scholarly journals Intranuclear Delivery of Nuclear Factor-Kappa B p65 in a Rat Model of Tooth Replantation

2021 ◽  
Vol 22 (4) ◽  
pp. 1987
Author(s):  
Chung-Min Kang ◽  
Seunghan Mo ◽  
Mijeong Jeon ◽  
Ui-Won Jung ◽  
Yooseok Shin ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Treatment Group ◽  
Bone Resorption ◽  
Rat Model ◽  
Root Resorption ◽  
Osteoclast Differentiation ◽  
Tartrate Resistant Acid Phosphatase ◽  
Nitric Oxide Release ◽  
Tooth Replantation ◽  
Trap Staining

After avulsion and replantation, teeth are at risk of bone and root resorption. The present study aimed to demonstrate that the intra-nuclear transducible form of transcription modulation domain of p65 (nt-p65-TMD) can suppress osteoclast differentiation in vitro, and reduce bone resorption in a rat model of tooth replantation. Cell viability and nitric oxide release were evaluated in RAW264.7 cells using CCK-8 assay and Griess reaction kit. Osteoclast differentiation was evaluated using quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and tartrate-resistant acid phosphatase (TRAP) staining. Thirty-two maxillary rat molars were extracted and stored in saline (n = 10) or 10 µM nt-p65-TMD solution (n = 22) before replantation. After 4 weeks, specimens were scored according to the inflammatory pattern using micro-computed tomography (CT) imaging and histological analyses. nt-p65-TMD treatment resulted in significant reduction of nitric oxide release and osteoclast differentiation as studied using PCR and TRAP staining. Further, micro-CT analysis revealed a significant decrease in bone resorption in the nt-p65-TMD treatment group (p < 0.05). Histological analysis of nt-p65-TMD treatment group showed that not only bone and root resorption, but also inflammation of the periodontal ligament and epithelial insertion was significantly reduced. These findings suggest that nt-p65-TMD has the unique capabilities of regulating bone remodeling after tooth replantation.

scholarly journals 4-Acetylantroquinonol B Inhibits Osteoclastogenesis by Inhibiting the Autophagy Pathway in a Simulated Microgravity Model

2020 ◽  
Vol 21 (18) ◽  
pp. 6971
Author(s):  
Chia-Hsin Wu ◽  
Ching-Huei Ou ◽  
I-Chuan Yen ◽  
Shih-Yu Lee
Keyword(s):  
Bone Resorption ◽  
Transmembrane Protein ◽  
Osteoclast Differentiation ◽  
Osteoclast Formation ◽  
Tartrate Resistant Acid Phosphatase ◽  
Nuclear Factor ◽  
Actin Ring ◽  
Activated T Cells ◽  
Cycle Arrest ◽  
Trap Staining

Astronauts suffer from 1–2% bone loss per month during space missions. Targeting osteoclast differentiation has been regarded as a promising strategy to prevent osteoporosis in microgravity (μXg). 4-acetylantroquinonol B (4-AAQB), a ubiquinone from Antrodia cinnamomea, has shown anti-inflammatory and anti-hepatoma activities. However, the effect of 4-AAQB on μXg-induced osteoclastogenesis remains unclear. In this study, we aimed to explore the mechanistic impact of 4-AAQB on osteoclast formation under μXg conditions. The monocyte/macrophage-like cell line RAW264.7 was exposed to simulated μXg (Rotary Cell Culture System; Synthecon, Houston, TX, USA) for 24 h and then treated with 4-AAQB or alendronate (ALN) and osteoclast differentiation factor receptor activator of nuclear factor kappa-B ligand (RANKL). Osteoclastogenesis, bone resorption activity, and osteoclast differentiation-related signaling pathways were analyzed using tartrate-resistant acid phosphatase (TRAP) staining, actin ring fluorescent staining, bone resorption, and western blotting assays. Based on the results of TRAP staining, actin ring staining, and bone resorption assays, we found that 4-AAQB significantly inhibited μXg-induced osteoclast differentiation. The critical regulators of osteoclast differentiation, including nuclear factor of activated T-cells cytoplasmic 1 (NFATc1), c-Fos, and dendritic cell-specific transmembrane protein (DC-STAMP), were consistently decreased. Meanwhile, osteoclast apoptosis and cell cycle arrest were also observed along with autophagy suppression. Interestingly, the autophagy inhibitors 3-methyladenine (3-MA) and chloroquine (CQ) showed similar effects to 4-AAQB. In conclusion, we suggest that 4-AAQB may serve as a potential agent against μXg-induced osteoclast formation.

