Search Results (1,630)

In rheumatoid arthritis (RA), activated synovial tissue-derived mesenchymal stem cells (MSC) acquire a pathogenic phenotype and produce pro-inflammatory cytokines, chemokines, metalloproteinases, pro-osteoclastic and pro-angiogenic factors. The acquisition of this aggressive phenotype might be due to modified expression of micro-RNAs. We aimed to clarify the role of specific micro-RNAs (miR-146a-5p, miR-221-3p, miR-34a-3p, miR-150, miR-203a-3p and miR-155-3p) in an in vitro model of RA. Methods: Micro-RNA expression was determined in RA patient plasma and in commercial human synovial tissue-derived MSC-like cells stimulated with a panel of pro-inflammatory mediators (poly I:C, TNF-α, IL-1β, IFN-γ) to mimic the rheumatoid arthritis pathogenic setting. Next, unstimulated cells or TNF-α stimulated cells were transfected with miR-146a-5p mimic or miR-221-3p mimic. Protein and/or mRNA expressions of chemokines, cytokines, VEGF, MMPs and RANKL were determined by ELISA or qRT-PCR. MiR-34a-3p, miR-146a-5p, miR-150, miR-221-3p and miR-203a-5p were upregulated in RA patient plasma versus healthy controls. Moreover, synovial tissue-derived MSC-like cells expressed miR-146a-5p and miR-221-3p in response to pro-inflammatory mediators. Overexpression of miR-146a-5p increased CCL2 and CXCL8 expression and miR-221-3p increased IL-1β and IL-6 expression in synovial tissue-derived MSC-like cells stimulated with TNF-α. Conclusion: Overexpression of miR-146a-5p and miR-221-3p might favour inflammation and participate in rheumatoid arthritis pathogenesis. Full article

Periodontal disease represents a major global health burden, beginning with gingivitis and progressing to periodontitis, which causes connective tissue breakdown, alveolar bone resorption, and eventual tooth loss. Beyond local pathology, periodontitis is a chronic inflammatory condition with systemic associations, including cardiovascular disease, diabetes, and metabolic disorders. Mesenchymal stem cells (MSCs) and their extracellular vesicles (EVs) have emerged as promising candidates for periodontal regeneration. This review aimed to map the current evidence on MSC-derived EVs (MSC-EVs) in periodontal regeneration, focusing on their mechanisms of action, therapeutic potential, and translational challenges. A comprehensive literature search was conducted across a major biomedical database (PubMed) to identify preclinical and clinical studies investigating MSC-EVs in the context of periodontitis. Data were charted on EV cargo composition, biological functions, regenerative outcomes, and reported limitations. Evidence indicates that MSC-EVs encapsulate bioactive molecules—including antimicrobial peptides, proteins, lipids, and microRNAs—that modulate immune responses, suppress pro-inflammatory signaling, and promote angiogenesis and tissue repair. In periodontal models, MSC-EVs attenuate osteoclast activity, enhance fibroblast proliferation, and stimulate extracellular matrix remodeling, supporting regeneration of periodontal ligament and alveolar bone. Exosome-based approaches demonstrate advantages such as reduced immunogenicity, improved safety, and feasibility for storage and standardization. However, most findings remain preclinical, with limited human data available. To bridge the translational gap, well-designed clinical trials are needed to confirm efficacy and safety while addressing regulatory challenges, GMP standards, and outcome measures. Harnessing their regenerative capacity while mitigating side effects may guide precision-targeted therapies, and continued mechanistic studies with standardized production will be key to advancing MSC-EVs into clinical practice. Full article

