A quinoxaline-based compound ameliorates bone loss in ovariectomized mice

2021 ◽  
pp. 153537022110321
Author(s):  
Ying Zhou ◽  
Xiaoyan Xue ◽  
Yanyan Guo ◽  
Huan Liu ◽  
Zheng Hou ◽  
...  
Keyword(s):  
Weight Gain ◽  
Bone Loss ◽  
Bone Formation ◽  
Marker Gene ◽  
Mice Model ◽  
Ovariectomized Mice ◽  
Bone Formation Markers ◽  
Small Molecule Compound ◽  
Glucagon Like Peptide 1 ◽  
Turnover Markers

DMB (6,7-dichloro-2-methylsulfonyl-3-Ntert-butylaminoquinoxaline) is a quinoxaline-based compound that has been investigated as a glucagon-like peptide-1 receptor (GLP-1R) agonist. To clarify anti-osteoporosis effect of DMB, an osteoporotic mice model was established by ovariectomy (OVX) operation. The OVX mice were given intraperitoneally DMB, exendin-4 (EX-4), or 17β-estradiol (E2) for two months. Then bone mass and structure, and bone morphometric parameters were examined by micro-CT. Weight gain and food consumption, bone turnover markers, and biomechanical strength of the femur were tested, and bone histomorphometry was analyzed. The food intake and weight gain was obviously reduced by E2 or EX-4, but not DMB. However, DMB or EX-4 treatment obviously inhibited skeletal deterioration and enhanced bone strength. The improvement involved in the increased osteoblast number and level of bone formation markers, and reduced osteoclasts number and level of bone resorption markers. In addition, DMB was found to stimulate osteoblastogenesis-related marker gene expression. These results demonstrated that DMB ameliorated bone loss mainly via induction of bone formation, which suggests that the small molecule compound might be applied to the management of postmenopausal osteoporosis.

scholarly journals Telmisartan Prevents Alveolar Bone Loss by Decreasing the Expression of Osteoclasts Markers in Hypertensive Rats With Periodontal Disease

2020 ◽  
Vol 11 ◽  
Author(s):  
Victor Gustavo Balera Brito ◽  
Mariana Sousa Patrocinio ◽  
Maria Carolina Linjardi de Sousa ◽  
Ayná Emanuelli Alves Barreto ◽  
Sabrina Cruz Tfaile Frasnelli ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Bone Loss ◽  
Bone Formation ◽  
Periodontal Disease ◽  
Alveolar Bone ◽  
Renin Angiotensin System ◽  
Alveolar Bone Loss ◽  
Hypertensive Rats ◽  
Bone Formation Markers ◽  
Tnf Α

Periodontal disease (PD) is a prevalent inflammatory disease with the most severe consequence being the loss of the alveolar bone and teeth. We therefore aimed to evaluate the effects of telmisartan (TELM), an angiotensin II type 1 receptor (Agtr1) antagonist, on the PD-induced alveolar bone loss, in Wistar (W) and Spontaneous Hypertensive Rats (SHRs). PD was induced by ligating the lower first molars with silk, and 10 mg/kg TELM was concomitantly administered for 15 days. The hemimandibles were subjected to microtomography, ELISA was used for detecting tumor necrosis factor (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), CXCL3, and CCL2, while qRT-PCR was used for analyzing expression of components of renin-angiotensin system (RAS) (Agt, Ace, Agt1r, Agt2r, Ace2, and Masr), and bone markers (Runx2, Osx, Catnb, Alp, Col1a1, Opn, Ocn, Bsp, Bmp2, Trap, Rank, Rankl, CtsK, Mmp-2, Mmp-9, and osteoclast-associated receptor (Oscar)). The SHR + PD group showed greater alveolar bone loss than the W + PD group, what was significantly inhibited by treatment with TELM, especially in the SHR group. Additionally, TELM reduced the production of TNF-α, IL-1β, and CXCL3 in the SHR group. The expression of Agt increased in the groups with PD, while Agtr2 reduced, and TELM reduced the expression of Agtr1 and increased the expression of Agtr2, in W and SHRs. PD did not induce major changes in the expression of bone formation markers, except for the expression of Alp, which decreased in the PD groups. The bone resorption markers expression, Mmp9, Ctsk, and Vtn, was higher in the SHR + PD group, compared to the respective control and W + PD group. However, TELM attenuated these changes and increased the expression of Runx2 and Alp. Our study suggested that TELM has a protective effect on the progression of PD, especially in hypertensive animals, as evaluated by the resorption of the lower alveolar bone. This can be partly explained by the modulation in the expression of Angiotensin II receptors (AT1R and AT2R), reduced production of inflammatory mediators, the reduced expression of resorption markers, and the increased expression of the bone formation markers.