scholarly journals Decitabine Inhibits Bone Resorption in Periodontitis by Upregulating Anti-Inflammatory Cytokines and Suppressing Osteoclastogenesis

Biomedicines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 199
Author(s):  
Urara Tanaka ◽  
Shunichi Kajioka ◽  
Livia S. Finoti ◽  
Daniela B. Palioto ◽  
Denis F. Kinane ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Bone Resorption ◽  
Bone Loss ◽  
Inflammatory Cytokines ◽  
Osteoclast Differentiation ◽  
Tartrate Resistant Acid Phosphatase ◽  
Dependent Manner ◽  
Bone Homeostasis ◽  
Osteoblastic Cell Line ◽  
Anti Inflammatory

DNA methylation controls several inflammatory genes affecting bone homeostasis. Hitherto, inhibition of DNA methylation in vivo in the context of periodontitis and osteoclastogenesis has not been attempted. Ligature-induced periodontitis in C57BL/6J mice was induced by placing ligature for five days with Decitabine (5-aza-2′-deoxycytidine) (1 mg/kg/day) or vehicle treatment. We evaluated bone resorption, osteoclast differentiation by tartrate-resistant acid phosphatase (TRAP) and mRNA expression of anti-inflammatory molecules using cluster differentiation 14 positive (CD14+) monocytes from human peripheral blood. Our data showed that decitabine inhibited bone loss and osteoclast differentiation experimental periodontitis, and suppressed osteoclast CD14+ human monocytes; and conversely, that it increased bone mineralization in osteoblastic cell line MC3T3-E1 in a concentration-dependent manner. In addition to increasing IL10 (interleukin-10), TGFB (transforming growth factor beta-1) in CD14+ monocytes, decitabine upregulated KLF2 (Krüppel-like factor-2) expression. Overexpression of KLF2 protein enhanced the transcription of IL10 and TGFB. On the contrary, site-directed mutagenesis of KLF2 binding site in IL10 and TFGB abrogated luciferase activity in HEK293T cells. Decitabine reduces bone loss in a mouse model of periodontitis by inhibiting osteoclastogenesis through the upregulation of anti-inflammatory cytokines via KLF2 dependent mechanisms. DNA methyltransferase inhibitors merit further investigation as a possible novel therapy for periodontitis.

scholarly journals Estrogen Decreases Cytoskeletal Organization by Forming an ERα/SHP2/c-Src Complex in Osteoclasts to Protect against Ovariectomy-Induced Bone Loss in Mice

Antioxidants ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 619
Author(s):  
Hyun-Jung Park ◽  
Malihatosadat Gholam-Zadeh ◽  
Sun-Young Yoon ◽  
Jae-Hee Suh ◽  
Hye-Seon Choi
Keyword(s):  
Bone Resorption ◽  
Bone Loss ◽  
Ring Formation ◽  
Tartrate Resistant Acid Phosphatase ◽  
Actin Ring ◽  
Collagen Crosslinks ◽  
Trap Staining ◽  
Src Activation

Loss of ovarian function is closely related to estrogen (E2) deficiency, which is responsible for increased osteoclast (OC) differentiation and activity. We aimed to investigate the action mechanism of E2 to decrease bone resorption in OCs to protect from ovariectomy (OVX)-induced bone loss in mice. In vivo, tartrate-resistant acid phosphatase (TRAP) staining in femur and serum carboxy-terminal collagen crosslinks-1 (CTX-1) were analyzed upon E2 injection after OVX in mice. In vitro, OCs were analyzed by TRAP staining, actin ring formation, carboxymethylation, determination of reactive oxygen species (ROS) level, and immunoprecipitation coupled with Western blot. In vivo and in vitro, E2 decreased OC size more dramatically than OC number and Methyl-piperidino-pyrazole hydrate dihydrochloride (MPPD), an estrogen receptor alpha (ERα) antagonist, augmented the OC size. ERα was found in plasma membranes and E2/ERα signaling affected receptor activator of nuclear factor κB ligand (RANKL)-induced actin ring formation by rapidly decreasing a proto-oncogene tyrosine-protein kinase, cellular sarcoma (c-Src) (Y416) phosphorylation in OCs. E2 exposure decreased physical interactions between NADPH oxidase 1 (NOX1) and the oxidized form of c-Src homology 2 (SH2)-containing protein tyrosine phosphatase 2 (SHP2), leading to higher levels of reduced SHP2. ERα formed a complex with the reduced form of SHP2 and c-Src to decrease c-Src activation upon E2 exposure, which blocked a signal for actin ring formation by decreased Vav guanine nucleotide exchange factor 3 (Vav3) (p–Y) and Ras-related C3 botulinum toxin substrate 1 (Rac1) (GTP) activation in OCs. E2/ERα signals consistently inhibited bone resorption in vitro. In conclusion, our study suggests that E2-binding to ERα forms a complex with SHP2/c-Src to attenuate c-Src activation that was induced upon RANKL stimulation in a non-genomic manner, resulting in an impaired actin ring formation and reducing bone resorption.

