Search Results (1,697)

Background/Objectives: Geranylgeraniol (GGOH), an isoprenoid intermediate of the mevalonate pathway, regulates bone cell viability and function, particularly by mitigating cellular toxicity induced by nitrogen-containing bisphosphonates (N-BPs). Despite this, its role in osteoporosis remains underexplored. This scoping review synthesises evidence on the effects of GGOH in in vitro and in vivo models of osteoporosis. Methods: PubMed, Scopus, and Ovid were searched using GGOH- and osteoporosis-related terms. Primary studies evaluating GGOH exposure in cellular or animal osteoporosis models were eligible. Twenty-nine studies met the inclusion criteria. Results: In vitro findings demonstrate that GGOH reverses N-BP-induced depletion of geranylgeranyl pyrophosphate, restoring protein prenylation which is essential for osteoclast and osteoblast survival, cytoskeletal organisation, and differentiation. GGOH reduced osteoclast apoptosis, restored nuclear factor of activated T-cells 1 and carbonic anhydrase II expression, and prevented N-BP-associated suppression of bone resorption. In osteoblasts and mesenchymal stem cells, GGOH improved viability, upregulated osteogenic markers including runt-related transcription factor 2, alkaline phosphatase, collagen type I, and bone morphogenetic proteins, and rescued mineralisation impaired by alendronate or zoledronate. Independent of N-BPs, GGOH exerted divergent effects on osteoclasts, by inhibiting osteoclastogenesis or promoting retinoic acid receptor-mediated bone resorption and attenuating zoledronate protection in vascular calcification settings in a model-specific manner. In vivo, dietary GGOH supplementation improved trabecular and cortical bone parameters and reduced serum C-terminal telopeptide of type I collagen in obese mice, indicating suppression of bone resorption. Conclusions: Overall, although GGOH shows osteoprotective potential, its capacity to antagonise N-BP efficacy limits systemic co-administration. Current evidence suggests that local delivery may warrant future investigation as a strategy to mitigate N-BP-induced skeletal toxicity. However, studies evaluating bone tissue exposure, pharmacokinetics, and clinically achievable concentrations are required before this approach can be translated. Full article

Background/Objectives: Oxidative stress is closely tied to diabetic bone disorders. Superoxide dismutase (SOD) is a key antioxidant enzyme, yet its sex-specific link with osteoporosis in type 2 diabetes mellitus (T2DM) remains unclear. This study aimed to investigate this association and explore its potential biological mechanism. Methods: A retrospective cross-sectional study was performed on 2023 T2DM patients (1137 males, 886 females) grouped by bone mineral density (BMD). Multivariate logistic regression was used, and in vitro experiments validated SOD3’s effect on osteoclast differentiation. Results: After adjustment for potential confounders, higher serum SOD activity (>135 U/mL) was independently associated with approximately 50% lower odds of prevalent osteoporosis at the lumbar spine and femoral neck in women, whereas no significant association was observed in men. Recombinant SOD3 inhibited osteoclast differentiation in a concentration-dependent way. Conclusions: Higher serum SOD activity was independently associated with a lower prevalence of osteoporosis in women with T2DM. Serum SOD activity may serve as a potential biomarker associated with osteoporosis in this population. These findings provide new insights into the relationship between oxidative stress and diabetic bone disease and warrant validation in prospective studies. Full article

Skeletal homeostasis relies on coordinated interactions among osteoblasts, osteoclasts, osteocytes, chondrocytes, and bone marrow stromal cells. Disruption of this balance contributes to the development of osteoporosis, osteoarthritis, impaired skeletal repair, and bone malignancies. Fat mass and obesity-associated protein (FTO), an RNA demethylase that removes N6-methyladenosine (m6A) and related RNA modifications, has emerged as a key context-dependent regulator of skeletal biology. Rather than acting uniformly as either a pro-osteogenic or disease-promoting factor, FTO exerts diverse effects that depend on the cell type, disease stage, target transcript, reader-protein context, and mode of therapeutic modulation. This narrative review summarizes current evidence on the role of FTO in osteoblast differentiation, osteoclast activity, bone marrow mesenchymal stem cell (BMSC) lineage commitment, cartilage homeostasis, osteosarcoma, multiple myeloma, and bone-related metastasis. We highlight areas of consensus, unresolved controversies, the strength of the available evidence, and major translational challenges. Collectively, FTO represents a promising therapeutic target in skeletal diseases; however, the current evidence remains largely preclinical and should be interpreted with caution until its efficacy and safety are validated in clinical settings. Full article

