Arctigenin inhibits RANKL‐induced osteoclastogenesis and hydroxyapatite resorption in vitro and prevents titanium particle–induced bone loss in vivo

2018 ◽  
Vol 120 (4) ◽  
pp. 5367-5376 ◽  
Author(s):  
Gejin Wei ◽  
Tihong Liang ◽  
Chengming Wei ◽  
Xiaolian Nong ◽  
Qiteng Lu ◽  
...  
Keyword(s):  
Bone Loss ◽  
Titanium Particle

scholarly journals Celastrol Attenuates RANKL-Induced Osteoclastogenesis in vitro and Reduces Titanium Particle-Induced Osteolysis and Ovariectomy-Induced Bone Loss in vivo

2021 ◽  
Vol 12 ◽  
Author(s):  
Qiang Xu ◽  
Guiping Chen ◽  
Huaen Xu ◽  
Guoming Xia ◽  
Meisong Zhu ◽  
...  
Keyword(s):  
Bone Loss ◽  
Transforming Growth Factor ◽  
Osteoclast Formation ◽  
Mitogen Activated Protein Kinase ◽  
Mice Model ◽  
Titanium Particle ◽  
Ovariectomized Mice ◽  
Prosthetic Loosening

Excessive bone resorption by osteoclasts contributes significantly to osteoclast-related diseases such as periprosthetic osteolysis and osteoporosis. Osteolysis in a titanium particle-induced calvarial model and bone loss in an ovariectomized mice model occurred similarly to those in humans; thus, these models can be used to evaluate potential therapies for aseptic prosthetic loosening and osteoporosis. Celastrol, which is extracted from the seeds of the genus Tripterygium, has been thoroughly investigated for its anti-inflammatory and anti-cancer pharmacological effects. However, the mechanisms involving bone metabolism by which celastrol inhibits osteoclastogenesis are not yet fully understood. We demonstrated that celastrol inhibited the receptor activator of nuclear factor κB ligand-induced osteoclastogenesis and the bone resorptive function of osteoclasts in vitro by inhibiting the activation of transforming growth factor β-activated kinase 1-mediated NF-κB and mitogen-activated protein kinase signaling pathways and downregulating osteoclastogenesis marker-related genes. Furthermore, celastrol was also shown to be beneficial in both the titanium particle-induced osteolysis calvarial and the murine ovariectomy-induced bone loss. Collectively, our results suggested that celastrol is promising for the prevention of aseptic prosthetic loosening and osteoporosis in the treatment of osteolytic diseases induced by disrupted osteoclast formation and function.

scholarly journals A novel BRD4 inhibitor suppresses osteoclastogenesis and ovariectomized osteoporosis by blocking RANKL-mediated MAPK and NF-κB pathways

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Ying Liu ◽  
Wenjie Liu ◽  
Ziqiang Yu ◽  
Yan Zhang ◽  
Yinghua Li ◽  
...  
Keyword(s):  
Bone Loss ◽  
Osteoporosis Treatment ◽  
Inhibitory Effect ◽  
Specific Gene ◽  
Actin Ring ◽  
Treatment Target ◽  
Significant Inhibitory Effect ◽  
Promising Treatment

AbstractBromodomain-containing protein 4 (BRD4) has emerged as a promising treatment target for bone-related disorders. (+)-JQ1, a thienotriazolodiazepine compound, has been shown to inhibit pro-osteoclastic activity in a BRD4-dependent approach and impede bone loss caused by ovariectomy (OVX) in vivo. However, clinical trials of (+)-JQ1 are limited because of its poor druggability. In this study, we synthesized a new (+)-JQ1 derivative differing in structure and chirality. One such derivative, (+)-ND, exhibited higher solubility and excellent inhibitory activity against BRD4 compared with its analogue (+)-JQ1. Interestingly, (-)-JQ1 and (-)-ND exhibited low anti-proliferative activity and had no significant inhibitory effect on RANKL-induced osteoclastogenesis as compared with (+)-JQ1 and (+)-ND, suggesting the importance of chirality in the biological activity of compounds. Among these compounds, (+)-ND displayed the most prominent inhibitory effect on RANKL-induced osteoclastogenesis. Moreover, (+)-ND could inhibit osteoclast-specific gene expression, F‐actin ring generation, and bone resorption in vitro and prevent bone loss in OVX mice. Collectively, these findings indicated that (+)-ND represses RANKL‐stimulated osteoclastogenesis and averts OVX-triggered osteoporosis by suppressing MAPK and NF-κB signalling cascades, suggesting that it may be a prospective candidate for osteoporosis treatment.

