Rapid CommunicationTelmisartan alleviates rosiglitazone-induced bone loss in ovariectomized spontaneous hypertensive rats
Introduction
Glucose intolerance, hyperlipidemia, insulin resistance (Type II diabetes), hypertension and other closely related cardiovascular risk factors are common features of the metabolic syndrome, a condition with rising prevalence in western countries [1], [2], [3]. Rosiglitazone (ROS), a thiazolidinedione (TZD) compound, is often used in clinic for its powerful insulin-sensitizing effects. However, evidence is mounting to link significant bone loss or factures with its use [4], [5], [6], [7], [8], especially in postmenopausal women [9]. Angiotensin AT1 receptor antagonists (sartans), drugs commonly used for the control of hypertension, are often co-administrated with TZDs to treat metabolic syndrome. Furthermore, recent advances on the role of angiotensin II in bone metabolism have revealed blockage of Ang II might be a novel therapeutic approach to prevent bone loss in hypertensive patients [10]. And this raises the intriguing possibility that sartans, when prescribed together with rosiglitazone in patients with metabolic syndrome, might prevent or attenuate rosiglitazone-induced bone loss.
Spontaneously hypertensive rats (SHR), the most widely used model for human essential hypertension, which also expresses the insulin resistance phenotypes [11], had been used as an experimental model to understand the pathological conditions of metabolic syndrome [11], [12], [13]. Ovariectomized spontaneously hypertensive rats were used in our study to mimic human metabolic syndrome with estrogen withdrawal.
Among angiotensin AT1 receptor antagonists (sartans), telmisartan was noted for its unique favorable effects on carbohydrate and lipid metabolism [14], [15], [16], [17]. Hydralazine is a vasodilator used to treat hypertension, congestive heart failure, myocardial infarction, and preeclampsia [18]. To rule out blood pressure as a cofounding factor in our experiment this drug was used as a reference drug. In the present study, we systematically examined telmisartan and hydralazine, on rosiglitazone-induced bone loss in ovariectomized spontaneously hypertensive rats. And indeed, in this model, although equally effective in reducing blood pressure, telmisartan (5 mg/kg/d, 90 days) but not hydralazine (10 mg/kg, 90 days) was able to significantly alleviate ROS (10 mg/kg/d, 90 days)-induced decrease in BMD of femur and lumbar vertebrae. The BMD changes were associated with positive biomechanical changes of lumbar vertebrae, improvements in microarchitecture of tibial metaphysic and normalized serum osteocalcin (OC) levels and urinary DPD/Cr ratio.
Section snippets
Animal experiment
Thirty-two 10-week-old female SHRs weighting 160–190 g were obtained from Vital River (Beijing, China). Rats were housed in standard cages (4 rats per cage) and they were maintained at 25 ± 1 °C and constant humidity (60%) with a 12 h light:12 h dark cycle. The animals were allowed free access to water and standard pellet diet. Animal care and treatment were conducted in accordance with the institutional guidelines.
Animals were allowed to acclimate for at least 8 days before the experiment and then
Body weight, heart rate and systolic blood pressure
Fig. 1A shows body weights of the rats in each group. As expected, the rats given ROS alone significantly increased their body weights by 19.6% (P < 0.01 vs. vehicle control) at the end of the study. However,the excess weight gain induced by ROS was significantly attenuated by TEL (−14.7%, P < 0.05 vs. ROS alone group). The systolic blood pressure measured by the tail-cuff method is shown in Fig. 1B. ROS lowered the systolic blood pressure of rats by 11.3% (P < 0.05 vs. vehicle control) but did not
Discussion
Thiazolidinediones (TZDs) have been used for the treatment of hyperglycaemia in type II diabetes since 1997. Currently, pioglitazone and rosiglitazone are the only compounds licensed for patients with insulin resistance or type II diabetes. TZDs can be used as monotherapy for blood glucose control or in combination with other agents for the treatment metabolic syndrome. Despite their powerful insulin-sensitizing effects and additional beneficial effects on cardiovascular risk factor, a number
Acknowledgments
This work was supported in part by the China National Science Foundation (Project NO. 30801424/c180112).