Immunotherapies, including chimeric antigen receptor (CAR) T cells, bispecific T-cell engagers (BiTEs), and antibody–drug conjugates (ADCs), have revolutionized the treatment landscape for multiple myeloma (MM). Despite robust initial response rates, achieving durable remissions remains challenging due to frequent relapses driven by complex therapeutic resistance mechanisms. In this review, we comprehensively examine intrinsic tumor resistance, such as innate and acquired antigen escape mediated by genomic alterations, structural variations, and epigenetic silencing. Furthermore, we highlight the critical role of the highly permissive bone marrow microenvironment in blunting the efficacy of modern therapies. Cellular compartments, including mesenchymal stromal cells, osteoclasts, and expanded immunosuppressive immune populations, actively foster tumor survival, promote metabolic competition, and T-cell exhaustion. We also review the unique clinical toxicities associated with T-cell-redirecting modalities, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Ultimately, deciphering the complex interplay between malignant plasma cells and their surrounding microenvironment is essential for optimizing treatment sequencing, preventing effector cell exhaustion, and designing next-generation therapeutic strategies to secure long-term, durable responses for patients. Full article

Background/Objectives: Estrogen is a key female hormone; however, its role in periodontitis remains poorly understood. This study investigated the effects of 17β-estradiol (E2) on experimental periodontitis using an ovariectomy (OVX) model with E2 administration. Methods: Female mice aged 8–10 weeks underwent OVX, followed by induction of ligature-induced periodontitis, and subsequent quantification of alveolar bone resorption. Additional groups received an aromatase inhibitor or E2 supplementation after OVX, with subsequent induction of periodontitis and evaluation of bone resorption. Histological analysis assessed multinucleated giant cells and tartrate-resistant acid phosphatase-positive osteoclasts on the bone surface. Gingival tissue was analyzed for gene expression related to osteoclastogenesis. The effect of E2 on osteoclast differentiation from bone marrow cells was also examined. Results: OVX significantly reduced serum E2 levels and decreased alveolar bone resorption. Aromatase inhibitor administration similarly reduced bone loss. Histological evaluation revealed a reduced number of resorbing osteoclasts in OVX mice, whereas E2 supplementation increased osteoclast numbers. No significant changes in inflammatory cytokine or receptor activator of nuclear factor-kappa B ligand (RANKL) expression were observed. E2 promoted osteoclast differentiation in vitro, and treatment with E2 prior to RANKL stimulation further increased the number of osteoclasts. This effect was suppressed by an estrogen receptor antagonist. Moreover, E2 enhanced the expression of osteoclast differentiation–associated genes in the presence of RANKL, an effect abolished by tamoxifen. Conclusions: E2 increased alveolar bone resorption in experimental periodontitis, likely by promoting osteoclast differentiation, independent of inflammatory cytokine or RANKL gene expression. Full article

Colony-stimulating factor-1 receptor (CSF1R) provides essential signals for macrophage and osteoclast proliferation, differentiation, and survival, but the roles of CSF1R+ macrophages and osteoclasts during limb morphogenesis are understudied. Here, we utilized a pharmacological model by feeding the CSF1R inhibitor PLX5622 to pregnant mice across gestation to examine how CSF1R disruption impacts embryonic limb development. CSF1R-expressing cells were significantly depleted in response to PLX5622 exposure, including a complete loss of embryonic osteoclasts and osteoclastic activity in the developing limb bones. Although the gross morphology of limb nerves, muscles, cartilage, and bone appeared intact between embryonic day 11.5 (E11.5) and E15.5, prenatal PLX5622 exposure resulted in a completely penetrant truncated phenotype for all postnatal day 1 (P1) limb bones analyzed, suggesting that CSF1R+ cells play important roles in mediating limb bone formation during late embryogenesis. Interestingly, strain-specific defects were observed in the heel, where most of the CD1 mice presented with absent talus and underdeveloped calcaneus bones, while the C57BL/6 mice presented with milder developmental disruptions in both bones. Taken together, our data demonstrate that PLX5622 effectively depletes CSF1R-expressing macrophages and osteoclasts in embryonic limbs and suggest an essential role for embryonic CSF1R+ cells in driving limb bone morphogenesis. Full article