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.

scholarly journals Scutellarein inhibits RANKL‐induced osteoclast formation in vitro and prevents LPS‐induced bone loss in vivo

2018 ◽  
Vol 234 (7) ◽  
pp. 11951-11959 ◽  
Author(s):  
Fangsheng Fu ◽  
Siyuan Shao ◽  
Ziyi Wang ◽  
Fangming Song ◽  
Xixi Lin ◽  
...  
Keyword(s):  
Bone Loss ◽  
Osteoclast Formation

Artesunate inhibits RANKL-induced osteoclastogenesis and bone resorption in vitro and prevents LPS-induced bone loss in vivo

2017 ◽  
Vol 233 (1) ◽  
pp. 476-485 ◽  
Author(s):  
Cheng-Ming Wei ◽  
Qian Liu ◽  
Fang-Ming Song ◽  
Xi-Xi Lin ◽  
Yi-Ji Su ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Loss

scholarly journals Crataegus pinnatifida Bunge Inhibits RANKL-Induced Osteoclast Differentiation in RAW 264.7 Cells and Prevents Bone Loss in an Ovariectomized Rat Model

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Minsun Kim ◽  
MinBeom Kim ◽  
Jae-Hyun Kim ◽  
SooYeon Hong ◽  
Dong Hee Kim ◽  
...  
Keyword(s):  
Bone Loss ◽  
Rat Model ◽  
Osteoclast Differentiation ◽  
Ovariectomized Rat ◽  
Raw 264.7 Cells ◽  
Raw 264.7 ◽  
Mineral Density ◽  
Crataegus Pinnatifida

Osteoporosis is characterized by a decrease in bone microarchitecture with an increased risk of fracture. Long-term use of primary treatments, such as bisphosphonates and selective estrogen receptor modulators, results in various side effects. Therefore, it is necessary to develop alternative therapeutics derived from natural products. Crataegus pinnatifida Bunge (CPB) is a dried fruit used to treat diet-induced indigestion, loss of appetite, and diarrhea. However, research into the effects of CPB on osteoclast differentiation and osteoporosis is still limited. In vitro experiments were conducted to examine the effects of CPB on RANKL-induced osteoclast differentiation in RAW 264.7 cells. Moreover, we investigated the effects of CPB on bone loss in the femoral head in an ovariectomized rat model using microcomputed tomography. In vitro, tartrate-resistant acid phosphatase (TRAP) staining results showed the number of TRAP-positive cells, and TRAP activity significantly decreased following CPB treatment. CPB also significantly decreased pit formation. Furthermore, CPB inhibited osteoclast differentiation by suppressing NFATc1, and c-Fos expression. Moreover, CPB treatment inhibited osteoclast-related genes, such as Nfatc1, Ca2, Acp5, mmp9, CtsK, Oscar, and Atp6v0d2. In vivo, bone mineral density and structure model index were improved by administration of CPB. In conclusion, CPB prevented osteoclast differentiation in vitro and prevented bone loss in vivo. Therefore, CPB could be a potential alternative medicine for bone diseases, such as osteoporosis.

scholarly journals Curcumin has immunomodulatory effects on RANKL‐stimulated osteoclastogenesis in vitro and titanium nanoparticle‐induced bone loss in vivo

