Elsevier

Life Sciences

Volume 205, 15 July 2018, Pages 184-192
Life Sciences

Irbesartan attenuates advanced glycation end products-mediated damage in diabetes-associated osteoporosis through the AGEs/RAGE pathway

https://doi.org/10.1016/j.lfs.2018.04.042Get rights and content

Abstract

Aims

Diabetes-associated osteoporosis is mainly caused by the formation and accumulation of advanced glycation end products (AGEs). Angiotensin II type 1 receptor blocker (ARB) has anabolic bone effects on the physicochemical properties of the bone in diabetes. We hypothesized that ARB could inhibit AGEs-induced deleterious effects.

Main methods

In this study, we chose seven-week-old Leprdb/Lepr+ (db/+) and Leprdb/Leprdb (db/db) mice. After 12 week intervention by irbesartan, the microarchitecture and mechanical strength of the bone of seven-week-old db/db mice were investigated systematically. Meanwhile, the molecular mechanisms of the osteoblasts were analyzed, after AGEs or irbesartan were added to the culture. Also, intracellular formation of reactive oxygen species (ROS) was measured with DCF fluorescence.

Key foundings

Results showed that 12-week irbesartan treatment could dramatically improve trabecular bone microarchitecture through increasing BV/TV (p = 0.003, +46.7%), Tb.N (p = 0.020, +52.0%), and decreasing that of Tb.Sp (p = 0.005, −21.2%) and SMI (p = 0.007, −26.4%), comparing with the db/db group. Irbesartan could also substantially raise biomechanical parameters including max load (p = 0.013, +20.7%), fracture load (p = 0.014, +70.5%), energy absorption (p = 0.019, +99.4%). Besides, it could inhibit AGEs-induced damage of cell proliferation and osteogenic differentiation of osteoblasts, as well as suppressing the activation of apoptosis caused by AGEs. Moreover, co-incubation with irbesartan could prevent the AGEs-induced increase of intracellular oxidative stress and RAGE expression in osteoblasts.

Significance

In conclusion, this study suggested that irbesartan might play a protective role in diabetes-related bone damages by blocking the deleterious effects of AGEs/RAGE-mediated oxidative stress. This may provide a revolutionary benefits to therapy with irbesartan on diabetic osteoporosis.

Introduction

Diabetes mellitus is one of the most common diseases in the world. So far, there are 382 million people with diabetes worldwide and this number will rise to 592 million in the year 2035 [1]. Increasing number of evidence identifies diabetes as a risk factor of low bone mass and fractures [2]. Hyperglycemia deteriorates bone material properties and structural characteristics in terms of collagen posttranslational modification such as enzymatic immature and mature cross-links and nonenzymatic advanced glycation end products (AGEs) formation.

AGEs, the end product of Maillard process, are covalent compounds of macroprotein derivatives, which are formed through a non-enzymatic reaction among reducing sugars, amino groups of proteins, lipids and nucleic acids. The formation of AGEs is progressed at an accelerated rate under the diabetes condition and its accumulation contributes to the aging of macromolecules [3]. AGEs dramatically increase bone fragility and impair bone quality of diabetes [4]. It was reported that AGEs could impair bone formation by attenuating the differentiation of osteoblastic lineage [5], inducing osteoblasts' apoptosis [6], inhibiting the expression of osteoblast-specific transcription factors and decreasing mineralization [7] in vitro.

Recently, academics have raised more concern about Renin-angiotensin system's (RAS) correlation with bone health, structure and metabolism, while various studies have been carried out to examine the role of RAS components on bone density and fractures risks. RAS acts on bone microenvironments both systemically and locally through classical angiotensin-converting enzyme (ACE)/angiotensin II (AngII)/angiotensin type-1 receptor (AT1R) axis [8,9]. The relation between the RAS and bone metabolism is mainly based on the regulation of AngII on bone metabolism [10]. AngII could promote bone resorption via AngII type I (AT1) and type II (AT2) receptors [11,12] and the blockage of either of these receptors was supposed to ameliorate differentiation and bone formation in cell culture and in ovariectomized animal models [11,13]. Interestingly, Donmez et al. [14] reported that Losartan, an AT1 receptor blocker (ARB), had a therapeutic effect on the physicochemical properties of diabetic rat bone, leading to the improvement of bone strength at the material level. However, current findings about the effects of RAS on bone in diabetes are still limited and controversial. In other animal studies, ARB did not effectively reverse bone injuries in type I diabetic mice model [15]. Also, the mechanism of how ARB can affect the bone in type II diabetes is unclear. Thus, it is necessary to explore the ARB's effect on diabetes-associated osteoporosis and the possible pathophysiological mechanism further. Based on current evidence, which suggests that ARB could inhibit AGEs formation or accumulation in diabetic animal model [16,17], we hypothesized that ARB attenuates AGEs-mediated damage in diabetes-associated osteoporosis through its receptor (RAGE) pathway.

