Search Results (1,624)

The global prevalence of osteoporosis is rising, particularly among the elderly and post-menopausal population. Although natural flavonoids can inhibit osteoclast overactivation, their low abundance and extraction challenges limit clinical translation. In this study, we synthesized a flavonoid derivative, SZQ-4, and evaluated its therapeutic potential for post-menopausal osteoporosis (PMO). Using an RANKL-induced osteoclastogenesis model in vitro, we demonstrated through TRAP staining, RT-qPCR, and bone resorption assays that SZQ-4 significantly suppresses osteoclast formation and activity. Mechanistically, RNA-seq, Western blot, siRNA knockdown, and plasmid-based overexpression experiments revealed that SZQ-4 reduces RANKL-induced reactive oxygen species (ROS) production, regulates SIRT3 expression, and improves mitochondrial function, thereby attenuating osteoclast differentiation. In an ovariectomy-induced bone loss mouse model, SZQ-4 treatment markedly alleviated femoral bone loss, decreased osteoclast numbers, and lowered ROS levels in the bone marrow microenvironment. Collectively, our findings indicate that SZQ-4 inhibits osteoclast-driven bone resorption by modulating the ROS-SIRT3–mitochondrial function axis, highlighting its potential as a candidate for preventing pathological bone loss. Full article

Chronic alcohol consumption increases the risk of osteoporosis and fracture by disrupting bone remodeling, in part by enhancing osteoclastogenesis. However, the cellular mechanisms underlying this process remain incompletely defined. We analyzed scRNA-seq data from osteoclasts differentiated in vitro from bone marrow mononuclear cells obtained from macaques following 12 months of chronic ethanol or isocaloric control solution consumption. Module scoring, trajectory inference with generalized additive modeling (tradeSeq), and CellChat-based analyses of intercellular communication were applied to uncover ethanol-induced changes in metabolic reprogramming, lineage progression, and signaling network dynamics. Module scoring indicated metabolic reprogramming toward oxidative phosphorylation, with reduced glycolytic, migratory, and phagocytic activities. Pseudotime analysis revealed accelerated osteoclast lineage commitment, broader intermediate differentiation states, and stabilization of mature osteoclasts. CellChat analysis showed globally amplified intercellular signaling, with mature osteoclasts functioning as dominant communication hubs sustained by autocrine feedback. Together, chronic alcohol consumption rewired osteoclastogenesis through early fate priming, metabolic adaptation, and hierarchical remodeling of intercellular communication, promoting enhanced osteoclastogenesis. These findings provide mechanistic insight into alcohol-induced bone pathology and highlight potential targets for therapeutic intervention. Full article

Quercetin (QE) is a widely distributed dietary flavonol with antioxidant and anti-inflammatory properties that has attracted interest as a modulator of bone remodeling and osteoporosis-related bone loss. In vitro data on osteoblasts, osteoclasts, and mesenchymal stem cells indicate that QE attenuates oxidative stress, suppresses pro-inflammatory signaling, and promotes osteogenic differentiation through modulation of pathways such as Nrf2/ARE, NF-κB, Wnt/β-catenin, and ER stress-related cascades. In vivo findings from animal models of estrogen deficiency, diabetes, and glucocorticoid-induced osteoporosis demonstrate that QE improves bone mineral density, trabecular microarchitecture, and biomechanical strength while reducing osteoclast number and activity, thereby attenuating osteoporotic bone deterioration. Collectively, preclinical evidence positions QE as a pleiotropic agent promoting osteoblastogenesis, inhibiting osteoclastogenesis, and balancing redox/inflammatory homeostasis in bone, despite bioavailability challenges. Future research should prioritize clinical trials with optimized formulations (e.g., nanoparticles) to validate efficacy, safety, and fracture outcomes in humans. The present review critically evaluates the chemical characteristics, pharmacokinetics, safety profile, and bone-targeted biological activity of QE, emphasizing effects on bone cells and skeletal metabolism. Full article

