Search Results (2,072)

Background: Osteoporosis has a rising global incidence and social burden. Serum uric acid’s dual roles in oxidative stress and inflammation may influence bone health, but findings are inconsistent and require further research. This study aimed to evaluate the relationship between SUA levels and osteoporosis in a multicenter cohort obtained from different regions of Türkiye. Methods: This multi-center retrospective study included 3280 individuals, postmenopausal women and men aged 45 and older, from 16 centers in Türkiye. Individuals were excluded if they recently consumed alcohol, had severe renal dysfunction, certain hormonal or mineral disorders, specific medications, or certain menopausal statuses. Bone mineral density (BMD) at the hip and lumbar spine was measured using dual-energy X-ray absorptiometry (DXA), and participants were classified as normal or having osteopenia or osteoporosis based on T-score thresholds. Results: Overall, 34.8% were male, and 65.2% were female. For the lumbar spine, 36.8% had osteopenia, and 13.5% had osteoporosis; similarly, for the total hip, 40.8% had osteopenia, and 7.9% had osteoporosis. ROC analysis identified a threshold of 3.9 mg/dL serum uric acid (SUA) (AUC 0.374; p < 0.001), which was positively associated with both lumbar and total hip BMD. Osteoporosis rates were higher in patients with SUA < 3.9 mg/dL compared to those with SUA ≥ 3.9 mg/dL at the lumbar spine (29.1% vs. 14.2%, p < 0.001) and total hip sites (23.6% vs. 15.9%, p = 0.003). After adjustment for potential confounders, SUA was a significant independent predictor of osteoporosis in the lumbar spine (OR 0.70; p < 0.001) and the hip (OR 0.80; p < 0.001). Conclusions: Serum uric acid levels are inversely linked to bone mineral density and osteoporosis risk, indicating a potential role in bone health. However, due to study limitations, causal relationships remain unproven, and further research is needed. Full article

Background: Beckwith–Wiedemann syndrome (BWS) is a rare congenital overgrowth disorder caused by genetic and epigenetic alterations on chromosome 11p15.5. While macroglossia, abdominal wall defects, and tumor predisposition are well recognized, hearing impairment has been sporadically reported. Objectives: The aim of this study is to review audiological features, surgical management, and rehabilitation in BWS, and we additionally present three cases with comprehensive longitudinal audiological follow-up. Methods: A systematic review of PubMed and Scopus was conducted according to PRISMA guidelines, including studies reporting audiological findings in patients with confirmed BWS. Studies without audiological data or reporting only normal-hearing patients were excluded. Data on hearing loss type, severity, genetics, clinical features, imaging, surgical interventions, and outcomes were extracted. A narrative synthesis was conducted; no meta-analysis was performed due to the heterogeneity and limited number of available studies. Data extraction was performed independently by two reviewers who independently screened titles, abstracts, and full texts, with disagreements resolved by discussion. In addition, three original case reports from our institution were included to further illustrate the clinical and rehabilitative variability of hearing impairment in BWS. Results: We identified 40 patients from the review, but only 12 of them reported audiological data (e.g., hearing thresholds, type of hearing loss, or diagnostic tests). Ossicular chain anomalies, particularly stapes fixation, were frequently observed. Surgical management improved hearing in selected cases, while bone conduction devices (BCD) or conventional amplification were effective alternatives when surgery was contraindicated. Genetic analyses revealed CDKN1C mutations or imprinting defects in nine patients. Conclusions: Hearing impairment in BWS is clinically relevant and often conductive, likely related to middle-ear anomalies. Early, multidisciplinary audiological evaluation—including imaging when indicated—and individualized rehabilitation can optimize auditory and communicative outcomes. The evidence is limited by the small number of studies and heterogeneous reporting of audiological outcomes. 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

