Search Results (3,439)

Diffuse Idiopathic Skeletal Hyperostosis (DISH) is a systemic, non-inflammatory skeletal disorder characterized by progressive calcification and ossification of spinal ligaments and entheses. Its strong associations with aging, obesity, type 2 diabetes, and metabolic syndrome raise the possibility that metabolic and inflammatory pathways may contribute to disease development. The gut microbiota participates in nutrient metabolism, short-chain fatty acid production, bile-acid transformation, intestinal-barrier maintenance, and immune regulation; these functions provide a plausible framework for examining whether intestinal dysbiosis may influence spinal and musculoskeletal tissues. This narrative review therefore evaluates the potential relationship between gut microbiota, DISH, and related spinal degenerative diseases. It considers the nutritional, metabolic, immunological, and host-interaction functions of the gut microbiota before examining proposed gut–spine, gut–bone, gut–joint, gut–disc, gut–ligament, and gut–muscle pathways. Particular attention is given to the apparent paradox that most microbiome–bone evidence concerns osteoporosis and bone loss, whereas DISH is characterized by excessive ectopic bone formation. Differences in short-chain fatty acid concentration, receptor expression, local versus systemic signaling, and osteoblast–osteoclast microenvironments may produce divergent skeletal effects, but these mechanisms have not been tested directly in DISH. Recent studies support associations between selected microbial taxa and intervertebral disc degeneration or spinal stenosis; however, direct clinical evidence linking gut microbiota to DISH remains limited. Consequently, dietary modification, probiotics, prebiotics, and fecal microbiota transplantation should be regarded as research considerations rather than established treatments for DISH. Well-characterized case–control and longitudinal studies integrating microbiome profiling, metabolomics, inflammatory markers, and serial imaging are required to determine whether reproducible microbial or metabolite signatures precede DISH onset or progression. The pathways discussed in this review are therefore presented as biologically plausible, testable hypotheses and not as established causal relationships. Full article

Diabetes mellitus is increasingly recognized as a disorder of skeletal quality in addition to metabolic dysregulation. Both type 1 and type 2 diabetes are associated with increased fracture risk, impaired fracture healing, and higher rates of orthopedic complications despite preserved or even elevated bone mineral density, highlighting the limitations of conventional densitometric assessment alone. Diabetic bone disease arises through complex and interconnected mechanisms involving osteoblast, osteocyte, and osteoclast dysfunction, accumulation of advanced glycation end products, oxidative stress, chronic inflammation, impaired insulin and insulin-like growth factor-1 signaling, and disruption of bone–pancreas and bone–adipose crosstalk. Here, we review the cellular, molecular, genetic, and epigenetic mechanisms that contribute to diabetic skeletal fragility and examine how these abnormalities impair bone remodeling, fracture healing, and orthopedic outcomes. Particular emphasis is placed on the disconnect between bone mineral density and bone quality, describing how alterations in bone microarchitecture and matrix integrity contribute to skeletal fragility beyond the conventional measures of bone mass. We further review emerging strategies for fracture risk assessment, including advanced imaging modalities and biomarkers that more accurately characterize diabetic bone disease, and discuss the influence of antidiabetic therapies, perioperative glycemic optimization, and emerging biologic and epigenetic therapeutic approaches on fracture healing and musculoskeletal outcomes. By integrating molecular mechanisms with clinical and orthopedic evidence, this review provides a comprehensive overview of diabetic bone disease while highlighting priorities for future research and clinical translation. Full article