Background: Orthodontic tooth movement is traditionally explained through mechanical deformation of the periodontal ligament (PDL); however, increasing evidence indicates that immune mechanisms critically shape bone remodeling outcomes. Mechanical stimuli influence immune cell recruitment, cytokine release, and phenotypic polarization, but these components are rarely integrated into a unified framework. Conceptual framework: We propose the Osteoimmune Axis Model, a conceptual framework describing how mechanical loading may bias immune polarity and thereby gate periodontal remodeling. Compressive loading appears to favor an M1 macrophage/Th17-dominant program associated with pro-inflammatory cytokines and enhanced RANKL-mediated osteoclastogenesis. In contrast, tensile or physiological strains may favor M2 macrophages and regulatory T cells (Treg), supporting IL-10, TGF-β, angiogenesis, extracellular-matrix repair, and osteoblastic activity. Stromal cells are proposed to act as mechanosensors and immune amplifiers that shape cytokine gradients and feedback loops. Predictions: The model predicts that identical forces may produce divergent outcomes depending on immune baseline; load duration may be more destructive than peak magnitude; tensile strain may stabilize M2/Treg pathways; thin periodontal phenotypes may shift toward the catabolic pole at lower mechanical loads; ROS may amplify immune-mediated bone loss; and immunomodulation may raise the threshold for pathological remodeling. Conclusion: The Osteoimmune Axis integrates mechanobiology and immunology into a testable framework for explaining variability in orthodontic periodontal remodeling and for generating hypothesis-driven, immune-aware risk assessment. Full article

Osteosarcoma (OS), the most common primary malignant bone tumor in children and young adults, is characterized by aggressive behavior, frequent metastasis, and resistance to chemotherapy, resulting in poor clinical outcomes. Increasing evidence indicates that OS progression is not solely driven by tumor-intrinsic factors but is strongly influenced by dynamic interactions within the tumor microenvironment (TME). This literature review synthesizes current research on the roles of endothelial cells, fibroblasts, mesenchymal stromal cells, immune populations, and osteoclasts in OS pathogenesis, with emphasis on cell–cell interactions mediated by direct contact, soluble factors, and extracellular vesicles. The studies demonstrate that these interactions promote tumor proliferation, immune evasion, extracellular matrix remodeling, metastatic dissemination, and therapeutic resistance. Adaptive responses of both tumor and stromal cells to environmental stressors contribute to chemoresistance and disease progression. Collectively, our findings highlight the multifactorial nature of OS driven by complex cellular crosstalk within the TME. Understanding these mechanisms highlights the limitations of conventional chemotherapy and encourages the development of combined therapeutic approaches, including targeted therapies, immunomodulation, and microenvironmental interventions. Continued investigation into tumor–microenvironment interactions may facilitate the identification of actionable targets and improve personalized treatment approaches for OS. Full article

Temporomandibular joint osteoarthritis (TMJOA) is a degenerative disease characterized by progressive cartilage degeneration and subchondral bone remodeling, resulting in chronic pain and functional impairment. Although conservative treatments such as physical therapy and non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used, their effectiveness is limited due to the poorly understood pathophysiology of TMJOA. Identifying reliable molecular biomarkers is essential to improving early diagnosis and guiding therapeutic development. This proof-of-concept study aims to identify candidate salivary biomarkers for TMJOA using an integrative approach combining clinical validation with in silico analysis. RNA sequencing was performed on saliva samples from TMJOA patients and healthy controls. In parallel, publicly available transcriptomic dataset GSE205389 was analyzed to identify differentially expressed genes (DEGs). DEGs were validated using qRT-PCR. Gene set enrichment analysis (GSEA) and Metascape were used to explore biological pathways associated with TMJOA. Integration of clinical and in silico RNA sequencing datasets identified 2758 and 3548 DEGs, respectively, with 743 overlapping genes. Pathway enrichment analyses highlighted immune-related, metabolic and osteoclast-related pathways. Four genes, CRIP1, PPA1 and TARS1 (statistically significant) and GCLC (non-significant trend), were validated by qRT-PCR in the clinical saliva samples, confirming elevated expression in TMJOA patients. Validation of the in silico dataset showed an upregulation of PTK2B, ABL1, TNF and IL-1B, supporting their relevance as salivary biomarkers in TMJOA. This exploratory study identifies four candidate salivary genes, CRIP1, PPA1, TARS1 and GCLC, as candidate salivary biomarkers for TMJOA, offering insights into disease mechanisms. Larger studies are needed to validate these findings and assess their clinical utility. Full article