Bone is a dynamic specialized connective tissue that undergoes continuous remodeling to preserve its health. Bone health is influenced throughout life by a combination of genetic, hormonal, and environmental factors, as well as physical activity and diet. This study aims to evaluate the effects of diets with different fat content on the femurs of mice fed for 16 or 20 weeks on a normal diet (ND16w and ND20w) or a Western diet (WD16w and WD20w) and for 20 weeks with their combinations on a ketogenic diet (KD) (WD + ND20w, ND + KD20w, and WD + KD20w). Micro-CT analysis on femoral cancellous bone revealed a non-significant trend toward decreased bone volume fraction (BV/TV) and trabecular thickness in mice fed a combined WD + KD20w compared to WD20w. Cortical bone thickness was significantly lower in mice fed WD16w and WD20w compared to those fed ND16w and ND20w (p = 0.049 and p = 0.039, respectively), in mice fed WD20w Ct.Th increased compared to WD + ND20w (p = 0.024) and a strong decrease is evident when comparing WD + ND20w to WD + KD20w (p < 0.0004). Consistently, histological analysis revealed that the number of osteoclasts per bone perimeter on cancellous bone increases compared with ND20w with ND + KD20w (p = 0.007) and WD + ND20w with ND + KD20w (p = 0.0006). In addition, a decrease in osteoblasts was observed (p < 0.041) in cortical bone, comparing ND20w with ND + KD20w; this suggests that the KD may have differential effects depending on the baseline condition. Osteocyte numbers did not significantly change when comparing the different treatments. Masson staining supports micro-CT results on both cortical and cancellous bone. In conclusion, transition from a high-fat diet to a normal diet may partially restore cortical bone health, whereas transition to a ketogenic diet exerts a trend toward additional detrimental effects on trabecular bone. Full article

Skeletal safety of glucagon-like peptide-1 receptor agonists (GLP-1RAs) remains uncharted, with emerging evidence suggesting a divergence between mono- and dual-agonist therapies. GLP-1RA monotherapy appears bone-neutral, with modest or no adverse effects on bone mineral density (BMD), whilst dual agonists may confer a relatively higher risk of osteoporosis and fractures, plausibly mediated by greater weight loss magnitude and concomitant reductions in lean body mass (LBM) rather than direct osteotoxicity. Intensified surveillance is warranted in susceptible phenotypes, including older adults and postmenopausal women with low baseline BMD under conditions of rapid weight loss. Osteoporosis risk is further amplified by pre-existing osteopenia, nutritional deficiencies, and concomitant exposure to bone-active agents. Given the limitations of serial dual-energy X-ray absorptiometry (DXA), including cumulative radiation exposure and limited sensitivity to early remodeling changes, biochemical markers potentially depict bone turnover more dynamically. Measurement of dynamic bone resorption markers enables early identification of skeletal disturbances, supporting proactive adjustment of therapeutic strategy, dosing, and duration. Specifically, deoxypyridinoline (DPD), a bone-specific collagen crosslink, is a highly sensitive and rapidly responsive urine biomarker of osteoclastic activity. Incorporating DPD urine testing into monitoring frameworks potentially facilitates individualized therapeutic modulation, optimizing the metabolic efficacy of GLP-1RAs while safeguarding skeletal integrity. Full article

Osteoradionecrosis of the jaw (ORNJ) remains one of the most severe late complications of head and neck radiotherapy. Current evidence suggests that ORNJ is a progressive and biologically heterogeneous disorder driven by microvascular injury, chronic hypoxia, oxidative stress, fibro-atrophic remodeling, impaired bone turnover, immune dysregulation, and systemic susceptibility factors. Within this complex pathogenic network, heat shock protein 27 (HSP27) emerges as a biologically plausible but unexplored mediator. HSP27 regulates multiple stress-response pathways, including redox homeostasis, cytoskeletal stabilization, endothelial protection, apoptosis control, fibroblast activation, and osteoblast–osteoclast function, all of which overlap with key mechanisms implicated in ORNJ. However, no studies have directly investigated HSP27 expression, activation, or functional significance in irradiated mandibular tissues or ORNJ-specific cohorts. This review summarizes current knowledge of ORNJ pathobiology, examines potential mechanistic links with HSP27, and outlines future research priorities involving biomarker development, tissue-level characterization, preclinical modeling, and therapeutic targeting. Integrating HSP27 into ORNJ research may improve understanding of pathogenesis, risk stratification, and the development of novel preventive and therapeutic strategies. Full article