Bone homeostasis is a dynamic process governed by the balanced activity of osteoblasts and osteoclasts, tightly regulated through complex signaling networks. Emerging evidence highlights sphingolipid metabolism as a critical modulator of skeletal integrity, influencing bone remodeling in both health and disease. Each individual step, however, appears to have a unique role in these processes, with some overlap in function that is not well understood yet. This review explores the interplay between sphingolipid metabolism and bone homeostasis. It provides a comprehensive overview of the diverse roles of the various sphingolipid metabolic enzymes in bone remodeling and the maintenance of bone health. Special focus is given to the key enzymes from the de novo and turnover pathways that have been shown to play a pivotal role in modulating osteoblast and osteoclast differentiation, survival, and function, thereby impacting bone formation and resorption. Emerging data also suggest that alterations in sphingolipid metabolism may serve as biomarkers or therapeutic targets in metabolic bone diseases. Understanding these sphingolipid-mediated mechanisms opens new avenues for targeted interventions in bone disorders. It also highlights the need for further research into the therapeutic potential of modulating the sphingolipid metabolic pathway. Full article

Alzheimer’s disease (AD) has traditionally been conceptualized as a disorder driven primarily by cerebral amyloid-β accumulation, tau pathology, synaptic failure, vascular dysfunction, and chronic neuroinflammation. However, emerging evidence suggests that AD pathobiology may also involve extracerebral cranial compartments positioned at the interface between the brain, meninges, cerebrospinal fluid, and skull bone marrow. Recent anatomical and experimental studies have identified direct vascular and osseous channels connecting skull bone marrow with the dura mater, allowing bidirectional exchange of immune cells, soluble mediators, and cerebrospinal fluid-derived signals. These findings support the concept that skull bone marrow functions as a specialized cranial immune reservoir capable of sensing central nervous system-derived molecular cues and supplying myeloid and lymphoid cells to meningeal and brain-border compartments. In AD models and human imaging studies, amyloid-β-related signals have been detected in skull marrow, where they may promote IL-6-dependent B lymphopoiesis, expansion of age-associated B cells, microglial activation, and amplification of cerebral amyloid pathology. In parallel, AD-related amyloid precursor protein and amyloid-β signaling may remodel the skull marrow niche through osteoblast dysfunction, altered osteoclast activity, vascular channel expansion, marrow adiposity, and inflammatory reprogramming. Human PET and MRI studies indicate that skull marrow-associated inflammatory, amyloid-related, and cerebrospinal-fluid drainage signals can be detected in vivo; however, these observations remain indirect, method-dependent, and insufficiently validated for diagnostic or prognostic use. Importantly, much of the anatomical foundation for skull marrow–meninges–brain communication derives from non-AD studies of CNS-border physiology, stroke, meningitis, spinal cord injury, and infection, whereas the strongest AD-specific mechanistic evidence is currently derived from transgenic mouse models. Accordingly, we frame the skull marrow–meninges–brain axis as a testable conceptual model rather than an established causal pathway in human AD. This review integrates anatomical, immunological, osteoimmune, and imaging evidence while explicitly distinguishing AD-specific findings from evidence extrapolated from other neurological or inflammatory contexts. Determining whether skull marrow alterations represent a cause, consequence, compensatory response, or amplifier of AD pathology will require longitudinal, biomarker-defined human studies and further mechanistic validation. The review also compares the principal in vivo strategies used to distinguish skull-marrow-derived immune cells from circulating leukocytes and examines ischemic stroke and brain tumors as comparator CNS conditions. These disease models demonstrate that cranial marrow responses can be rapid, spatially organized, and either protective or pathogenic depending on cellular phenotype and disease context, reinforcing the interpretation of skull marrow as a general CNS-border immune organ rather than an AD-specific compartment. Full article

