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Osteoporosis, characterized by low bone mass and bone microarchitecture breakdown, has become a growing public health problem. The increase in oxidative stress could lead to an imbalance between osteoblasts-mediated osteogenesis and osteoclast-mediated bone resorption, which gives rise to osteoporosis. Nrf2 is a master transcription factor that regulates oxidative stress and has recently been reported to take part in the development of osteoporosis. Icariin, a leading active flavonoid in herbal Epimedium pubescens, has significant antioxidant activity in and is widely applied for treating bone diseases. In this study, we aimed to explore the effect of icariin on osteoclastogenesis and its potential mechanism from the perspective of oxidative stress inhibition, using ovariectomized (OVX) rats and RANKL-induced RAW264.7 cells. Our results demonstrated that icariin-treated OVX rats exhibited higher bone density, fewer tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts, and lower ROS levels in bone tissues than vehicle-treated OVX rats. Also, icariin suppressed osteoclast differentiation and inhibited the expression of osteoclastogenesis-related genes, such as NFATc1, Ctsk, Trap, and c-Fos, in RANKL-induced RAW264.7 cells. Icariin also reduced intracellular ROS levels by increasing the expression of nuclear Nrf2 and HO-1. Further mechanistic studies showed icariin inhibited Cullin 3 expression and could delay Nrf2 degradation by reducing the ubiquitination of endogenous Nrf2 in RANKL-stimulated RAW264.7 cells, and these effects were markedly reversed by cullin three overexpression. These findings suggest icariin alleviated osteoporosis by suppressing osteoclastogenesis via targeting the Cullin 3/Nrf2/OH signaling pathway. Our study implied that icariin may be a potential candidate to treat osteoporosis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Osteoporosis is a common chronic bone disorder in postmenopausal women. Ginsenosides are primary active components in ginseng and the effects of various ginsenoside variants in osteoporosis treatment have been widely revealed. We planned to explore the impact of ginsenoside Rc on bone resorption in an osteoporosis rat model. We used ovariectomized rats to assess the potential impact of ginsenoside Rc on osteoporosis. μ-CT was implemented for analyzing the microstructure of the distal left femur in rats. H&E staining together with Masson staining were applied for bone histomorphometry evaluation. ELISA kits were implemented to detect serum concentrations of TRACP-5b, OCN, CTX, as well as PINP. Ginsenoside Rc treatment lessened the serum levels of TRACP-5b as well as CTX, while increasing serum levels of OCN, and PINP of OVX rats. Moreover, we found that ginsenoside Rc contributed to the synthesis of type I collagen via increasing Col1a1 and Col1a2 levels in femur tissues of ovariectomized rats. Our findings also revealed that ginsenoside Rc activated the TGF-β/Smad pathway by increasing TGF-β as well as phosphorylated Smad2/3 protein levels. Ginsenoside Rc alleviates osteoporosis in rats through promoting the TGF-β/Smad pathway.

Osteoporosis (OP) is a bone remodeling disease characterized by an imbalance between bone resorption and formation. Osteoclasts are the primary therapeutic targets for treating bone destruction. Koumine (KM), the most bioactive component in Gelsemium alkaloids, exhibits antitumor, immunosuppressive, anti-inflammatory, and analgesic properties. However, the effects of bone loss have not been well studied. This study conducted in vitro and in vivo verification experiments on KM. The results showed that KM inhibited bone resorption and tartrate-resistant acid phosphatase positive (TRAP+) osteoclasts development by mature osteoclasts in a dose-dependent manner. Moreover, KM prevented OVX-induced OP in vivo and potentially inhibited ubiquitination, a process closely related to various biological activities, including protein interaction, transcription, and transmembrane signal transduction regulation, especially within the nuclear factor-κB (NF-κB) pathway. Previous studies have demonstrated that several proteins ubiquitination promotes osteoclastogenesis, our study indicated that KM inhibits early NF-κB activation and receptor activator of NF-κB ligand induced ubiquitination, a critical factor in osteoclast differentiation. In conclusion, our research suggests that KM holds potential as an effective therapeutic agent for OP., (© 2023 Wiley Periodicals LLC.)

This paper reviews the application of metabolomics in the early diagnosis of osteoporosis in recent years. The authors searched electronic databases for the keywords "metabolomics", "osteoporosis" and "biomarkers", then analyzed the relationship between functional markers and osteoporosis using categorical summarization. Lipid metabolism, amino acid metabolism and energy metabolism are closely related to osteoporosis development and can become early diagnostic markers of the condition. However, the existing studies in metabolomics suffer from varying application methods, difficulty in identifying isomers, small study cohorts and insufficient research on metabolic mechanisms. Consequently, it is important for future research to focus on broadening and standardizing the scope of the application of metabolomics. High-quality studies on a large scale should also be conducted while promoting the early diagnosis of osteoporosis in a more precise, comprehensive and sensitive manner.