Prostate cancer (PCa) is a prevalent malignancy in men worldwide, and both androgen deprivation therapy (ADT) and radiotherapy (RT) are key components of its management. However, these treatments significantly affect bone health by inducing bone mineral density (BMD) loss, osteopenia, osteoporosis and increased fracture risk. ADT promotes a high bone turnover state through hormonal suppression and molecular mechanisms involving increased RANKL expression and osteoclast activation. RT generates direct cytotoxic damage and inflammatory changes that compromise bone microarchitecture. Combined ADT + RT exerts synergistic detrimental effects. This narrative review synthesizes the molecular basis, clinical evidence, preventive strategies and emerging technologies related to bone health in men with PCa undergoing ADT and/or RT. Full article

Background/Objectives: Tenosynovial giant cell tumours (TGCT) are a group of mesenchymal tumours involving the synovium, bursae, and tendon sheaths, comprising two subtypes: nodular and diffuse. Although predominantly benign, diffuse forms can be locally aggressive, resulting in bone destruction. The pathogenesis of TGCTs is still poorly understood. The aim of this study was to systematically review the current literature on the factors, mechanisms, and markers involved in TGCT disease, focussing on their potential role in bone destruction. Methods: This systematic review was conducted using the PRISMA guidelines. A search was performed using PubMed, Scopus, and Cochrane Library, and all original scientific research into mechanisms/pathways/signalling involving TGCTs was included. Results: After the review process, 51 studies were included for data extraction. Extracted data included authorship, publication year, patient numbers and aetiology (nTGCT/dTGCT), demographics, investigative methods, and studied biological factors, mechanisms, and markers. Cross-tabulation of reported elements revealed 159 unique factors, with most appearing only once. Eight elements were reported five or more times: CSF1, CD68, Ki-67, MMP9, CD163, TRAP, TNF-α, and IL-1β. Although representing just 5% of all identified factors, these appeared in 69% of the included studies, highlighting their prominence in the literature. Conclusions: Apart from the well-known osteoclastogenesis factor CSF1, inflammatory cytokines (TNF-α and IL-1β) and monocyte–macrophage lineage makers (CD68, CD163) are signalling pathways key to TGCT disease progression and associated bone destruction. Full article

Osteoimmunology examines the bidirectional interactions between the skeletal and immune systems, focusing on the mechanisms by which immune cells regulate bone homeostasis and how the bone microenvironment modulates immune responses. Chronic inflammation is a major driver of bone loss, and infections of bacterial or viral origin perturb bone remodeling with consequences for host defense. In infected bone tissue, immune cell infiltration and the release of cytokines and soluble mediators alter the activity of osteoclasts and osteoblasts, thereby promoting bone erosion and structural remodeling. Recent studies highlight how immune dysregulation contributes to the pathogenesis of osteomyelitis and other infection-associated bone disorders, implicating specific inflammatory pathways and cellular interactions as potential therapeutic targets. This review synthesizes current evidence on direct and indirect mechanisms by which infection affects bone, identifies gaps in mechanistic understanding, and discusses implications for diagnosis and intervention. Full article