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Telmisartan impairs the in vitro osteogenic differentiation of mesenchymal stromal cells from spontaneously hypertensive male rats
2021, European Journal of PharmacologyCitation Excerpt :A recent study observed no effect on bone turnover markers in newly diagnosed stage I hypertensive patients (Aydogan et al., 2019). In the SHR, it was reported that TELM treatment reduced the rosiglitazone-induced bone loss in ovariectomized SHR (Ma et al., 2010), and protect against periodontitis-induced alveolar bone loss (Brito et al., 2020), however, Birocale et al. (2016) suggest that TELM favors bone loss in male SHR. Additionally, indirect action were also proposed by Zhao et al. (2014) who showed TELM to improve bone fracture healing in mice, associated with increased chondrocytes proliferation and neovascularization.
The ACE-2/Ang1-7/Mas cascade enhances bone structure and metabolism following angiotensin-II type 1 receptor blockade
2017, European Journal of PharmacologyCitation Excerpt :These results are consistent with other investigations. Telmisartan palliated rosiglitazone-associated bone loss in spontaneously hypertensive OVX rats in one study (Ma et al., 2010) and reduced bone loss in OVX mice in another study (Kang et al., 2013). Olmesartan treatments also ameliorate the OVX-induced decrease in bone density (Shimizu et al., 2008).
Bone mineral density is reduced by telmisartan in male spontaneously hypertensive rats
2016, Pharmacological ReportsCitation Excerpt :These data suggests that the renin–angiotensin system may be involved in bone metabolism [8]. In animal models of bone loss induced by rosiglitazone, bone loss was prevented by an increase in the bone/tissue volume ratio, number of trabeculae, and the trabecular thickness when ovariectomized spontaneously hypertensive rats were administrated rosiglitazone along with telmisartan, an angiotensin receptor blocker (ARB) [9]. This observation indicates that the renin–angiotensin system is, in fact, somehow involved in bone metabolism.
Angiotensin II type 1 receptor antagonists in animal models of vascular, cardiac, metabolic and renal disease
2016, Pharmacology and TherapeuticsCitation Excerpt :This has mostly been done by oral administration, but parenteral administration schemes, e.g. based on osmotic minipumps chronically delivering an ARB subcutaneously have also been used (Nishimura et al., 1998b). Again, all ARBs having been tested effectively lowered BP under these conditions, e.g. azilsartan (Sueta et al., 2013; Hye Khan et al., 2014a; Isegawa et al., 2015), candesartan (Mizuno et al., 1992b; Inada et al., 1994; Mizuno et al., 1994; Takeda et al., 1994; Mori et al., 1995; Nishimura et al., 1998b; Tsuchihashi et al., 1999; Jones et al., 2004; Chen et al., 2010; Ishimitsu et al., 2010; Jones et al., 2012; Isegawa et al., 2015), irbesartan (Lacour et al., 1994), losartan (Inada et al., 1994; Li & Widdop, 1996; Hashimoto et al., 1997; Dai et al., 2007), olmesartan (Koike et al., 2001), telmisartan (Wienen et al., 2001; Mandarim-de-Lacerda & Pereira, 2004; Li et al., 2006; Dai et al., 2007; Kumai et al., 2008; Liu et al., 2009a; Chen et al., 2010; Ma et al., 2010; Khan & Imig, 2011; Liu et al., 2011; Zhong et al., 2011; Müller-Fielitz et al., 2012; Zhu et al., 2012; Xu & Liu, 2013) and valsartan (Chow et al., 1995; Scheidegger et al., 1996; Tea et al., 2000). Such findings apparently apply to various substrains of SHR (Li et al., 2006).
Losartan increases bone mass and accelerates chondrocyte hypertrophy in developing skeleton
2015, Molecular Genetics and MetabolismCitation Excerpt :In rodents, type 2 angiotensin receptor is formed by a single protein encoded by Agtr2 gene, while the type 1 angiotensin receptor is a receptor complex consisting of Agtr1a and Agtr1b receptors. Multiple reports in adult mouse and rat models [8–10] have shown that blockage of Agtr1a or Agtr2 effectively increased bone mass under physiological conditions and in an ovariectomy (OVX) induced osteoporosis model. In contrast, one study showed that an ACE inhibitor reduced BMD in the distal femoral metaphysis in mice [11].