Chronic musculoskeletal disorders, including osteoarthritis, rheumatoid arthritis, and tendinopathies, converge on persistent synovial inflammation, matrix catabolism, and impaired repair. This review synthesizes molecular evidence that the cholinergic anti-inflammatory pathway (CAP), the efferent vagal arm of the inflammatory reflex, behaves as a rheostat of the musculoskeletal microenvironment. Activation of the α7 nicotinic acetylcholine receptor (α7nAChR) on macrophages, chondrocytes, osteoblasts, and synoviocytes suppresses nuclear factor-κB (NF-κB) and NLRP3 inflammasome signaling, downregulates MMP-1, MMP-3, and MMP-13, and reduces osteoblast RANKL production; effects on OPG and on the RANKL/OPG ratio under vagal stimulation remain uncharacterized, while favoring a pro-resolution M2-like macrophage program; context-dependent pro-inflammatory responses have also been reported. Bidirectional CAP and mesenchymal stromal cell (MSC) crosstalk indicates that MSCs both sense cholinergic cues and require an intact vagal arc for full immunomodulation. Along the gut–vagus–joint axis, dysbiosis and endotoxin translocation attenuate vagal signaling and amplify systemic inflammatory tone. Because orthobiologics such as platelet-rich plasma, bone marrow aspirate concentrate, and MSCs act within this milieu, cholinergic tone appears associated with the terrain that conditions their efficacy. Heart rate variability stratification and vagal neuromodulation may represent testable adjuncts, although prospective validation in orthobiologic populations remains absent. Preclinical and early clinical evidence is critically appraised throughout. Full article

Magnesium phosphate cements (MPCs) are promising bone substitutes, but rapid setting, high exothermicity, and poor handling limit their clinical application. This study developed a dual-setting MPC by integrating chitosan-derived hydrogels into the cement matrix. Zinc ion-crosslinked carboxymethyl chitosan (CMCS) and thermosensitive chitosan/β-glycerophosphate (CS/GP) hydrogels were initially evaluated as modifiers of borax-containing (0.5% B) MPC formulations, after which the CS/GP formulation was further optimized by varying the CS (1.0/1.5%) and GP (5.6%/8.0%) concentrations. The effects of these modifications on setting behavior, physicochemical characteristics, mechanical performance, biodegradation, and cytocompatibility were systematically investigated. The B/CS/GP systems prolonged setting time, reduced the reaction temperature, moderated pH evolution, and markedly improved qualitative injectability and cohesion. XRD, FTIR, and SEM confirmed preservation of the characteristic phase composition, chemical structure, and microstructure. All formulations maintained favorable mechanical properties and supported osteoblast viability above the threshold. Among the investigated groups, the cement containing 0.5% B, 1.5% CS, and 5.6% GP exhibited the most balanced performance, combining improved handling characteristics with enhanced compressive strength. These findings demonstrate that the integration of CS-derived hydrogels, particularly the thermosensitive CS/GP system, provides a promising strategy for developing injectable dual-setting MPCs with improved handling characteristics without compromising their fundamental physicochemical and biological properties. Full article

Bone defects from trauma, tumor resection, infection, and degenerative disease remain a large clinical problem, and the grafting strategies used to treat them still carry familiar limitations: donor-site morbidity for autografts, variable integration and supply constraints for allografts. Synthetic substitutes have narrowed the gap but rarely combine mechanical competence with biological activity in a single material. Zirconium dioxide (ZrO₂) has been used in orthopedics and dentistry for decades on the strength of its fracture toughness, which derives from the stress-induced tetragonal-to-monoclinic transformation, together with chemical stability and an established safety record. At the nanoscale, ZrO₂ can provide functionalities beyond mechanical reinforcement in appropriately engineered systems. Its high surface area, tunable surface chemistry, and potential mesoporosity have been exploited in selected formulations for matrix reinforcement, surface-mediated cellular interactions, therapeutic cargo loading and release, and antibacterial applications. This review covers the physicochemical basis of ZrO₂ behavior, including crystal phases, transformation toughening, surface chemistry and hydrothermal stability, and the influence of synthesis route on particle size and dispersion, and links these to protein adsorption, osteoblast response, osteogenic signaling, and immunomodulatory and antibacterial effects. Recent applications are surveyed across scaffold reinforcement, bone cements and fillers, implant surface modification, local drug delivery, and infection control. Recurring issues are examined throughout, including the reported loading ranges associated with mechanical performance and the effects of particle agglomeration, the confounding effect of porosity on reported strength, and the need to pair ZrO₂’s bioinertness with bioactive phases. The review closes with cytotoxicity, long-term particle fate, scale-up and regulatory barriers, and prospects in additive manufacturing, personalized grafts, and theragnostic design. Full article