Introduction: Chronic inflammation in axial spondyloarthritis (axSpA) promotes osteoclast formation and bone resorption, leading to osteoporosis and an increased risk of fragility fractures. Osteoporotic fractures significantly impact the quality of life in patients with axSpA. While the Fracture Risk Assessment Tool (FRAX) is widely used to evaluate fracture risk, data on FRAX-based fracture risk assessment in axSpA, particularly in German patients, are limited. Objective: The primary objective of this study was to assess the prevalence of low bone mineral density (BMD) and fracture risk using FRAX for major osteoporotic fractures (MOF) and hip fractures (HF) in German patients with axSpA. Secondary objectives were to compare FRAX scores and BMD between genders and between patients with and without previous fractures, and to identify which FRAX parameters were most frequently abnormal. Materials and Methods: This retrospective study analyzed demographic and clinical data, along with DXA-measured BMD, T-scores and Z-scores of the lumbar spine and femoral neck in 58 axSpA patients aged 43–81 years from routine clinical practice. Calculations for MOF and HF were performed using the FRAX model for Germany. Low BMD was defined as a T-score < −1 SD or a Z-score < −2 SD. Statistical analyses included independent t-tests and chi-square tests. Results: The mean age of patients was 65 years with a mean BMI of 29.5 kg/m². The prevalence of low BMD was 44.8% at the lumbar spine and 60.4% at the femoral neck. Overall, 10 (17.2%) patients reported previous fractures of the spine, forearm, hip, or shoulder. Female patients had higher FRAX scores for MOF (8.2%) than males (6.8%, p = 0.02), while male patients had higher FRAX scores for HF (2.8% vs. 2%, p = 0.04). There was no significant difference in BMD between patients with or without a history of fracture. However, patients with previous fractures had significantly higher FRAX scores for MOF (10.2%) compared to those without fractures (7.3%, p = 0.030); the difference in HF scores was not statistically significant (3.5% vs. 2%, p = 0.056). Conclusions: This study highlights the elevated fracture risk in axSpA patients assessed with FRAX. In this cohort, BMD alone was not associated with fracture history, suggesting that other factors—such as age, sex, glucocorticoid exposure, and prior fractures—may play a more prominent role. FRAX provides a valuable tool for evaluating fracture risk in axSpA, emphasizing the importance of a comprehensive assessment that incorporates both clinical risk factors and BMD. Full article

Magnolia kobus (M. kobus) has long been used to treat nasal congestion, allergic rhinitis, and sinusitis. In the current study, we demonstrate the effects and underlying mechanisms of M. kobus flower water extract (ME) and ME-derived constituent magnolin on in vitro osteoblastogenic and anti-osteoclastogenic responses. Treatment with ME or magnolin markedly enhanced the osteoblast differentiation and mineralization in MC3T3-E1 pre-osteoblasts. This osteoblastogenic activity of ME or magnolin was closely associated with upregulation of osteoblast-specific molecules, including RUNX2, DLX5, OSX, alkaline phosphatase, collagen type I, and osteopontin, as well as the activation of mitogen-activated protein kinase (MAPK) signaling pathways. Concurrently, magnolin inhibited osteoclast differentiation through inactivating MAPK pathways and downregulating NFATc1, c-Fos, tartrate-resistant acid phosphatase, and cathepsin K in RANKL-treated RAW264.7 cells. These observations suggest that ME and magnolin have pharmacological potential for the treatment and prevention of metabolic bone disorders, including osteoporosis. Full article

This narrative review summarizes current evidence on the molecular and cellular effects of low-dose methotrexate (LD-MTX) on bone tissue. In addition, it critically examines the limited and heterogeneous data on LD-MTX-associated osteopathy, a rare and incompletely understood condition that may be underrecognized in clinical practice. Finally, the review highlights key knowledge gaps and outlines future research directions aimed at improving diagnosis, management, and prevention. In total, 451 relevant articles were retrieved, and 71 studies were included in our review. Methotrexate (MTX) has been shown to prevent bone loss associated with inflammatory rheumatic diseases, primarily through its anti-inflammatory properties. However, current evidence highlights a variety of negative effects on bone associated with LD-MTX therapy, including osteoblast dysfunction, increased osteoclastogenesis, and endothelial damage. Collectively, these effects may result in deterioration of microarchitecture, impaired bone healing and insufficiency fractures. Despite the long and successful use of MTX in rheumatology, our knowledge of its effects on bone and awareness of LD-MTX osteopathy remain limited, potentially leading to delayed or missed diagnoses. Recent clinical studies highlight the potential underestimation of this condition and emphasize the need for further research to establish clear diagnostic criteria and treatment guidelines, as well as to achieve a more comprehensive understanding of the complex pathophysiology underlying LD-MTX osteopathy. Full article

