epidemiol.
Discrepancies in bone mineral density and fracture risk in patients with type 1 and type 2 diabetes—a meta-analysis
Osteoporos. Int.
Hip fracture mortality. Relation to age, treatment, preoperative illness, time of surgery, and complications
Clin. Orthop. Relat. Res.
Physiological challenges of bone repair
J. Orthop. Trauma
Bone size normalizes with age in children and adolescents with type 1 diabetes
Diabetes Care
Bone mass and structure in adolescents with type 1 diabetes compared to healthy peers
Osteoporos. Int.
Role of collagen enzymatic and glycation induced cross-links as a determinant of bone quality in spontaneously diabetic WBN/Kob rats
Osteoporos. Int.
High-resolution peripheral quantitative computed tomographic imaging of cortical and trabecular bone microarchitecture in patients with type 2 diabetes mellitus
J. Clin. Endocrinol. Metab.
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These three authors contributed equally to this work.