Transcriptomic technologies have revolutionized our understanding of skeletal biology by shifting research from descriptive cellular characterization to a systems-level analysis of bone homeostasis and pathology. The rapid evolution of bulk RNA sequencing (bulk RNA-seq), single-cell RNA sequencing (scRNA-seq), spatial transcriptomics, and integrative multi-omics approaches has enabled unprecedented resolution of the molecular and cellular complexity of the skeletal microenvironment. Bone remodeling is a tightly regulated process driven by coordinated interactions among bone marrow-derived mesenchymal stem/stromal cells (BMSCs), osteoblasts, osteoclasts, osteocytes, immune cells, and other bone microenvironment components. This narrative review summarizes recent advances in bulk RNA-seq, scRNA-seq, spatial transcriptomics, and emerging multi-omics approaches that have transformed the study of bone development, remodeling, and disease. We discuss how transcriptomic analyses have revealed the heterogeneity of BMSCs and osteoblasts, elucidated the molecular mechanisms regulating osteoclast differentiation, and identified transcriptional changes associated with osteoclast dysregulation in metabolic, inflammatory, and age-related bone disorders. We further evaluate the limitations of bulk and scRNA-seq, including technical biases, loss of spatial information, and computational challenges. Finally, we highlight how spatial transcriptomics and integrative multi-omics approaches are overcoming these limitations by combining transcriptional, spatial, epigenetic, proteomic, and metabolomic data to provide a comprehensive understanding of skeletal biology, accelerate biomarker discovery, identify novel therapeutic targets, and advance precision medicine for bone diseases. Full article

Background: Osteoporosis (OP) arises from dysregulated bone metabolism driven by genetic and epigenetic factors. Osteoblasts are central to bone formation, and their functional heterogeneity—shaped by genetic background and receptor expression profiles—may critically influence OP susceptibility. This study aimed to identify osteoblast-specific genes robustly associated with OP and elucidate their underlying pathogenic mechanisms. Methods: We analyzed single-cell RNA sequencing (scRNA-seq), bulk RNA sequencing (bulk RNA-seq), and spatial transcriptomics (ST) datasets of osteoblasts. Differentially expressed genes (DEGs) were identified from scRNA-seq and bulk RNA-seq datasets, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Three machine learning methods and an artificial neural network (ANN)-based weighting analysis, together with weighted gene co-expression network analysis (WGCNA), were used to prioritize candidate OP-associated genes. ST data were integrated with CellChat analysis based on scRNA-seq data to investigate spatial expression patterns and potential cell–cell communication. Candidate genes were validated by immunohistochemical staining in human femoral head samples and quantitative real-time PCR (qRT-PCR) in MC3T3-E1 cells. Results: The intersecting DEGs from the scRNA-seq and bulk RNA-seq datasets were potentially related to inhibition of ossification. Three machine learning methods identified five osteoporosis-associated candidate genes: TTYH3, NRBP2, MPG, HSPG2, and GPR153, which were subsequently evaluated using ANN-based weighting analysis. Among these, TTYH3 and MPG were identified as OP-related genes by WGCNA. Integration of the scRNA-seq, ST, and CellChat results suggested that SPP1 was highly expressed in osteoblasts from the OP sample and exhibited a spatially heterogeneous expression pattern. Immunohistochemical staining of human femoral head tissues from individuals with normal bone mass and osteoporosis, together with qRT-PCR analysis in MC3T3-E1 cells, further validated the differential expression of TTYH3 and MPG. Conclusions: This study identified candidate osteoporosis-associated biomarkers and provided insights into potential pathogenic mechanisms, thereby establishing a basis for future mechanistic and clinical validation. Full article