The fixed herbal drug composition “Saikokaryukotsuboreito” prevents bone loss with an association of serum IL-6 reductions in ovariectomized mice model

Phytomedicine ◽  
2010 ◽  
Vol 17 (3-4) ◽  
pp. 170-177 ◽  
Author(s):  
T. Hattori ◽  
W. Fei ◽  
T. Kizawa ◽  
S. Nishida ◽  
H. Yoshikawa ◽  
...  
Keyword(s):  
Bone Loss ◽  
Herbal Drug ◽  
Mice Model ◽  
Ovariectomized Mice

scholarly journals Effects of Estrogen Receptor and Wnt Signaling Activation on Mechanically Induced Bone Formation in a Mouse Model of Postmenopausal Bone Loss

2020 ◽  
Vol 21 (21) ◽  
pp. 8301
Author(s):  
Astrid Liedert ◽  
Claudia Nemitz ◽  
Melanie Haffner-Luntzer ◽  
Fabian Schick ◽  
Franz Jakob ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Bone Loss ◽  
Bone Formation ◽  
Bone Mass ◽  
Postmenopausal Bone Loss ◽  
Paracrine Factors ◽  
Treatment Of Osteoporosis ◽  
Ovariectomized Mice ◽  
Underlying Mechanisms ◽  
Signaling Activation

In the adult skeleton, bone remodeling is required to replace damaged bone and functionally adapt bone mass and structure according to the mechanical requirements. It is regulated by multiple endocrine and paracrine factors, including hormones and growth factors, which interact in a coordinated manner. Because the response of bone to mechanical signals is dependent on functional estrogen receptor (ER) and Wnt/β-catenin signaling and is impaired in postmenopausal osteoporosis by estrogen deficiency, it is of paramount importance to elucidate the underlying mechanisms as a basis for the development of new strategies in the treatment of osteoporosis. The present study aimed to investigate the effectiveness of the activation of the ligand-dependent ER and the Wnt/β-catenin signal transduction pathways on mechanically induced bone formation using ovariectomized mice as a model of postmenopausal bone loss. We demonstrated that both pathways interact in the regulation of bone mass adaption in response to mechanical loading and that the activation of Wnt/β-catenin signaling considerably increased mechanically induced bone formation, whereas the effects of estrogen treatment strictly depended on the estrogen status in the mice.

scholarly journals The Effect of Gonadotropin-Releasing Hormone Agonist on Type I Collagen C-Telopeptide and N-Telopeptide: the Predictive Value of Biochemical Markers of Bone Turnover

1998 ◽  
Vol 83 (2) ◽  
pp. 333-338 ◽  
Author(s):  
Ernest A. Amama ◽  
Michiyoshi Taga ◽  
Hiroshi Minaguchi
Keyword(s):  
Bone Resorption ◽  
Bone Loss ◽  
Bone Formation ◽  
Biochemical Markers ◽  
Type I Collagen ◽  
Type I ◽  
Bone Resorption Markers ◽  
Bone Formation Markers ◽  
Z Scores ◽  
The Mean

To evaluate the clinical utility of recently developed biochemical markers in the assessment of bone metabolism during GnRH agonist (GnRHa) treatment, we compared five bone resorption markers[ C-telopeptide (CTX) and N-telopeptide (NTX) of type I collagen, hydroxyproline (Hpr), pyridinoline (Pyr), and deoxypyridinoline (Dpyr)] and two bone formation markers [total alkaline phosphatase (Alp) and osteocalcin (OC)]. Sixty-eight normally menstruating women were injected with a long-acting GnRHa once a month for 24 weeks for the treatment of endometriosis or leiomyoma. The mean percentage bone loss at the lumbar spine was 3.79% at the end of treatment. Although levels of all markers increased significantly as the treatment progressed, CTX and NTX exhibited the highest correlation coefficients between bone loss at 24 weeks and the seven markers measured at 0, 4, 12, 16, and 24 weeks of treatment. Serum estradiol levels were similarly suppressed during the treatment in both fast losers (whose bone loss was more than the mean) and slow losers (whose bone loss was less than the mean). However, significantly higher z-scores of bone resorption markers, but not of bone formation markers, were observed in the fast losers at 24 weeks of treatment, suggesting a more accelerated bone resorption in this group. Whereas the three highest z-scores at 24 weeks of treatment were CTX, NTX, and Dpyr (in that order), the highest z-score (P < 0.05) was observed for CTX in the fast losers. The subjects in the highest quartile of CTX, the highest, and second highest quartiles of NTX at 24 weeks of treatment experienced 2.1, 2.2, and 1.7 times more bone loss (P < 0.001), respectively, than those in the lowest quartiles. Furthermore, the subjects in the highest quartile of both CTX and NTX experienced 3.6 times more bone loss (P < 0.001) than those in the lowest quartile of both markers. These results indicate that both CTX and NTX are useful and sensitive markers for bone resorption in a hypoestrogenic state induced by GnRHa.

