Puerarin prevents bone loss in ovariectomized mice and inhibits osteoclast formation in vitro

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.

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

Journal of Cellular Physiology ◽

10.1002/jcp.27888 ◽

2018 ◽

Vol 234 (7) ◽

pp. 11951-11959 ◽

Cited By ~ 3

Author(s):

Fangsheng Fu ◽

Siyuan Shao ◽

Ziyi Wang ◽

Fangming Song ◽

Xixi Lin ◽

...

Keyword(s):

Bone Loss ◽

Osteoclast Formation

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Hedgehog Inhibitors Suppress Osteoclastogenesis in In Vitro Cultures, and Deletion of Smo in Macrophage/Osteoclast Lineage Prevents Age-Related Bone Loss

International Journal of Molecular Sciences ◽

10.3390/ijms21082745 ◽

2020 ◽

Vol 21 (8) ◽

pp. 2745

Author(s):

Yukihiro Kohara ◽

Ryuma Haraguchi ◽

Riko Kitazawa ◽

Yuuki Imai ◽

Sohei Kitazawa

Keyword(s):

Bone Resorption ◽

Bone Loss ◽

Signaling Pathway ◽

Early Stage ◽

Osteoclast Differentiation ◽

Osteoclast Formation ◽

Age Related ◽

Hh Signaling

The functional role of the Hedgehog (Hh)-signaling pathway has been widely investigated in bone physiology/development. Previous studies have, however, focused primarily on Hh functions in bone formation, while its roles in bone resorption have not been fully elucidated. Here, we found that cyclopamine (smoothened (Smo) inhibitor), GANT-58 (GLI1 inhibitor), or GANT-61 (GLI1/2 inhibitor) significantly inhibited RANKL-induced osteoclast differentiation of bone marrow-derived macrophages. Although the inhibitory effects were exerted by cyclopamine or GANT-61 treatment during 0–48 h (early stage of osteoclast differentiation) or 48–96 h (late stage of osteoclast differentiation) after RANKL stimulation, GANT-58 suppressed osteoclast formation only during the early stage. These results suggest that the Smo-GLI1/2 axis mediates the whole process of osteoclastogenesis and that GLI1 activation is requisite only during early cellular events of osteoclastogenesis. Additionally, macrophage/osteoclast-specific deletion of Smo in mice was found to attenuate the aging phenotype characterized by trabecular low bone mass, suggesting that blockage of the Hh-signaling pathway in the osteoclast lineage plays a protective role against age-related bone loss. Our findings reveal a specific role of the Hh-signaling pathway in bone resorption and highlight that its inhibitors show potential as therapeutic agents that block osteoclast formation in the treatment of senile osteoporosis.

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Suppression Effect of Astaxanthin on Osteoclast Formation In Vitro and Bone Loss In Vivo

International Journal of Molecular Sciences ◽

10.3390/ijms19030912 ◽

2018 ◽

Vol 19 (3) ◽

pp. 912 ◽

Cited By ~ 12

Author(s):

Yun-Ho Hwang ◽

Kwang-Jin Kim ◽

Su-Jin Kim ◽

Seul-Ki Mun ◽

Seong-Gyeol Hong ◽

...

Keyword(s):

Bone Loss ◽

Osteoclast Formation ◽

Suppression Effect

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A Bone-Targeting Enoxacin Delivery System to Eradicate Staphylococcus Aureus-Related Implantation Infections and Bone Loss

Frontiers in Bioengineering and Biotechnology ◽

10.3389/fbioe.2021.749910 ◽

2021 ◽

Vol 9 ◽

Author(s):