Prolonged spaceflight and sustained bed rest induce mechanical unloading, leading to disuse osteoporosis and an elevated risk of fractures. Although post-translational modifications are increasingly recognized as key contributors to the pathogenesis of disuse bone loss, the functional role and underlying molecular mechanisms of O-linked N-acetylglucosaminylation (O-GlcNAcylation) remain poorly understood. Here, we demonstrate that mechanical unloading via 2D clinorotation downregulates the levels of O-GlcNAc transferase (OGT) and global protein O-GlcNAcylation in MC3T3-E1 cells, whereas osteogenic induction elicits the opposite effect. Both small interfering RNA (siRNA) targeting OGT and pharmacological inhibition using OSMI-1 recapitulated unloading-induced deficits, significantly impairing osteogenic differentiation and matrix mineralization. Conversely, OGT overexpression or inhibition of O-GlcNAcase (OGA) with Thiamet-G enhanced these processes. Importantly, OGT re-expression partially reversed the deficits caused by mechanical unloading. Notably, exogenous elevation of global O-GlcNAcylation levels via Thiamet-G treatment even after OGT knockdown also partially restored osteogenic capacity. Together, these findings establish the OGT/O-GlcNAcylation axis as a critical regulator of unloading-induced suppression of osteogenesis and identify it as a promising therapeutic target for disuse osteoporosis. Full article

Aging and glycative stress are major, interrelated drivers of skeletal fragility, yet the extent to which they act through shared versus distinct biological pathways remains poorly defined, limiting integrated therapeutic strategies. This review compares the convergent and divergent mechanisms by which aging and glycative stress affect osteocytes, osteoblasts, and osteoclasts, extracellular matrix properties, and bone mechanotransduction. Both conditions converge on oxidative stress, mitochondrial dysfunction, chronic low-grade inflammation, cellular senescence, impaired autophagy, NLRP3 inflammasome activation, and ferroptosis, ultimately reducing osteocyte viability and disrupting RANKL/OPG-mediated remodeling. They diverge in their primary drivers: Aging is characterized by hormonal decline, stem-cell exhaustion, and progressive loss of bone mass and microarchitecture, whereas glycative stress acts through AGE–RAGE signaling and collagen cross-linking, compromising bone quality and mechanosensitivity while often preserving bone mineral density, explaining the disproportionate fracture risk seen in diabetes. Since current anabolic and anti-resorptive therapies do not specifically target AGE-related pathways, combined strategies incorporating senolytic, antiglycative, and mechanoprotective approaches—alongside lifestyle interventions—may be needed to more effectively reduce fracture risk in aged and diabetic populations. Full article

Extracellular vesicles (EVs) have emerged as promising cell-free therapeutic agents for bone regeneration due to their ability to modulate osteogenesis, angiogenesis, and immune responses. This review summarizes the current knowledge on EV biology, including their classification, biogenesis, and molecular cargo, with a particular focus on their role in bone healing. EVs derived from mesenchymal stromal cells and other cell types promote osteoblast differentiation, inhibit osteoclast activity, enhance vascularization, and modulate inflammation through the transfer of bioactive proteins and non-coding RNAs. Recent advances in EV engineering, biomaterial-assisted delivery, and isolation techniques are discussed, together with their translational potential for the treatment of critical bone defects and avascular osteonecrosis. Although preclinical evidence is highly encouraging, clinical evidence remains limited, particularly in orthopedics, and clinical translation is challenged by EV heterogeneity, lack of dose standardization, limited understanding of biodistribution, scalable manufacturing, and regulatory requirements. Overall, EV-based therapies represent a promising future strategy for regenerative orthopedics and bone tissue engineering. Full article