scholarly journals TZDs and Bone: A Review of the Recent Clinical Evidence

PPAR Research ◽  
2008 ◽  
Vol 2008 ◽  
pp. 1-6 ◽  
Author(s):  
Ann V. Schwartz
Keyword(s):  
Clinical Trials ◽  
Bone Loss ◽  
Bone Formation ◽  
In Vitro Models ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Turnover Markers ◽  
Test Treatments ◽  
Bone Research

Over the past two years, evidence has emerged that the currently available thiazolidinediones (TZDs), rosiglitazone, and pioglitazone have negative skeletal consequences, at least in women, which are clinically important. Increased fracture risk in women, but not men, was reported for both TZDs, based on analyses of adverse event reports from clinical trials. In short-term clinical trials in women, both TZDs caused more rapid bone loss. In these trials, changes in bone turnover markers suggest a pattern of reduced bone formation without a change in resorption. Although limited, these results support the hypothesis based on rodent and in vitro models that reduced bone formation resulting from activation of peroxisome proliferator-activated receptor- (PPAR) is a central mechanism for TZDs_ effect on bone. Research is needed to better understand the mechanisms of bone loss with TZDs, to identify factors that influence susceptibility to TZD-induced osteoporosis, and to test treatments for its prevention.

scholarly journals Recombinant Irisin Prevents the Reduction of Osteoblast Differentiation Induced by Stimulated Microgravity through Increasing β-Catenin Expression

2020 ◽  
Vol 21 (4) ◽  
pp. 1259 ◽  
Author(s):  
Zhihao Chen ◽  
Yan Zhang ◽  
Fan Zhao ◽  
Chong Yin ◽  
Chaofei Yang ◽  
...  
Keyword(s):  
Bone Formation ◽  
Osteoblast Differentiation ◽  
Simulated Microgravity ◽  
Marker Gene ◽  
Calcium Deposition ◽  
Bone Homeostasis ◽  
Mice Model ◽  
Beneficial Effects

Background: Irisin, a novel exercise-induced myokine, was shown to mediate beneficial effects of exercise in osteoporosis. Microgravity is a major threat to bone homeostasis of astronauts during long-term spaceflight, which results in decreased bone formation. Methods: The hind-limb unloading mice model and a random position machine are respectively used to simulate microgravity in vivo and in vitro. Results: We demonstrate that not only are bone formation and osteoblast differentiation decreased, but the expression of fibronectin type III domain-containing 5 (Fdnc5; irisin precursor) is also downregulated under simulated microgravity. Moreover, a lower dose of recombinant irisin (r-irisin) (1 nM) promotes osteogenic marker gene (alkaline phosphatase (Alp), collagen type 1 alpha-1(ColIα1)) expressions, ALP activity, and calcium deposition in primary osteoblasts, with no significant effect on osteoblast proliferation. Furthermore, r-irisin could recover the decrease in osteoblast differentiation induced by simulated microgravity. We also find that r-irisin increases β-catenin expression and partly neutralizes the decrease in β-catenin expression induced by simulated microgravity. In addition, β-catenin overexpression could also in part attenuate osteoblast differentiation reduction induced by simulated microgravity. Conclusions: The present study is the first to show that r-irisin positively regulates osteoblast differentiation under simulated microgravity through increasing β-catenin expression, which may reveal a novel mechanism, and it provides a prevention strategy for bone loss and muscle atrophy induced by microgravity.

scholarly journals Biochemical Bone Turnover Markers and Osteoporosis in Older Men: Where Are We?