2019 ◽  
Vol 24 (2) ◽  
pp. 1553-1567 ◽  
Author(s):  
Chao Yang ◽  
Kechao Zhu ◽  
Xiangwei Yuan ◽  
Xianlong Zhang ◽  
Yebin Qian ◽  
...  
Keyword(s):  
Bone Loss ◽  
Immunomodulatory Effects

scholarly journals Pristimerin Inhibits Osteoclast Differentiation and Bone Resorption in vitro and Prevents Ovariectomy-Induced Bone Loss in vivo

2020 ◽  
Vol Volume 14 ◽  
pp. 4189-4203
Author(s):  
Peng Sun ◽  
Qichang Yang ◽  
Yanben Wang ◽  
Jiaxuan Peng ◽  
Kangxian Zhao ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Loss ◽  
Osteoclast Differentiation

scholarly journals 3579 The role of CypD/mPTP during osteogenic differentiation - a potential target to prevent bone loss

2019 ◽  
Vol 3 (s1) ◽  
pp. 24-24
Author(s):  
Rubens Sautchuk ◽  
Brianna H. Shares ◽  
Roman A. Eliseev
Keyword(s):  
Bone Loss ◽  
Bone Formation ◽  
Mitochondrial Function ◽  
Ectopic Bone Formation ◽  
Regulatory Mechanisms ◽  
Mrna Levels ◽  
Prevent Bone Loss ◽  
Ectopic Bone

OBJECTIVES/SPECIFIC AIMS: The study aims to further investigate how cyclophilin D (CypD), the key mPTP opening regulator, affects BMSCs fate and to determine potential regulatory mechanisms involved in CypD regulation during osteogenesis. METHODS/STUDY POPULATION: We evaluated CypD mRNA expression in mouse BMSCs and in osteogenic-like (OL) cells during the course of OB differentiation. CypD protein level was also probed. Moreover, BMSCs had their mPTP activity recorded during osteoinduction. We further analyzed the effect of CypD genetic deletion on osteogenesis in vitro and in vivo. For our in vivo model, we performed the ectopic bone formation assay to asses differences in ossicle formation when CypD KO BMSCs were transplanted compared to wild type littermate BMSCs. In our in vitro model, we transfected OL cells with either CypD gain of function or CypD loss of function vector and measured their osteogenic differentiation potential. Additionally, we treated BMSCs with CypD inhibitor and compare to non-treated BMSCs for mineralization level. To determine potential regulatory mechanisms involved in CypD regulation, we analyzed the CypD gene (Ppif) promoter for potential transcription factor (TF) binding sites and found multiple Smad-binding elements within this promoter. Smads (Smad1, 5, 8) are TFs downstream from Bone Morphogenic Protein (BMP) signaling pathway that transmit cell differentiation signaling, and exert either activating or inhibitory effects on a variety of genes. We also transfect OL cells with Smad1 vector and analyzed for CypD mRNA levels. RESULTS/ANTICIPATED RESULTS: - Our data showed that CypD mRNA levels decreased in both primary cells and OL cells at day 7 and day 14 in osteogenic media. - Osteogenic induction also decreased mPTP activity. - In vivo ectopic bone formation assay showed increased ossicle fo DISCUSSION/SIGNIFICANCE OF IMPACT: Our data suggest that downregulation of CypD increases OB differentiation due to improved OxPhos activity led by mPTP closure. Our results corroborate reports of CypD downregulation and mPTP closure during neuronal differentiation in developing rat brains as well as in cardiomyocyte differentiation in developing mouse hearts. Our studies also suggest a yet unknown mechanism linking differentiation signaling with mitochondrial function – BMP/Smad mediated downregulation of CypD transcription. As initially mentioned, in a previous study, our lab showed that CypD KO mice present higher mitochondrial function and osteogenicity in aged BMSCs and less osteoporosis burden. Taken together, these results suggest that CypD can be a potential target to prevent bone loss in aging.

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