Edgeworthia papyrifera Regulates Osteoblast and Osteoclast Differentiation In Vitro and Exhibits Anti-osteoporosis Activity in Animal Models of Osteoporosis

Planta Medica ◽  
2019 ◽  
Vol 85 (09/10) ◽  
pp. 766-773 ◽  
Author(s):  
Pansoo Kim ◽  
Yeon-Ju Nam ◽  
Woo Jung Kim ◽  
Jin Kyu Kim ◽  
Gyeongbeen Lee ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Animal Models ◽  
Osteoclast Differentiation ◽  
Raw 264.7 Cells ◽  
Tartrate Resistant Acid Phosphatase ◽  
Raw 264.7 ◽  
Treatment Of Osteoporosis ◽  
Increased Risk ◽  
Interesting Candidate

AbstractOsteoporosis is a clinical condition characterized by low bone strength that leads to an increased risk of fracture. Strategies for the treatment of osteoporosis involve inhibition of bone resorption by osteoclasts and an increase of bone formation by osteoblasts. Here, we identified the extract derived from the stem part of Edgeworthia papyrifera that enhanced differentiation of MC3T3-E1 cells to osteoblast-like cells and inhibited osteoclast differentiation of RAW 264.7 cells in vitro. In support of our observation, rutin and daphnoretin, which were previously reported to inhibit osteoclast differentiation, were identified in E. papyrifera extract. In an animal model of osteoporosis, the ovariectomy-induced increases in bone resorption biomarkers such as pyridinoline and tartrate-resistant acid phosphatase were significantly reduced by E. papyrifera extract administration at 25.6 and 48.1%, respectively. Furthermore, the ovariectomy-induced bone loss in animal models of osteoporosis was significantly prevented by the administration of E. papyrifera in our study. Taking these observations into account, we suggest that E. papyrifera is an interesting candidate for further exploration as an anti-osteoporotic agent.

scholarly journals A Novel Sandwich ELISA for Tartrate-Resistant Acid Phosphatase 5a and 5b Protein Reveals that Both Isoforms are Secreted by Differentiating Osteoclasts and Correlate to the Type I Collagen Degradation Marker CTX-I In Vivo and In Vitro

2019 ◽  
Vol 106 (2) ◽  
pp. 194-207 ◽  
Author(s):  
Laia Mira-Pascual ◽  
Christina Patlaka ◽  
Suchita Desai ◽  
Staffan Paulie ◽  
Tuomas Näreoja ◽  
...  
Keyword(s):  
Acid Phosphatase ◽  
Bone Resorption ◽  
Sandwich Elisa ◽  
Osteoclast Differentiation ◽  
Collagen Degradation ◽  
Considerable Proportion ◽  
Tartrate Resistant Acid Phosphatase ◽  
Osteoclast Number ◽  
Serum Trap ◽  
Trap 5B