Temporomandibular disorders (TMDs) are multifactorial conditions traditionally attributed to excessive mechanical loading on the temporomandibular joint, leading to clinical manifestations ranging from joint sounds to structural deformation. Contributing factors include trauma, occlusal abnormalities, psychological stress, and bruxism. However, immune and molecular alterations associated with early disease activity are not systematically integrated into structure-centered TMD frameworks. Emerging evidence indicates that temporomandibular joint osteoarthritis (TMJOA) involves activation of innate immunity caused by damage-associated molecular patterns (DAMPs) generated through mechanical loading, together with non-antigen-specific adaptive immune responses, including macrophage polarization and T helper 17 (Th17) and regulatory T (Treg) cell imbalance. Inflammatory and mechanical inputs converge through shared signaling modules and mechanoresponsive transcriptional programs, promoting extracellular matrix degradation, fibrotic remodeling, and subchondral bone remodeling. This review synthesizes the current immunopathological and mechanobiological evidence and introduces temporomandibular immunologic disease (TMID) as a mechanism-oriented framework, characterized by a reinforcing cycle between mechanically induced tissue damage and immune activation within the temporomandibular joint (TMJ) microenvironment. TMID complements TMJOA and Diagnostic Criteria for Temporomandibular Disorders (DC/TMD) structural diagnostic categories while excluding antigen-specific autoimmune arthritides such as rheumatoid arthritis, thus functioning as a mechanistic overlay framework for the integration of immuno-mechanical signaling networks in immune-active, mechanically driven TMJ pathology. Full article

Bone formation requires a substantial energy supply to sustain extracellular matrix production and mineralization, yet the temporal contribution of lipid metabolism during osteoblast maturation remains incompletely characterized. This study investigated the molecular and transcriptional remodeling of lipid metabolism. Intracellular lipid distribution was analyzed by confocal microscopy using Nile Red staining. Transcriptional modulation of lipid synthesis, storage, lipolysis, genes associated with mitochondrial fatty acid oxidation, and osteogenic markers were assessed by quantitative real-time PCR, and the biochemical composition was evaluated by Raman spectroscopy. Early stages of spheroid development showed higher expression of genes involved in lipid synthesis and storage (FASN, DGAT2, and PLIN2) together with intracellular lipid accumulation, whereas later stages displayed increased expression of lipolytic and β-oxidation markers (PNPLA2/ATGL, CPT1A, and HADHA), accompanied by the redistribution of lipid droplets. The Raman analysis revealed a time-dependent variation of lipid-associated CH₂/CH₃ bands and modulation of protein-related Amide I–III signals, consistent with biochemical remodeling during maturation. Overall, the data indicate a coordinated transcriptional shift from lipid accumulation-associated pathways toward lipid mobilization during osteogenic progression in a 3D culture. This model provides a controlled experimental platform for investigating metabolic regulation during bone formation and for studying metabolic alterations associated with skeletal disorders. Full article

Background: Work-related musculoskeletal disorders (WMSDs) are prevalent among orthopaedic surgeons as a result of prolonged exposure to non-neutral postures and forceful manual tasks during surgery. Although working height is a key determinant of trunk and upper-limb posture, the systematic evaluation of ergonomic working-height recommendations in orthopaedic surgery remains limited. Methods: A simulated left total knee arthroplasty (TKA) was divided into twelve critical surgical steps and analysed across four commonly used surgeon positions (A–D). Two conditions were compared: uncorrected working height (N) and working height corrected according to Canadian Centre for Occupational Health and Safety (CCOHS) recommendations (C). Joint angles were measured from standardized photographs using Kinovea software, and postural load was quantified with the Rapid Entire Body Assessment (REBA) method. Two trained evaluators conducted three independent assessments, yielding 288 REBA scores. Results: Mean REBA scores decreased across all surgeon positions following ergonomic correction, with statistically significant reductions observed in positions A, B, and D. When pooled across all position–step combinations (n = 48), the mean reduction was 0.92 REBA points (95% CI 0.50–1.33; p < 0.001). Notably, 27 of the 48 position–step comparisons exceeded the minimal detectable change threshold. The largest reductions occurred during force-intensive surgical steps, including bone cutting, drilling, and implant impaction. Conclusions: Adjusting working height in accordance with CCOHS ergonomic recommendations reduces surgeons’ postural load during TKA. These findings support the integration of evidence-based ergonomic adjustments into routine orthopaedic surgical practice. Full article