Cong Yao ◽

Meisong Zhu ◽

Xiuguo Han ◽

Qiang Xu ◽

Min Dai ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Bone Loss ◽

Bone Tissue ◽

Mesoporous Silica Nanoparticles ◽

Osteoclast Differentiation ◽

Osteoclast Formation ◽

Bacterial Biofilm ◽

Orthopaedic Implant

Post-operative infections in orthopaedic implants are severe complications that require urgent solutions. Although conventional antibiotics limit bacterial biofilm formation, they ignore the bone loss caused by osteoclast formation during post-operative orthopaedic implant-related infections. Fortunately, enoxacin exerts both antibacterial and osteoclast inhibitory effects, playing a role in limiting infection and preventing bone loss. However, enoxacin lacks specificity in bone tissue and low bioavailability-related adverse effects, which hinders translational practice. Here, we developed a nanosystem (Eno@MSN-D) based on enoxacin (Eno)-loaded mesoporous silica nanoparticles (MSN), decorated with the eight repeating sequences of aspartate (D-Asp8), and coated with polyethylene glycol The release results suggested that Eno@MSN-D exhibits a high sensitivity to acidic environment. Moreover, this Eno@MSN-D delivery nanosystem exhibited both antibacterial and anti-osteoclast properties in vitro. The cytotoxicity assay revealed no cytotoxicity at the low concentration (20 μg/ml) and Eno@MSN-D inhibited RANKL-induced osteoclast differentiation. Importantly, Eno@MSN-D allowed the targeted release of enoxacin in infected bone tissue. Bone morphometric analysis and histopathology assays demonstrated that Eno@MSN-D has antibacterial and antiosteoclastic effects in vivo, thereby preventing implant-related infections and bone loss. Overall, our study highlights the significance of novel biomaterials that offer new alternatives to treat and prevent orthopaedic Staphylococcus aureus-related implantation infections and bone loss.

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Identification and Functional Characterization of Metabolites for Bone Mass in Peri-/Post-menopausal Chinese Women

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgab146 ◽

2021 ◽

Author(s):

Rui Gong ◽

Hong-Mei Xiao ◽

Yin-Hua Zhang ◽

Qi Zhao ◽

Kuan-Jui Su ◽

...

Keyword(s):

Fatty Acids ◽

Bone Loss ◽

Osteoclast Differentiation ◽

Dodecanoic Acid ◽

Mineral Density ◽

Ovariectomized Mice ◽

Post Menopausal ◽

Functional Mechanisms

Abstract Context Although metabolic profiles appear to play an important role in menopausal bone loss, the functional mechanisms by which metabolites influence bone mineral density (BMD) during menopause are largely unknown. Objective We aimed to systematically identify metabolites associated with BMD variation and their potential functional mechanisms in peri-/post-menopausal women. Design and Methods We performed serum metabolomic profiling and whole-genome sequencing for 517 perimenopausal (16%) and early postmenopausal (84%) women aged 41 to 64 years in this cross-sectional study. Partial least squares (PLS) regression and general linear regression analysis were applied to identify BMD-associated metabolites, and weighted gene co-expression network analysis was performed to construct co-functional metabolite modules. Furthermore, we performed Mendelian randomization analysis to identify causal relationships between BMD-associated metabolites and BMD variation. Finally, we explored the effects of a novel prominent BMD-associated metabolite on bone metabolism through both in vivo/in vitro experiments. Results Twenty metabolites and a co-functional metabolite module (consisting of fatty acids) were significantly associated with BMD variation. We found dodecanoic acid (DA), within the identified module, causally decreased total hip BMD. Subsequently, the in vivo experiments might support that dietary supplementation with DA could promote bone loss, as well as increase the osteoblast and osteoclast numbers in normal/ovariectomized mice. DA treatment differentially promoted osteoblast and osteoclast differentiation, especially for osteoclast differentiation at higher concentrations in vitro (e.g.,10, 100μM). Conclusions This study sheds light on metabolomic profiles associated with postmenopausal osteoporosis risk, highlighting the potential importance of fatty acids, as exemplified by DA, in regulating BMD.

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GSH attenuates RANKL-induced osteoclast formation in vitro and LPS-induced bone loss in vivo

Biomedicine & Pharmacotherapy ◽

10.1016/j.biopha.2020.110305 ◽

2020 ◽

Vol 128 ◽

pp. 110305 ◽

Cited By ~ 2

Author(s):

Bing Han ◽

Huan Geng ◽

Liang Liu ◽

Zhixin Wu ◽

Yizhong Wang

Keyword(s):

Bone Loss ◽

Osteoclast Formation

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IκB kinase (IKK)β, but not IKKα, is a critical mediator of osteoclast survival and is required for inflammation-induced bone loss

Journal of Experimental Medicine ◽

10.1084/jem.20042081 ◽

2005 ◽

Vol 201 (10) ◽

pp. 1677-1687 ◽

Cited By ~ 193

Author(s):

Maria Grazia Ruocco ◽

Shin Maeda ◽

Jin Mo Park ◽

Toby Lawrence ◽

Li-Chung Hsu ◽

...