Abstract Tartrate-resistant acid phosphatase type 5 (TRAP) exists as two isoforms, 5a and 5b. 5b is a marker of osteoclast number and 5a of chronic inflammation; however, its association with bone resorption is unknown. In this study, a double-TRAP 5a/5b sandwich ELISA measuring 5a and 5b protein in the same sample was developed. TRAP 5a and 5b protein levels were evaluated as osteoclast differentiation/activity markers in serum and in culture, and their correlation to the resorption marker CTX-I was examined. Serum TRAP 5a and 5b concentrations in healthy men were 4.4 ± 0.6 ng/ml and 1.3 ± 0.2 ng/ml, respectively, and they correlated moderately to each other suggesting that their secretion is coupled under healthy conditions. A correlation was also observed between serum TRAP 5a and 5b with CTX-I, suggesting that both TRAP isoforms associate with osteoclast number. During osteoclast differentiation on plastic/bone, predominantly 5b increased in media/lysate from M-CSF/RANKL-stimulated CD14+ PBMCs. However, substantial levels of 5a were detected at later stages suggesting that both isoforms are secreted from differentiating OCs. More TRAP 5b was released on bone indicating a connection to osteoclast resorptive activity, and a peak in TRAP 5b/5a-ratio coincided with rapid CTX-I release. At the end of the culture period of M-CSF + RANKL-stimulated CD14+ PBMCs, there was a correlation between the secretion of TRAP 5a and 5b proteins with CTX-I. The correlation of not only 5b but also 5a with collagen degradation, both in serum and osteoclast cultures indicates that a considerable proportion of the TRAP 5a originates from osteoclasts and may reflect a hitherto undisclosed regulatory mechanism during bone resorption and bone remodeling.

scholarly journals TGF-β and Physiological Root Resorption of Deciduous Teeth

2016 ◽  
Author(s):  
Emi Shimazaki ◽  
Takeo Karakida ◽  
Ryuji Yamamoto ◽  
Saeko Kobayashi ◽  
Makoto Fukae ◽  
...  
Keyword(s):  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Root Resorption ◽  
Mrna Level ◽  
Osteoclast Differentiation ◽  
Activity Level ◽  
Deciduous Teeth ◽  
Beta Activity ◽  
Tartrate Resistant Acid Phosphatase ◽  
Trap Activity

The present study was performed to examine that transforming growth factor beta (TGF-&beta;) in root-surrounding tissues on deciduous teeth during the physiological root resorption regulates the differentiation induction into odontoclast. We prepared root-surrounding tissues with (R) or without (N) physiological root resorption scraped off at three regions (R1-R3 or N1-N3) from the cervical area to the apical area of the tooth and measured both TGF-&beta; and the tartrate-resistant acid phosphatase (TRAP) activities. The TGF-&beta; activity level was increased in N1-N3, whereas the TRAP activity was increased in R2 and R3. In vitro experiments for RANKL-mediated osteoclast differentiation revealed that TGF-&beta; in N1-N3 and R1-R3 enhanced the TRAP activity in RAW264 cells. A genetic study indicated that the mRNA level of TGF-&beta;1 in N1 and N2 was significantly increased, and corresponded with that of osteoprotegerin (OPG). In contrast, the expression level of receptor activator of NF-&kappa;B ligand (RANKL) was increased in R2 and R3. Our findings suggest that TGF-&beta; is closely related to the regulation of OPG induction and RANKL-mediated odontoclast differentiation depending on the timing of RANKL and OPG mRNA expression in the root-surrounding tissues of deciduous teeth during physiological root resorption.

scholarly journals The emerging role of IMD 0354 on bone homeostasis by suppressing osteoclastogenesis and bone resorption, but without affecting bone formation

2019 ◽  
Vol 10 (9) ◽  
Author(s):  
Wenxiang Chen ◽  
Ziang Xie ◽  
Pan Tang ◽  
Yongli Wang ◽  
Zhiwei Jie ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Formation ◽  
Osteoclast Differentiation ◽  
Nuclear Factor Κb ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Therapeutic Drug ◽  
Tartrate Resistant Acid Phosphatase ◽  
Nuclear Factor ◽  
Bone Homeostasis

Abstract Osteoporosis is caused by an imbalance between bone formation and bone resorption. Receptor activator of nuclear factor-κB ligand (RANKL) promotes the activity and differentiation of osteoclasts via activating the nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways. IMD 0354 is a selective molecular inhibitor of inhibitor of NF-κB kinase subunit beta (IKKβ) and effective for treatment of acute and subacute inflammatory diseases through the suppression of NF-κB activation. However, the effect of IMD 0354 on bone homeostasis is unknown. In this study, we demonstrated that IMD 0354 significantly attenuated ovariectomy-induced bone loss and inhibited osteoclastogenesis in mice, whereas bone formation was not affected. Additionally, IMD 0354 dramatically inhibited osteoclast differentiation and function induced by RANKL and macrophage colony-stimulating factor in bone marrow monocytes as verified by tartrate-resistant acid phosphatase (TRAP) staining as well as bone resorption assay in vitro. Subsequently, we found that activation of NF-κB signaling and the ERK/c-Fos axis were blunted during osteoclast formation induced by RANKL. Transcription factors nuclear factor of activated T cells c1 (NFATc1) and c-Fos were suppressed with the decreased expression of osteoclast-related genes by IMD 0354. Our findings suggest that IMD 0354 could be a potential preventive and therapeutic drug for osteoporosis.