The effects of incorporating Nb₂O₅ or Ta₂O₅, both intermediate oxides, on the structure and ion release behavior of calcium borate-based sol−gel glasses [(70 − x)B₂O₃-30CaO-xM₂O₅, x = 0, 2.5, 5, and 7.5 (mol%), and M = Nb or Ta] were investigated. The glasses were prepared by dissolving niobium (V) ethoxide or tantalum (V) ethoxide in methanol, followed by the addition of boric acid and calcium lactate pentahydrate, stirring, drying, and calcination. Nb₂O₅ incorporation was accompanied by FT-IR spectral changes consistent with a transition from pyroborate to metaborate, and sustained release of B and Ca for up to 24 h. These observations suggest an increase in bridging oxygens, which could be associated with enhanced structural stability. Conversely, Ta₂O₅ incorporation resulted in concentration-dependent changes in density-related structural parameters. These structural changes may have contributed to the plateau in ion dissolution from 6 h onward. The specific surface area remained nearly unchanged with Nb₂O₅ incorporation but increased with Ta₂O₅ incorporation; however, no clear correlation was observed between specific surface area and ion release behavior. Cell culture tests using mouse-derived osteoblast-like cells demonstrated cell proliferation in the glass extracts, and by day 3 of cultivation, the number of viable cells was comparable to that of the control sample, indicating cytocompatibility. Therefore, the glasses are promising candidates as suppliers of therapeutic ions for biomaterial applications. Full article

Titanium and its alloys remain the dominant materials in oral implantology, but degradation products released through corrosion, tribocorrosion, and wear are biologically active. This critical narrative review examines oxidized-lipid signaling and ferroptosis as candidate downstream mechanisms connecting titanium-associated redox dysregulation with peri-implant bone loss. A targeted literature search of PubMed, Web of Science, and Scopus was updated through 2 August 2026 and integrated evidence from dental peri-implant studies, titanium-particle osteolysis models, and broader skeletal research. Titanium-derived particles can promote mitochondrial and non-mitochondrial reactive oxygen species, membrane phospholipid peroxidation, reactive aldehyde formation, and oxidized-phospholipid signaling. Experimental titanium-particle models demonstrate GPX4 repression and osteoblast ferroptosis, while skeletal studies indicate that ferroptotic dysfunction of osteoblasts and osteocytes can impair mineralization, increase the RANKL/OPG ratio, and favor osteoclastogenesis. Human peri-implant fluid data provide emerging but non-diagnostic evidence, including altered GPX4 and malondialdehyde levels. Specialized pro-resolving mediators may counterbalance the destructive lipid-peroxidation branch. Current evidence supports a biologically plausible and experimentally testable pathway rather than established causation in human dental peri-implant tissues. Direct tissue-level confirmation using redox lipidomics, iron mapping, pathway-specific rescue experiments, and spatial osteoimmune profiling is required. Full article

Periodontitis-associated alveolar bone loss reflects not only persistent inflammation but also profound metabolic remodeling within the periodontal microenvironment. This review synthesizes current evidence on how lipid metabolic reprogramming regulates periodontal bone remodeling and its therapeutic significance. Under physiological conditions, fatty acid uptake and β-oxidation, lipid droplet turnover, and lipid-derived signaling support osteoblast bioenergetics, stem-cell osteogenesis, and balanced bone remodeling. In contrast, dyslipidemia and chronic inflammatory stress promote the accumulation of free fatty acids, oxidized lipoproteins, cholesterol derivatives, and sphingolipid metabolites, thereby enhancing reactive oxygen species production, lipid peroxidation, inflammasome activation, and pro-inflammatory immune polarization. These changes suppress osteogenic differentiation, stimulate osteoclastogenesis, and impair periodontal regeneration. We further integrate major regulatory networks, including PPARγ–Wnt/β-catenin, AMPK–mTOR, NF-κB/NLRP3, and GSK3β–NRF2/ferroptosis signaling. Therapeutic strategies targeting these lipid–redox–immune circuits include specialized pro-resolving lipid mediators, n-3 polyunsaturated fatty acids, statins, metabolic modulators, and local biomaterial- or nanocarrier-based delivery systems. Accordingly, lipid metabolic reprogramming may provide a framework for developing metabolism-oriented adjunctive and regenerative strategies for periodontitis. Full article