The study was designed to assess the theory that irbesartan may be able to cancel the AGEs-induced deleterious effects on animal model and osteoblasts, by conducting a series of experiments and analyzing the bone mass and strength of db/db mice, a common-used animal model for type II diabetes.

Section snippets

Animal

All experiments performed were endorsed by the Animal Ethics Committee of the Southern Medical University. Seven-week-old male Leprdb/Lepr+ (db/+) and Leprdb/Leprdb (db/db) mice were purchased from the Model Animal Research Center of Nanjing University. The previous research indicated that bone metabolism could be affected by estrogen [18]. Therefore, we excluded female mice in our original proposal to prevent the influence of estrogen. Mice were maintained in the Laboratory Animal Center of

Irbesartan improved bone microarchitecture of db/db mice

Representative data of two-dimensional images of femoral metaphysis were shown in Fig. 1A. Compared with the db/+ group, mice in the db/db group displayed a less, thinner and more broken trabecular bone microarchitecture. Irbesartan treatment dramatically alleviated these damages of trabecular in diabetic mice. Trabecular bone parameters including BV/TV, Tb.N, and BMD in the db/db group were significantly lower than those in the control db/+ group, while the values of Tb.Sp. and SMI were

Discussion

Various studies have been carried out to examine the role of RAS components on bone density and fractures risks, and the RAS-induced osteoporosis which was demonstrated independently of hypertension [19]. Moreover, plentiful evidence from epidemiology gives proofs that ARB is able to decrease the risk of fractures and enhance the bone mass [11,20]. ARB could inversely influence osteoclastic activity by suppressing the AngII–induced up-regulation of Receptor Activator for Nuclear Factor-κ B

Conflict of interest

The authors declare that there are no conflicts of interest.

Acknowledgments

The study was supported by grants from the National Natural Science Foundation of China (Grant No. 81270966, No. 81500679), the Natural Science Foundation of Guangdong Province, China (Grant No. S2012010009494, 2014A030310036, 2014A030310472 and 2017A030313519), Science and Technology Plan of Guangdong Province (Grant No. 2016A020215097, 2017A020215045) and the Natural Science Foundation of Southern Medical University, Guangdong Province, China (Grant No. PY2013N050).

References (44)

  • M. Tohidnezhad et al.

    Role of platelet-released growth factors in detoxification of reactive oxygen species in osteoblasts

    Bone

    (2014)
  • N.N. Danial et al.

    Cell death: critical control points

    Cell

    (2004)
  • V. Petronilli et al.

    The voltage sensor of the mitochondrial permeability transition pore is tuned by the oxidation-reduction state of vicinal thiols. Increase of the gating potential by oxidants and its reversal by reducing agents

    J. Biol. Chem.

    (1994)
  • G. Li et al.

    Receptor for advanced glycation end products inhibits proliferation in osteoblast through suppression of Wnt, PI3K and ERK signaling

    Biochem. Biophys. Res. Commun.

    (2012)
  • P. Jackuliak et al.

    Osteoporosis, fractures, and diabetes

    Int. J. Endocrinol.

    (2014)
  • L.C. Hofbauer et al.

    Osteoporosis in patients with diabetes mellitus

    J. Bone Miner. Res.

    (2007)
  • M. Brownlee et al.

    Advanced glycosylation end products in tissue and the biochemical basis of diabetic complications

    N. Engl. J. Med.

    (1988)
  • K. Okazaki et al.

    Advanced glycation end products (AGEs), but not high glucose, inhibit the osteoblastic differentiation of mouse stromal ST2 cells through the suppression of osterix expression, and inhibit cell growth and increasing cell apoptosis

    Calcif. Tissue Int.

    (2012)
  • R. Sanguineti et al.

    Pentosidine effects on human osteoblasts in vitro

    Ann. N. Y. Acad. Sci.

    (2008)
  • J.L. Lavoie et al.

    Minireview: overview of the renin-angiotensin system—an endocrine and paracrine system

    Endocrinology

    (2003)
  • K. Sakai et al.

    Local production of angiotensin II in the subfornical organ causes elevated drinking

    J. Clin. Invest.

    (2007)
  • Y. Gebru et al.

    Potential of RAS inhibition to improve metabolic bone disorders

    Biomed. Res. Int.

    (2013)
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    These authors contributed equally to this work.

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