2011 ◽  
Vol 2011 ◽  
pp. 1-5 ◽  
Author(s):  
Pawel Szulc
Keyword(s):  
Bone Resorption ◽  
Bone Formation ◽  
Bone Turnover ◽  
Bone Turnover Markers ◽  
Fragility Fractures ◽  
Older Men ◽  
Testosterone Replacement Therapy ◽  
Mineral Density ◽  
Bone Formation Markers ◽  
Turnover Markers

In men aged less than 60, the association of serum and urinary levels of biochemical bone turnover markers (BTMs) and bone mineral density (BMD) is weak or not significant. After this age, higher BTM levels are correlated weakly, but significantly, with lower BMD and faster bone loss. Limited data from the cohort studies suggest that BTM measurement does not improve the prediction of fragility fractures in older men in comparison with age, BMD, history of falls and fragility fractures. Testosterone replacement therapy (TRT) decreases bone resorption. During TRT, bone formation markers slightly increase (direct effect on osteoblasts), then decrease (slowdown of bone turnover). Bisphosphonates (alendronate, risedronate, ibandronate, zoledronate) induce a rapid decrease in bone resorption followed by a milder decrease in bone formation. In men receiving antiresorptive therapy for prostate cancer, zoledronate, denosumab and toremifene decrease significantly levels of bone resorption and bone formation markers. Teriparatide induced a rapid increase in serum concentrations of bone formation markers followed by an increase in bone resorption. We need more studies on the utility of BTM measurement for the improvement of the persistence and adherence to the anti-osteoporotic treatment in men.

scholarly journals Morroniside promotes the osteogenesis by activating PI3K/Akt/mTOR signaling

2021 ◽  
Vol 85 (2) ◽  
pp. 332-339
Author(s):  
Hui Liu ◽  
Xi Li ◽  
Jingui Lin ◽  
Miaokuo Lin
Keyword(s):  
Bone Loss ◽  
Bone Formation ◽  
Osteoblast Differentiation ◽  
Mtor Signaling ◽  
Detailed Mechanism ◽  
Pharmacological Inhibition ◽  
Prevent Bone Loss ◽  
In Vivo Assays ◽  
Ovariectomized Mice

ABSTRACT Morroniside exerts a proosteogenic effect, which can prevent bone loss. However, the detailed mechanism underlying Morroniside-regulated bone formation is unclear. Morroniside can maintain cell homeostasis by promoting PI3K/Akt/mTOR signaling. The purpose of this study is to explore the significance of PI3K/Akt/mTOR signaling in Morroniside-regulated osteogenesis. The results showed that Morroniside promoted the activities of PI3K, Akt, and mTOR in osteoblast precursor MC3T3-E1. The differentiation of MC3T3-E1 to mature osteoblasts promoted by Morroniside can be reversed by the pharmacological inhibition of PI3K or mTOR. Importantly, in the presence of Morroniside, the osteoblast differentiation suppressed by PI3K inhibitor was reversed by mTOR overexpression. In vivo assays showed that in bone tissue of ovariectomized mice, Morroniside-enhanced osteoblast formation was reversed by the pharmacological inhibition of PI3K or mTOR. In conclusion, Morroniside can promote the osteogenesis through PI3K/Akt/mTOR signaling, which provides a novel clue for the strategy of Morroniside in treating osteoporosis.

scholarly journals The contribution of serum cortisone and glucocorticoid metabolites to detrimental bone health in patients receiving hydrocortisone therapy

2020 ◽  
Author(s):  
Rosemary Dineen ◽  
Lucy-Ann Behan ◽  
Grainne Kelleher ◽  
Mark J Hannon ◽  
Jennifer J Brady ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Bone Formation ◽  
Bone Turnover ◽  
Replacement Therapy ◽  
Negative Correlation ◽  
Bone Health ◽  
Bone Turnover Markers ◽  
Serum Cortisol ◽  
Bone Formation Markers ◽  
Turnover Markers