Background: Musculoskeletal disorders (MSDs) are a major contributor to global disability. Exercise-based rehabilitation is widely recommended as first-line management; however, in clinical practice, it is frequently combined with adjunct therapeutic modalities, and the incremental effectiveness of these approaches remains unclear. The present review addressed the research question: Do adjunct modalities provide additional benefits beyond exercise-based rehabilitation alone in individuals with musculoskeletal disorders? Methods: This systematic review was conducted according to PRISMA 2020 guidelines and prospectively registered in the PROSPERO database (registration number CRD420261309183). Electronic searches were performed in PubMed/MEDLINE, Scopus, Web of Science, and the Cochrane Central Register of Controlled Trials to identify controlled clinical trials evaluating exercise-based rehabilitation delivered alone or combined with adjunct modalities. Outcomes included pain, functional disability, physical performance, strength, structural or imaging-based measures, biomechanical variables, injury risk, and work-related outcomes. Due to methodological heterogeneity across studies, a structured narrative and tabular synthesis were performed. Results: Twenty-one controlled clinical trials were included, encompassing tendinopathies (n = 7), knee osteoarthritis (n = 5), post-ACL reconstruction (n = 2), chronic spinal pain (n = 3), sarcopenia (n = 2), low bone mass (n = 2), and occupational musculoskeletal conditions (n = 1), with sample sizes ranging from 22 to 823 participants. Pain outcomes were reported in 18 studies (86%) and functional outcomes in 16 studies (76%). Exercise-based rehabilitation consistently produced clinically meaningful improvements across studies, whereas adjunct modalities demonstrated short-term advantages in a limited number of trials but rarely showed sustained long-term superiority. Conclusions: Evidence from controlled clinical trials indicates that exercise-based rehabilitation is an effective primary intervention for improving pain, functional capacity, and physical performance across diverse musculoskeletal conditions. Adjunct modalities may provide condition-specific or short-term benefits but do not consistently enhance long-term outcomes beyond structured exercise programs. Full article

Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy, with most cases arising from B-cell precursors expressing the CD19 marker. CD19 negativity in B-lineage ALL (B-ALL) is very rare de novo and poses diagnostic and therapeutic challenges. Sometimes, de novo CD19-negative B-ALL is associated with hypercalcemia, which is a potentially life-threatening metabolic disorder in children, rarely occurring in cancers. Most often it is reported in solid tumors, and few cases are reported in pediatric acute leukemia. CD19-negative B-ALL relapse is also an increasing dramatic event, secondary to immunotherapy. We describe a ten-month-old infant presenting with hypercalcemia, anemia, and osteolytic bone lesions. Bone marrow analysis revealed CD10-positive and CD19-negative B-ALL. The patient achieved complete remission but later experienced two relapses and died of respiratory failure after a second allogeneic hematopoietic stem cell transplantation (HSCT). Only nine cases of de novo CD19-negative B-ALL have been reported so far. Many are associated with hypercalcemia and osteolytic lesions. However, here we highlight the clinical impact of the more common secondary form of CD19-negative B-ALL as a relapse of CD19-positive ALL, right after the administration of targeted immunotherapy. Full article

Background/Objectives: Hereditary alpha-tryptasemia (HαT) is increasingly recognized as a genetic modifier of mast cell-mediated disease severity and has been associated with heightened mediator-related symptoms and an elevated risk of anaphylaxis. This study aimed to describe the clinical characteristics, multisystem manifestations, and treatment responses of eight patients with HαT and concomitant mast cell disorders. Methods: In this single-center retrospective study, eight adults with confirmed TPSAB1 copy number gain and a diagnosis of systemic mastocytosis (SM), cutaneous mastocytosis (CM), or mast cell activation syndrome (MCAS) were evaluated. Baseline assessments included demographics, clinical history, basal serum tryptase (BST), TPSAB1 genotyping, KIT D816V testing, and bone marrow examination when indicated. Symptom burden was quantified at baseline and week 8 using the Mastocytosis Activity Score (MAS). All patients received mediator-targeted therapy; omalizumab was administered in selected high-risk cases. Results: Eight patients (62.5% male, mean age 53.9 ± 12.0 years) carried TPSAB1 duplication. The median BST was 16.2 ng/mL (range, 14.3–51.2). Severe anaphylaxis occurred in 75% of patients, predominantly drug-induced, while Hymenoptera venom triggered the remaining cases. Gastroesophageal reflux (87.5%), cutaneous symptoms (62.5%), neuropsychiatric features (62.5%), and autonomic dysfunction (37.5%) were common. The mean MAS decreased significantly from 27.25 ± 7.40 to 18.25 ± 6.48 after 8 weeks of high-dose antihistamines, with omalizumab providing marked additional benefit in selected patients. Conclusions: In this cohort, patients with HαT and coexisting mast cell disorders exhibited a high burden of mediator-related symptoms and a notable frequency of anaphylaxis. TPSAB1 genotyping may provide additional genetic information that aids in contextualizing clinical heterogeneity and mediator-related symptom burden in patients with mast cell disorders. Incorporation of HαT testing into routine evaluation may optimize individualized management. Full article