Keyword(s):

Bone Loss ◽

Nuclear Factor Κb ◽

Osteoclast Formation ◽

Catalytic Subunits ◽

Iκb Kinase ◽

Induced Apoptosis ◽

Factor Α ◽

Osteoclast Survival

Transcription factor, nuclear factor κB (NF-κB), is required for osteoclast formation in vivo and mice lacking both of the NF-κB p50 and p52 proteins are osteopetrotic. Here we address the relative roles of the two catalytic subunits of the IκB kinase (IKK) complex that mediate NF-κB activation, IKKα and IKKβ, in osteoclast formation and inflammation-induced bone loss. Our findings point out the importance of the IKKβ subunit as a transducer of signals from receptor activator of NF-κB (RANK) to NF-κB. Although IKKα is required for RANK ligand-induced osteoclast formation in vitro, it is not needed in vivo. However, IKKβ is required for osteoclastogenesis in vitro and in vivo. IKKβ also protects osteoclasts and their progenitors from tumor necrosis factor α–induced apoptosis, and its loss in hematopoietic cells prevents inflammation-induced bone loss.

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A Bone-Targeting Enoxacin Delivery System to Eradicate Staphylococcus Aureus-Related Implantation Infections and Bone Loss

10.21203/rs.3.rs-645601/v1 ◽

2021 ◽

Author(s):

Cong Yao ◽

Qiang Xu ◽

Xiuguo Han ◽

Qianyuan Tao ◽

Xuwen Luo ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Bone Loss ◽

Mesoporous Silica Nanoparticles ◽

Osteoclast Formation ◽

Orthopaedic Implant ◽

Inhibitory Effects ◽

Conventional Antibiotics ◽

Targeted Release

Abstract Post-operative infections in orthopaedic implants are severe complications that require urgent solutions. Although conventional antibiotics limit bacterial biofilms formation, they ignore the bone loss caused by osteoclast formation during post-operative orthopaedic implant-related infections. Fortunately, enoxacin exerts dual antibacterial and osteoclast inhibitory effects, playing a pivot in limiting infection and preventing bone loss. However, enoxacin lacks specificity in bone tissue and low bioavailability-relate side effects, which hinders translational practice. Herein, we developed a nanosystem (Eno@MSN-D) based on enoxacin (Eno)-loaded mesoporous silica nanoparticles (MSN), decorated with the eight repeating sequences of aspartate (D-Asp8), and coated with polyethylene glycol (PEG). This Eno@MSN-D delivery nanosystem exhibited both antibacterial and anti-osteoclast properties in vitro. More importantly, Eno@MSN-D allowed the targeted release of enoxacin in infected bone tissues and prevented implant-related infection and bone loss in vivo. Therefore, our work highlights the significance of novel biomaterials that offer new alternatives to treat and prevent orthopaedic staphylococcus aureus-related implantation infections and bone loss.

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Anti-Osteoporotic Activity of Pueraria lobata Fermented with Lactobacillus paracasei JS1 by Regulation of Osteoblast Differentiation and Protection against Bone Loss in Ovariectomized Mice

Fermentation ◽

10.3390/fermentation7030186 ◽

2021 ◽

Vol 7 (3) ◽

pp. 186

Author(s):

Seon Yu Kim ◽

Hee-Ju Lee ◽

Taehyun Kim ◽

Yeong-Geun Lee ◽

Jeong Eun Kwon ◽

...

Keyword(s):

Bone Loss ◽

Bone Mineral ◽

Lactobacillus Paracasei ◽

Calcium Deposition ◽

Pueraria Lobata ◽

Mineral Density ◽

Vitro Assay ◽

Ovariectomized Mice ◽

Mg63 Cells

Osteoporosis is the most common bone disease associated with low bone mineral density. It is the process of bone loss and is most commonly caused by decreased estrogen production in women, particularly after menopause. Pueraria lobata, which contains various metabolites, especially isoflavone, is widely known as regulator for bone mineral contents. In this study, the effects of the P. lobata extract (PE) with or without fermentation with Lactobacillus paracasei JS1 (FPE) on osteoporosis were investigated in vitro and in vivo. The effects of PE and FPE on human osteoblastic MG63 cells, RAW 264.7 cells, and ovariectomized (OVX)-induced model mice were analyzed at various ratios. We found that FPE increased calcium deposition and inhibited bone resorption by in vitro assay. Furthermore, treatment with PE and FPE has significantly restored destroyed trabecular bone in the OVX-induced bone loss mouse model. Overall, FPE demonstrated bioactivity to prevent bone loss by decreasing bone turnover.

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