scholarly journals Inhibitory Effects of 2N1HIA (2-(3-(2-Fluoro-4-Methoxyphenyl)-6-Oxo-1(6H)-Pyridazinyl)-N-1H-Indol-5-Ylacetamide) on Osteoclast Differentiation via Suppressing Cathepsin K Expression

Molecules ◽  
2018 ◽  
Vol 23 (12) ◽  
pp. 3139 ◽  
Author(s):  
Sun-Hee Ahn ◽  
Zhihao Chen ◽  
Jinkyung Lee ◽  
Seok-Woo Lee ◽  
Sang Min ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Osteoclast Differentiation ◽  
Cell Formation ◽  
Cathepsin K ◽  
Bone Diseases ◽  
Specific Gene ◽  
Tartrate Resistant Acid Phosphatase ◽  
Potential Candidate ◽  
Dependent Manner ◽  
Gene Markers

Osteoclasts are large multinucleated cells which are induced by the regulation of the receptor activator of nuclear factor kappa-Β ligand (RANKL), which is important in bone resorption. Excessive osteoclast differentiation can cause pathologic bone loss and destruction. Numerous studies have targeted molecules inhibiting RANKL signaling or bone resorption activity. In this study, 11 compounds from commercial libraries were examined for their effect on RANKL-induced osteoclast differentiation. Of these compounds, only 2-(3-(2-fluoro-4-methoxyphenyl)-6-oxo-1(6H)-pyridazinyl)-N-1H-indol-5-ylacetamide (2N1HIA) caused a significant decrease in multinucleated tartrate-resistant acid phosphatase (TRAP)-positive cell formation in a dose-dependent manner, without inducing cytotoxicity. The 2N1HIA compound neither affected the expression of osteoclast-specific gene markers such as TRAF6, NFATc1, RANK, OC-STAMP, and DC-STAMP, nor the RANKL signaling pathways, including p38, ERK, JNK, and NF-κB. However, 2N1HIA exhibited a significant impact on the expression levels of CD47 and cathepsin K, the early fusion marker and critical protease for bone resorption, respectively. The activity of matrix metalloprotease-9 (MMP-9) decreased due to 2N1HIA treatment. Accordingly, bone resorption activity and actin ring formation decreased in the presence of 2N1HIA. Taken together, 2N1HIA acts as an inhibitor of osteoclast differentiation by attenuating bone resorption activity and may serve as a potential candidate in preventing and/or treating osteoporosis, or other bone diseases associated with excessive bone resorption.

scholarly journals Magnolol Ameliorates Ligature-Induced Periodontitis in Rats and Osteoclastogenesis:In VivoandIn VitroStudy

2013 ◽  
Vol 2013 ◽  
pp. 1-12 ◽  
Author(s):  
Sheng-Hua Lu ◽  
Ren-Yeong Huang ◽  
Tz-Chong Chou
Keyword(s):  
Bone Resorption ◽  
Bone Loss ◽  
Periodontal Disease ◽  
Alveolar Bone ◽  
Morphological Changes ◽  
Osteoclast Differentiation ◽  
Alveolar Bone Loss ◽  
Tartrate Resistant Acid Phosphatase ◽  
Nuclear Factor ◽  
Raw264.7 Macrophages