Bone metastasis develops within a specialized marrow ecosystem where hematopoiesis, immune regulation, vascular trafficking, and skeletal remodeling intersect. Neutrophil-lineage cells occupy a unique position in this setting because they are generated, retained, mobilized, aged, and reprogrammed within the same bone marrow niches that disseminated tumor cells exploit for homing and survival. This review examines how neutrophils, tumor-associated neutrophils, immature neutrophils, low-density neutrophils, and PMN-MDSCs shape skeletal colonization. We discuss tumor-to-marrow signaling, CXCR2-dependent recruitment, CXCR4/CXCL12-mediated marrow retention, neutrophil–circulating tumor cell interactions, vascular arrest, dormancy escape, NET-mediated matrix remodeling, immune suppression, and effects on osteoclast–osteoblast coupling. Evidence is strongest in breast and prostate cancer models, where pathways such as CXCL5/CXCR2, CTNND1–CXCR4/CXCL12, PR3–RAGE, and DKK1–CKAP4–STAT6–CHI3L3 link neutrophil-lineage cells to skeletal progression and immunotherapy resistance. However, several mechanisms, including CTC–neutrophil clustering and NET-driven dormancy awakening, remain partly extrapolated from non-skeletal models. We therefore emphasize evidence hierarchy, methodological limitations, and therapeutic opportunities, arguing that selective reprogramming or functional inhibition of pro-metastatic neutrophil states may be more promising than indiscriminate neutrophil depletion in metastatic bone disease. A clearer understanding of these context-dependent neutrophil programs may help refine biomarker development and guide combination therapies for patients with skeletal metastases. Full article

Layer chickens have dual physiological demands for rapid growth and continuous egg production. The maintenance of skeletal homeostasis in layer chickens relies on the precise coordination among OCs, osteoblasts (OBs), and osteocytes. The imbalances in the supply of nutrients such as calcium (Ca) and phosphorus (P), as well as dysfunction of the “gut–bone” axis, can disrupt normal bone development in layer chickens, leading to bone diseases such as tibial dyschondroplasia (TD) and osteoporosis (OP), seriously damaging the production performance of layer chickens. This review systematically summarizes the knowledge background of the metabolic reprogramming of OCs in layer chickens, especially mitochondria-mediated biological processes, including oxidative phosphorylation (OXPHOS), glycolysis, reactive oxygen species (ROS) signaling, mitophagy, etc. Notably, the co-culture system of OCs derived from the bone marrow cavity of embryos in vitro has been established in laying chickens. However, there are few reports on the study of mitochondrial metabolism of OCs using this model. Therefore, this review particular focuses on the bone metabolism mediated by OCs in layer chickens and proposes future research priorities, including the application of gene editing and multi-omics methods to ultimately achieve targeted nutritional or pharmacological interventions for optimizing mitochondrial function and promoting bone health. Full article

Periodontitis, driven by Porphyromonas gingivalis (P. gingivalis) biofilms, is a global health burden with limited treatment options due to antibiotic resistance. Chrysanthemum lavandulifolium is traditionally used in China for clearing heat and reducing swelling, yet its anti-periodontitis potential remains uncharacterized. This study evaluated the antibacterial and therapeutic effects of its essential oil (CLEO) against periodontitis. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of CLEO against P. gingivalis were determined by broth microdilution. Anti-biofilm activity was assessed via XTT assay. Network pharmacology, molecular docking, and 100 ns molecular dynamics simulations were employed to identify active compounds and core targets. Experimental periodontitis was induced in C57BL/6 mice by molar ligation. Mice received topical CLEO at concentrations of 2, 3, and 4 mg/mL, 2% minocycline, or vehicle once daily for 14 days. Periodontal inflammation, alveolar bone loss, collagen organization, osteoclast activity, and serum levels of MMP-9 and COX-2 were evaluated. CLEO exhibited potent anti-P. gingivalis activity, with an MIC of 2 mg/mL and MBC of 4 mg/mL. At the MIC, CLEO disrupted 57.5% of pre-formed P. gingivalis biofilms. Network pharmacology and molecular docking identified α-bisabolol, chamazulene, and 1,8-cineole as key active compounds, with the chamazulene-HSP90AA1 complex showing the strongest binding affinity (−10.0 kcal/mol). The 100 ns MD simulation confirmed the stability of this complex (RMSD < 1 nm). In the mouse periodontitis model, topical application of CLEO at 3 and 4 mg/mL significantly reduced gingival inflammation, alveolar bone resorption, and the number of TRAP-positive osteoclasts compared with the vehicle-treated periodontitis group (all p < 0.05). Furthermore, CLEO treatment dose-dependently lowered serum MMP-9 levels (from 24.15 ± 0.24 pg/mL in the model group to 12.36 ± 0.54 pg/mL in the high-dose group) and COX-2 levels (from 15.38 ± 0.62 pg/mL to 8.99 ± 0.57 pg/mL). The therapeutic efficacy of the high-dose CLEO group was comparable to that of the 2% minocycline group. CLEO exerts anti-P. gingivalis and anti-biofilm effects in vitro and ameliorates periodontitis in vivo through multi-target mechanisms, providing pharmacological evidence for its traditional use in inflammatory conditions. Full article