Background: Osteoporosis is a systemic bone disease characterized by decreased bone density and quality, destruction of bone microstructure, and increased bone fragility. Extracellular vesicles are lipid bilayer nanoparticles that participate in intercellular communication. Extracellular vesicles are becoming popular in the study of osteoporosis and the bone cell microenvironment. Extracellular vesicles can transmit cell signals and regulate bone homeostasis. Our previous studies revealed that the Chinese herbal medicine Guilu Erxian Glue promotes type I collagen synthesis and osteoprotegerin secretion by osteoblasts in rats, reverses the imbalance of bone homeostasis, and alleviates osteoporosis., Objective: We investigated how osteoblast-derived extracellular vesicles treated with Guilu Erxian Glue affected osteoclasts in vitro., Methods: We quantified osteoclast differentiation of RAW 264.7 using TRAP staining, cell apoptosis using flow cytometry, extracellular vesicle uptake by fluorescence tracing, bone absorption functions by bone resorption lacuna , and transcription of key genes by quantitative real-time PCR., Results: Fluorescently labeled mouse preosteoblastic MC3T3-E1 cells secreted nanoscale substances less than 1 μm in diameter. Mouse macrophage RAW 264.7 cells adsorbed these nanoparticles and PKH26-labeled extracellular vesicles derived from MC3T3-E1 cells on the cell membrane surface. Extracellular vesicles from MC3T3-E1 cells treated with Guilu Erxian Glue inhibited the differentiation of osteoclasts induced by receptor activator of nuclear factor-κB ligand and macrophage colony-stimulating factor and reduced the number of lacunae formed by osteoclasts in vitro compared with controls. Extracellular vesicles from MC3T3-E1 cells treated with Guilu Erxian Glue downregulated the relative messenger RNA expression of c-Fos, cathepsin K, nuclear factor of activated T cells 1, and tartrate-resistant acid phosphatase in osteoclasts, which may be part of the mechanism by which they regulate osteoclasts., Conclusions: Our results demonstrate that extracellular vesicles are essential for signal exchange between osteoblasts and osteoclasts. Although we do not know how Guilu Erxian Glue affects the signaling molecules carried by extracellular vesicles, we have shown for the first time, to our knowledge, that Guilu Erxian Glue can inhibit osteoclast differentiation and function via osteoblast-derived extracellular vesicles. Our findings are conducive to providing a new target for the development of osteoporosis drugs.

Objective: To analyze the expression characteristics of osteoporosis-related genes by bioinformatics and elucidate the pathogenesis of osteoporosis., Methods: The differentially expressed genes (DEGs), microRNA (miRNA), and genes with differentially methylated regions (DMRS) in promoters were identified. The protein-protein interaction (PPI) network was constructed and performed. The Clue Gene Ontology analysis and miRNA-mRNA (messenger RNA) regulatory network were constructed using Cytoscape., Results: Fifty-nine DEGs, 10 differential miRNAs, and 2083 genes with DMRs were screened out. The Proteasome-Modulator (PSMD) family proteins and estrogen receptor 1 (ESR1) are vital for the PPI analysis of DEGs. The interaction network of the Smad3 protein showed that the degree of connection to ESR1, PSMD11, and transcription factor 4 (TCF4) is very high. Homo sapiens (hsa)-miR-106b-5p was differential and regulated TCF4 through building the miRNA-mRNA regulatory network. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment of DEGs focused on vascular smooth muscle contraction, thyroid hormone signaling pathway, and estrogen signaling pathway. The Gene Ontology (GO) function analysis of genes with DMRs in promoters was primarily concentrated in the cell differentiation, positive regulation of CDP-diacylglycerol-serine O-phosphatidyltransferase activity, and positive regulation of C-palmitoyltransferase activity. The KEGG enrichment of genes with DMRs in promoters largely focused on glycerol phospholipid metabolism, histidine metabolism, Adenosine 5'-monophosphate-activated protein kinase signaling pathway, Hedgehog signaling pathway, and mRNA surveillance pathway., Conclusion: Hsa-miRNA-106b-5p regulates bone formation and the pathogenesis of osteoporosis by controlling TCF4, and methylation modification of TCF4 can also affect the pathogenesis of osteoporosis., (© 2022 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Background: Osteoporosis, as a metabolic disease, has become one of the most rapidly growing complications of diabetes mellitus. Previously, we conducted a systematic review to report the estimated prevalence of osteoporosis among patients with type 2 diabetes mellitus (T2DM) from 2001 to 2016. However, some newer studies have been reported, and more potential risk factors for osteoporosis remain controversial and vague. Therefore, the presented review is tailored to synthesize available evidence regarding the pooled prevalence and related risk factors of osteoporosis among T2DM patients in mainland China., Methods: Both cross-sectional study and cohort study reporting on the prevalence of osteoporosis among patients with T2DM in mainland China, published in Chinese or English, will be considered for inclusion. Records from 4 English databases and 2 Chinese databases will be retrieved from their inceptions to March 2020. The process of study selection, data extraction, and methodologic quality assessment will be independently executed by 2 reviewers. The pooled prevalence of osteoporosis and the prevalence in the exposed and unexposed groups for each potential risk factor will be calculated by the software Stata version 12.0., Results: The current systematic review and meta-analysis will provide more precise prevalence rates and associated risk factors of osteoporosis among people with T2DM in mainland China., Conclusion: The study will offer high-quality and explicit evidence for assisting diabetic patients to prevent osteoporosis in mainland China., Osf Registration: DOI 10.17605/OSF.IO/5ZKJ6.