Treatment for large critical-sized bone defects and impaired fracture healing remain challenging. Clinically used protein-based osteoinductive factors, such as recombinant bone morphogenetic proteins (BMPs), can be effective; however, they are costly and limited by stability, dose-delivery issues, and safety concerns. Preclinical small molecules offer an alternative because they are chemically stable, scalable to manufacture, and readily integrated for systemic administration or localized release from scaffolds, hydrogels, cements, and implant coatings. With an emphasis on delivery formats and mechanistic themes, this review examines small molecules that have been shown to improve bone regeneration in preclinical models, contrasting those of biological origin with synthetic and repurposed compounds. Across studies, these selected compounds promote osteoblast commitment, differentiation, and matrix mineralization via BMP/Smad signaling and Wnt/beta-catenin (β-catenin) activation, often through glycogen synthase kinase-3 beta (GSK-3β) inhibition or relief of pathway antagonism or Hedgehog (Hh) pathway stimulation. Beyond osteoinduction, several candidates address issues that commonly limit repair, including angiogenesis, oxidative stress, inflammatory tone, osteoimmune regulation, and suppression of osteoclast-mediated resorption. Direct head-to-head comparisons are rare across both classes and reporting heterogeneity complicates interpretation. Key translational gaps include limited cytotoxicity and immunologic profiling, dose and release optimization, durability of benefit, and insufficient evaluation of rational combinations. More rigorous in vivo studies, including larger animal models and standardized outcome metrics, are needed to prioritize promising candidates and guide clinical development. Full article

Postmenopausal osteoporosis is an age-related condition in which estrogen deficiency drives low-grade inflammation and oxidative stress, disrupting the homeostatic balance between bone formation and resorption. Since osteopenia represents a critical intermediate stage, preventive strategies are essential to mitigate its progression. Preclinical studies suggest that hydrogen sulfide (H₂S), a gaseous mediator with antioxidant properties, protects bone metabolism by supporting osteoblast function and suppressing osteoclast activity. Building on this evidence, we conducted the first exploratory clinical trial assessing the effects of inhalation therapy with sulfurous mineral waters on systemic biomarkers in postmenopausal women with osteopenia. Thirty-eight eligible participants underwent a daily inhalation of sulfurous waters (14.6 mg/L sulfide) for 12 consecutive days. Biomarkers of oxidative stress, inflammation, and bone turnover were assessed at baseline, immediately post-treatment, and five days after cessation in the serum of patients. The treatment was well tolerated and did not cause any early adverse effect. Serum H₂S levels, measured in a subset of participants, significantly increased, confirming systemic bioavailability. Sulfurous water inhalation induced a marked change in oxidative stress, with malondialdehyde levels declining by up to 37% from baseline. Pro-inflammatory cytokines, particularly IL-8 and MIP-1α, were significantly decreased (up to 50–70%) at the end of the treatment. Reference bone turnover markers P1NP and CTX-1 did not show significant changes; however, BALP exhibited a significant increase, suggesting the activation of pathways linked to biomineralization. These findings provide preliminary human evidence that inhaled sulfurous waters enhance systemic H₂S bioavailability and modulate redox and inflammatory pathways associated with bone remodeling in osteopenic women, supporting the rationale for further controlled pharmacodynamic investigations evaluating the potential of H₂S in bone health. Full article

Background/Objectives: Osteoporosis is a progressive systemic skeletal disease, with male osteoporosis emerging as a critical global concern due to high morbidity and mortality from fractures. This study investigated the anti-osteoporotic potential of CGAC—a herbal mixture of Cervus elaphus Linnaeus, Glycine max (L.) Merr., Angelica gigas Nakai, and Cnidium officinale Makino—and its underlying mechanisms in an orchiectomized (ORX) mouse model. Methods: C57BL/6J mice underwent ORX for 8 weeks, followed by CGAC administration (250 and 500 mg/kg) for an additional 8 weeks. Molecular mechanisms were further validated using MG63 osteoblastic and RAW 264.7 osteoclast assays. Results: ORX induced severe osteoporotic phenotypes, including significant reductions in bone mineral density (BMD) and trabecular microarchitecture. Notably, at the time point examined, ORX was associated with a suppressed bone remodeling state, reflected by reductions in both TRAP-positive osteoclasts and ALP-positive osteoblasts, together with lower serum BALP, CTX-1, and Gla/Glu-OC ratio. Conversely, CGAC normalized this stagnant state and restored physiological remodeling. This was accompanied by reduced marrow fat accumulation through the AMPK signaling axis, which upregulated Runx2 and downregulated PPAR-γ. In vitro results confirmed that CGAC promoted osteoblast differentiation and mineralization while suppressing RANKL-induced osteoclastogenesis. These actions suggest that CGAC may be involved in regulating Wnt/β-catenin signaling. Conclusions: Overall, CGAC is a promising therapeutic candidate for male osteoporosis, offering pharmacological benefits particularly relevant to aging populations. Full article

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