Snake venom is a remarkably complex cocktail of bioactive molecules capable of hijacking diverse host physiological processes, yet how individual venom components drive these cellular responses remains a bit of a black box. To map these dynamics, we ran a comparative transcriptomic analysis on human osteoclastogenic cultures, exposing them continuously to crude Bothrops moojeni venom and its high (HMM) and low (LMM) molecular mass fractions throughout differentiation. This allowed us to capture the cumulative transcriptional shifts that unfold across the entire lifecycle of osteoclast development. The crude venom triggered a sweeping response, deeply impacting neuroimmune, extracellular matrix remodeling, inflammatory, and apoptotic pathways—reflecting a massive reshuffling of cellular regulatory networks. When we looked at the fractions, clear dividing lines emerged. The HMM fraction, packed with metalloproteinases and serine proteases, mostly drove pathways tied to cytoskeletal remodeling, intracellular trafficking, and osteoclast-associated signaling. In contrast, the LMM fraction—home to phospholipases A₂, disintegrins, and small peptides—steered a much more targeted course, influencing immune regulation, proliferative signaling, and metabolic homeostasis while noticeably turning down catalytic and binding functions. Interestingly, all venom-treated groups shared a drop-off in ATP-dependent and ligand-binding categories, pointing to a common disruption in core metabolic and signaling processes. Taken together, these findings offer a clearer mechanistic look at how different B. moojeni venom components target bone remodeling pathways, highlighting the power of transcriptomics for untangling complex venom–host interactions. Full article

Periodontitis is a chronic inflammatory disease driven largely by dysregulated host responses that lead to destruction of periodontal tissues. Integrins are heterodimeric transmembrane receptors that regulate cell adhesion and bidirectional signaling in epithelial cells, immune cells, periodontal ligament fibroblasts, and osteoclasts. During disease progression, integrin-related responses may shift across overlapping molecular phases. Epithelial integrins such as α3β1 and α6β4 support barrier integrity, whereas α5β1 may facilitate microbial interaction and inflammatory signaling. β2 integrins and α4β1 contribute to leukocyte recruitment and inflammatory amplification, whereas increased α9β1-associated signaling and reduced αvβ6-mediated regulation of transforming growth factor β (TGF-β) may promote inflammatory persistence. Matrix-associated integrins, including α2β1 and α11β1, support extracellular matrix (ECM) organization and mechanotransduction, whereas αvβ3 cooperates with Receptor activator of nuclear factor kappa B ligand (RANKL) to promote osteoclast activity and alveolar bone resorption. Impaired β1 integrin-dependent signaling and potentially reduced αvβ5-associated efferocytosis may contribute to defective resolution and regeneration. Importantly, integrin expression, activation, and downstream signaling are distinct, and the strength of evidence varies among integrin subtypes. This review proposes a conceptual framework in which periodontitis reflects a dynamic imbalance in integrin-mediated processes that link inflammation, bone resorption, and regenerative failure, rather than being a direct equivalent of clinical periodontal stages or grades. Full article

Osteosarcoma remains the most common primary malignant bone tumor in adolescents and is characterized by aggressive metastasis, resistance to therapy, and extensive bone microenvironment remodeling. Therefore, the identification of novel multi-target therapeutic agents capable of simultaneously inducing ferroptosis and disrupting tumor-supportive signaling is urgently needed. This study employed a multi-omics-guided approach to investigate the anti-osteosarcoma potential of metabolites derived from the sea cucumber Holothuria scabra. LC–MS/MS profiling identified major bioactive constituents, including holothurins, scabrasides, fucosterol, desmosterol, and 24-methylenecholesterol. Integrated transcriptomic analysis of the GSE42352 dataset revealed key ferroptosis- and bone microenvironment-associated targets, including CXCR4, CTSK, RUNX2, VEGFA, and TFRC. In silico pharmacological prediction and molecular docking demonstrated favorable anticancer properties and strong binding affinities of several metabolites toward these targets, with fucosterol and holothurin A exhibiting the most promising interactions. Functional validation in MG-63 osteosarcoma cells showed concentration-dependent reductions in cell viability and migration following H. scabra treatment. Furthermore, treatment decreased GPX4, NRF2, and GSH levels while increasing TFRC and MDA, indicating activation of ferroptotic cell death. In a MG-63/RAW264.7 co-culture model, H. scabra suppressed RANKL, VEGFA, MMP9, and TRAP-positive osteoclast formation, suggesting inhibition of osteoclastogenesis, angiogenesis, and metastatic potential. Collectively, these findings identify H. scabra as a promising marine source of multi-target compounds for osteosarcoma management through coordinated induction of ferroptosis and remodeling of the bone tumor microenvironment. Full article