Fracture healing is a multistage regenerative process requiring the coordinated regulation of inflammation, osteogenesis, and bone remodeling, yet pharmacological agents that effectively modulate these processes remain limited. Adenophorae Radix (AR), a traditional medicinal herb used for tissue repair, has not been mechanistically investigated in skeletal regeneration. In this study, a mouse femoral fracture model was employed to evaluate the effects of short-term (7 days) and long-term (5 weeks) oral administration of AR. Bone regeneration was assessed using micro-computed tomography, histological staining, and quantitative real-time polymerase chain reaction. Network pharmacology and molecular docking were applied to predict bioactive AR constituents and their target pathways, followed by in vivo validation. Short-term AR treatment significantly upregulated osteogenic markers, including RUNX2 and osteocalcin, in the bone marrow, indicating early activation of osteoblast differentiation. Long-term administration enhanced bone mineral density, trabecular organization, and callus maturation. Network pharmacology analysis identified cycloartenol acetate, β-sitosterol, and mandenol as major active compounds targeting osteogenesis- and osteoclast-related pathways, converging on HIF1A, PTGS2, and PPARG. Molecular docking demonstrated strong binding affinities between these compounds and their predicted targets, which was supported by increased expression of HIF1A, PTGS2, and PPARG in AR-treated femora. Collectively, these findings suggest that AR promotes fracture healing by regulating osteogenic differentiation and bone remodeling through multi-target transcriptional networks. Full article

Background: Osteoporosis is a complex disorder involving bone loss and muscle degeneration. Multi-omics technologies provide novel insights into its molecular mechanisms and may support biomarker discovery, patient stratification, and therapeutic development. Objective: This scoping review aimed to synthesize current evidence on the application of multi-omics approaches in osteoporosis, focusing on molecular insights, methodological diversity, and translational potential. Methods: A literature search of PubMed, Embase, and Scopus retrieved 433 records using the keywords “osteoporosis,” “osteosarcopenia,” and “omics.” After removing duplicates and screening titles, abstracts, and full texts, 30 studies met the inclusion criteria. Data on study populations, biological samples, multi-omics techniques, and integration methods were extracted. Results: Studies employed transcriptomics, proteomics, metabolomics, lipidomics, epigenomics, and metagenomics, often combined in multi-omics analyses with computational modeling. Key pathways included osteoclast differentiation, immune regulation, ferroptosis, and microbiome–metabolite interactions. Multi-omics integration enabled the identification of molecular subtypes, candidate biomarkers, and potential therapeutic targets. Limitations included small or single-center cohorts, heterogeneous designs, and limited validation, restricting generalizability and clinical translation. Conclusions: Multi-omics approaches offer a powerful framework to uncover the molecular mechanisms underlying bone and muscle degeneration and to guide precision diagnostics and interventions. Future studies should prioritize large, multicenter, longitudinal designs integrating multi-omics data with clinical and functional validation to facilitate clinical application. Full article

Developing novel anabolic agents for bone regeneration remains a clinical priority. Polydeoxyribonucleotide (PDRN) exhibits tissue-regenerative properties, but its direct cellular effects on bone remodeling remain unclear. This in vitro study investigated PDRN’s effects on osteoblast (MC3T3-E1) and osteoclast (primary bone marrow-derived macrophages) differentiation. We evaluated metabolic activity, gene/protein expression, and specific differentiation markers using MTS, qRT-PCR, Western blotting, and functional assays (ALP, Alizarin Red S, TRAP, pit formation). In osteoblasts, PDRN dose-dependently modulated metabolic activity while upregulating the early transcription factor Runx2. PDRN significantly enhanced osteoblast differentiation, evidenced by increased ALP activity, elevated mineralized matrix deposition, and robust upregulation of osteocalcin and Runx2. Conversely, PDRN exhibited no direct effect on osteoclast precursor metabolic activity, differentiation, or resorptive function. These findings support a working hypothesis in which PDRN selectively promotes osteoblast differentiation without directly affecting osteoclastogenesis. While further pharmacological investigations are required to definitively elucidate the specific purinergic receptor mechanisms, our results highlight PDRN as a promising candidate anabolic agent for bone regeneration. Full article