Abstract Background: Glucocorticoid therapy is the most common cause of iatrogenic osteoporosis. Less is known regarding the effect of glucocorticoids when used as replacement therapy on bone remodelling in patients with adrenal insufficiency. Enhanced intracellular conversion of inactive cortisone to active cortisol, by 11 beta-hydroxysteroid dehydrogenase type 1(11β-HSD1) and other enzymes leading to alterations in glucocorticoid metabolism, may contribute to a deleterious effect on bone health in this patient group.Methods: Study design: An open crossover prospective study randomizing ten hypopituitary men, with severe ACTH deficiency, to three commonly used hydrocortisone dose regimens. Measurements: Following 6 weeks of each regimen, patients underwent 24-hour serum cortisol/cortisone sampling, measurement of bone turnover markers, and a 24-hour urine collection for measurement of urinary steroid metabolites by gas chromatography-mass spectrometry (GC-MS). Serum cortisone and cortisol were analysed by liquid chromatography-mass spectrometry (LC-MS).Results: Dose-related and circadian variations in serum cortisone were seen to parallel those for cortisol, indicating conversion of ingested hydrocortisone to cortisone. The median area under the curve (AUC) of serum cortisone was significantly higher in patients on dose A (20mg/10mg) [670.5 (IQR 621-809.2)] compared to those on dose C (10mg/5mg) [562.8 (IQR 520.1-619.6), p=0.01]. A negative correlation was observed between serum cortisone and bone formation markers, OC[1-49] (r=-0.42, p=0.03), and PINP (r=-0.49, p=0.01). There was a negative correlation between the AUC of night-time serum cortisone levels with the bone formation marker, OC[1-49] (r=-0.41, p=0.03) but there were no significant correlations between day-time serum cortisone or cortisol with bone turnover markers. There was a negative correlation between total urinary cortisol metabolites and the bone formation markers, PINP (r=-0.39, p=0.04), and OC[1-49] (r=-0.35, p=0.06).Conclusion: Serum cortisol and cortisone and total urinary corticosteroid metabolites are associated with alterations in bone turnover markers even at replacement doses of hydrocortisone suggesting a potentially negative role of tissue-specific metabolism of glucocorticoids on bone metabolism in patients receiving hydrocortisone replacement therapy.

scholarly journals The contribution of serum cortisone and glucocorticoid metabolites to detrimental bone health in patients receiving hydrocortisone therapy

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Rosemary Dineen ◽  
Lucy-Ann Behan ◽  
Grainne Kelleher ◽  
Mark J. Hannon ◽  
Jennifer J. Brady ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Bone Formation ◽  
Bone Turnover ◽  
Negative Correlation ◽  
Bone Health ◽  
Bone Turnover Markers ◽  
Serum Cortisol ◽  
Chromatography Mass Spectrometry ◽  
Bone Formation Markers ◽  
Turnover Markers

Abstract Background Glucocorticoid therapy is the most common cause of iatrogenic osteoporosis. Less is known regarding the effect of glucocorticoids when used as replacement therapy on bone remodelling in patients with adrenal insufficiency. Enhanced intracellular conversion of inactive cortisone to active cortisol, by 11 beta-hydroxysteroid dehydrogenase type 1(11β-HSD1) and other enzymes leading to alterations in glucocorticoid metabolism, may contribute to a deleterious effect on bone health in this patient group. Methods Study design: An open crossover prospective study randomizing ten hypopituitary men, with severe ACTH deficiency, to three commonly used hydrocortisone dose regimens. Measurements: Following 6 weeks of each regimen, patients underwent 24-h serum cortisol/cortisone sampling, measurement of bone turnover markers, and a 24-h urine collection for measurement of urinary steroid metabolites by gas chromatography-mass spectrometry (GC-MS). Serum cortisone and cortisol were analysed by liquid chromatography-mass spectrometry (LC-MS). Results Dose-related and circadian variations in serum cortisone were seen to parallel those for cortisol, indicating conversion of ingested hydrocortisone to cortisone. The median area under the curve (AUC) of serum cortisone was significantly higher in patients on dose A (20 mg/10 mg) [670.5 (IQR 621–809.2)] compared to those on dose C (10 mg/5 mg) [562.8 (IQR 520.1–619.6), p = 0.01]. A negative correlation was observed between serum cortisone and bone formation markers, OC [1–49] (r = − 0.42, p = 0.03), and PINP (r = − 0.49, p = 0.01). There was a negative correlation between the AUC of night-time serum cortisone levels with the bone formation marker, OC [1–49] (r = − 0.41, p = 0.03) but there were no significant correlations between day-time serum cortisone or cortisol with bone turnover markers. There was a negative correlation between total urinary cortisol metabolites and the bone formation markers, PINP (r = − 0.39, p = 0.04), and OC [1–49] (r = − 0.35, p = 0.06). Conclusion Serum cortisol and cortisone and total urinary corticosteroid metabolites are negatively associated with bone turnover markers in patients receiving replacement doses of hydrocortisone, with nocturnal glucocorticoid exposure having a potentially greater influence on bone turnover. Trial registration Irish Medicines Board Clinical Trial Number – CT900/459/1 and EudraCT Number – 2007-005018-37. Registration date: 07-09-2007.

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