Periodontal disease characterized by alveolar bone resorption and bacterial pathogen-evoked inflammatory response has been believed to have an important impact on human oral health. The aim of this study was to evaluate whether magnolol, a main constituent ofMagnolia officinalis, could inhibit the pathological features in ligature-induced periodontitis in rats and osteoclastogenesis. The sterile, 3–0 (diameter; 0.2 mm) black braided silk thread, was placed around the cervix of the upper second molars bilaterally and knotted medially to induce periodontitis. The morphological changes around the ligated molars and alveolar bone were examined by micro-CT. The distances between the amelocemental junction and the alveolar crest of the upper second molars bilaterally were measured to evaluate the alveolar bone loss. Administration of magnolol (100 mg/kg, p.o.) significantly inhibited alveolar bone resorption, the number of osteoclasts on bony surface, and protein expression of receptor activator of nuclear factor-κB ligand (RANKL), a key mediator promoting osteoclast differentiation, in ligated rats. Moreover, the ligature-induced neutrophil infiltration, expression of inducible nitric oxide synthase, cyclooxygenase-2, matrix metalloproteinase (MMP)-1 and MMP-9, superoxide formation, and nuclear factor-κB activation in inflamed gingival tissues were all attenuated by magnolol. In thein vitrostudy, magnolol also inhibited the growth ofPorphyromonas gingivalis and Aggregatibacter actinomycetemcomitansthat are key pathogens initiating periodontal disease. Furthermore, magnolol dose dependently reduced RANKL-induced osteoclast differentiation from RAW264.7 macrophages, tartrate-resistant acid phosphatase (TRAP) activity of differentiated cells accompanied by a significant attenuation of resorption pit area caused by osteoclasts. Collectively, we demonstrated for the first time that magnolol significantly ameliorates the alveolar bone loss in ligature-induced experimental periodontitis by suppressing periodontopathic microorganism accumulation, NF-κB-mediated inflammatory mediator synthesis, RANKL formation, and osteoclastogenesis. These activities support that magnolol is a potential agent to treat periodontal disease.

scholarly journals Effects of Isoliquiritigenin on Bone Metabolism and Uterus in Ovariectomized Rats

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 469-469
Author(s):  
Lara Sattgast ◽  
Carmen Wong ◽  
Daniel Doerge ◽  
William Helferich ◽  
Urszula Iwaniec ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bone Resorption ◽  
Epithelial Cell ◽  
Osteoclast Differentiation ◽  
Ovariectomized Rats ◽  
Tartrate Resistant Acid Phosphatase ◽  
Uterine Weight ◽  
Uterine Epithelial Cell ◽  
Ovx Rats

Abstract Objectives Isoliquiritigenin (ILQ) is a phenolic compound found in licorice and is a popular dietary supplement. ILQ exhibits model-specific antioxidant, anti-inflammatory, anti-tumor, and estrogenic activities. Limited data suggest the potential of ILQ to prevent or treat osteoporosis. Therefore, this study evaluated the effects of short-duration treatment with ILQ on bone and uterine tissue in estrogen-deplete ovariectomized (ovx) rats. The uterus was important to evaluate because ILQ stimulates proliferation of MCF7 breast cancer cells through an estrogen receptor-dependent mechanism. Methods Six-week-old rats (ovx'd at 4 weeks of age) were fed diets containing 0, 100, 250 or 750 ppm ILQ (n = 5/treatment) for 1 week and sacrificed. Gene expression in femur and uterus, blood markers of global bone turnover, body composition, and uterine weight and epithelial cell height were determined. In addition, the effect of ILQ on in vitro differentiation of osteoclasts derived from bone marrow was assessed. Results Treatment resulted in a dose-dependent increase in serum ILQ with levels reaching 2.4 ± 0.2 mM in rats receiving the highest dose. ILQ did not alter serum levels of osteocalcin, a global marker of bone formation, or osteocalcin gene expression in femur. Additionally, there was little or no effect of ILQ on genes related to osteoblast differentiation or activity in femur. These largely null findings contrast with a reduction in serum CTX, a global marker of bone resorption, at all dose levels of ILQ. At the gene level, ILQ resulted in lower mRNA for genes related to osteoclast differentiation and function in femur, including Acp5 (tartrate resistant acid phosphatase), Timp2 and Mmp2, and suppressed osteoclast differentiation in vitro. ILQ had no effect on the ovx-induced increase in body weight. Ovx resulted in lower uterine weight. Treatment with ILQ at 750 ppm resulted in development of severe uterine epithelial cell hyperplasia in two of five animals. Conclusions ILQ supplementation led to reduced biochemical and gene expression markers of bone resorption in vivo and reduced osteoclast differentiation in vitro without increasing estrogen-dependent gene expression. However, the potential benefits must be weighed against potential detrimental off-target effects, including uterine hypertrophy. Funding Sources NIH [P50AT006268].

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