The aim of this study was to investigate the effect of evodiamine (EV) on dexamethasone-induced osteoporosis in zebrafish. Zebrafish larvae were exposed to different concentrations of dexamethasone to obtain the osteoporosis in zebrafish. Calcium, phosphorus, and alizarin red staining determination were performed to evaluate the effects of EV on bone mineralization. Alkaline phosphatase (ALP), hydroxyproline (HP), and tartrate resistant acid phosphatase (TRAP) were also measured by commercial kits. The expression of MMP3-OPN-MAPK pathway in zebrafish was measured by Western blot. RT-PCR was used to determine mRNA levels of MMP3, OPN, and MAPK. EV could significantly increase the content of calcium and phosphorus. The results of alizarin red staining showed that EV could significantly increase the calcium sink of horse fish, increasing the area of bone formation. EV could increase the content of hydroxyproline in zebrafish. EV also increased ALP and TRAP in zebrafish. Western blot and RT-PCR results showed that EV restored the MMP3-OPN-MAPK pathway in zebrafish. In conclusion, we found that EV can alleviate dexamethasone-induced osteoporosis in zebrafish. The mechanism is related to activating MMP3-OPN-MAPK pathway and then activating bone remodeling.

The current study was to evaluate the protective effects of Chinese medicine prescription Zuogui Pill (ZGP) on osteoporosis (OP) in zebrafish larvae induced by dexamethasone. Alizarin Red staining, calcium and phosphorus determination were performed to evaluate the effect of ZGP on bone mineralization. Hydroxyproline (HP), Alkaline phosphatase (ALP), and tartrate resistant acid phosphatase (TRAP) were also measured by commercial kits. We found that ZGP had positive effects in increasing bone mineral content (BMC), strengthening bone biomechanical, promoting bone formation, inhibiting bone resorption, and mediating protein levels of TGF-β1/Smads signaling pathway. The findings demonstrated that ZGP treatments inhibited the phosphorylation of TGF-β and p-Smad 3 as well as the expressions of collagen I and collagen II by western blot. Taken together, we demonstrated that ZGP may prevent osteoporosis via reversing the imbalance of bone fomation/bone resorption and activating the TGF-β-Smad signal., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Osteoporosis is a chronic inflammatory disease that severely affects quality of life. Cornus officinalis is a Chinese herbal medicine with various bioactive ingredients, among which morroniside is its signature ingredient. Although anti-bone resorption drugs are the main treatment for bone loss, promoting bone anabolism is more suitable for increasing bone mass. Therefore, identifying changes in bone formation induced by morroniside may be conducive to developing effective intervention methods. In this study, morroniside was found to promote the osteogenic differentiation of bone marrow stem cells (BMSCs) and inhibit inflammation-induced bone loss in an in vivo mouse model of inflammatory bone loss. Morroniside enhanced bone density and bone microstructure, and inhibited the expression of IL6, IL1β, and ALP in serum (p < 0.05). Furthermore, in in vitro experiments, BMSCs exposed to 0–256 μM morroniside did not show cytotoxicity. Morroniside inhibited the expression of IL6 and IL1β and promoted the expression of the osteogenic transcription factors Runx2 and OCN. Furthermore, morroniside promoted osteocalcin and Runx2 expression and inhibited TRAF6-mediated NF-κB and MAPK signaling, as well as osteoblast growth and NF-κB nuclear transposition. Thus, morroniside promoted osteogenic differentiation of BMSCs, slowed the occurrence of the inflammatory response, and inhibited bone loss in mice with inflammatory bone loss. [ABSTRACT FROM AUTHOR]