Musculoskeletal disorders and injuries are highly prevalent and encompass a broad range of conditions, including bone fractures and segmental defects, tendinopathies and tendon injury, and cartilage disorders such as osteoarthritis, cartilage defects, and intervertebral disc disease. These conditions can arise from diverse causes including trauma and injury, tumor resection, congenital abnormalities, and age-related degeneration. In the past decades, administration of chemically modified mRNA (cmRNA) encoding growth factors and transcriptional regulators has demonstrated effectiveness in repairing musculoskeletal tissues in preclinical studies. This review summarizes recent advancements in bone, tendon, cartilage, intervertebral disc, and muscle regeneration achieved through the localized delivery of protein-encoding mRNAs to express therapeutic target proteins. Delivery of cmRNA encoding growth factors such as BMP-2, BMP-9, VEGF, FGF-18, and IGF-1, or transcriptional regulators including Runx1, to various animal models has shown beneficial effects on bone, tendon, cartilage, and muscle injury repair in preclinical models. Alongside these progresses, the advantages and disadvantages of applying chemically modified mRNA for musculoskeletal tissue regeneration are also discussed. While studies show the promise of cmRNA for therapeutic applications in orthopedic tissue regeneration, more research is required to optimize growth factors and delivery methods, as well as validate long-term safety and efficacy prior to successful translation into new therapies to benefit patients. Full article

Background/Objectives: Osteoporosis is a systemic skeletal disorder characterized by reduced bone mass and microarchitectural deterioration, resulting in an increased risk of fragility fractures, particularly vertebral fractures. Genetic factors are considered important in osteoporotic fracture susceptibility, and polymorphisms of the vitamin D receptor (VDR) gene have been widely studied because of their role in bone metabolism. To evaluate the distribution of VDR gene polymorphisms (FokI, BsmI, ApaI, and TaqI) in patients with osteoporotic vertebral fractures and to assess their association with fracture susceptibility. Methods: This case–control study included 86 individuals: 43 patients who underwent vertebroplasty for osteoporotic vertebral fractures and 43 osteoporotic individuals without vertebral fractures serving as controls. VDR gene polymorphisms ApaI, TaqI, BsmI and FokI were analyzed using real-time polymerase chain reaction. Genotype distributions were compared using Fisher’s exact test, and Hardy–Weinberg equilibrium was evaluated. Results: A significant difference between groups was observed only for the ApaI polymorphism (p = 0.002). The GG genotype was more frequent in patients, whereas the variant genotypes (GT and TT) were more prevalent in controls. The GG genotype was associated with an increased risk of vertebral fractures, while the presence of variant genotypes may be associated with reduced fracture susceptibility. No significant associations were found for TaqI, BsmI, or FokI polymorphisms. Conclusions: The ApaI polymorphism of the VDR gene may represent a protective genetic factor against osteoporotic vertebral fractures. In contrast, no associations were identified for the TaqI, BsmI, or FokI polymorphisms in this cohort. Larger studies in diverse populations are required to confirm these findings and to clarify the role of VDR gene variants in fracture susceptibility. Full article

Background/Objectives: Osteoarthritis is a chronic joint disorder involving the progressive breakdown of articular cartilage, which leads to joint pain and impaired mobility. The present study investigated the effects of curcuminoids phospholipid (CP) on osteoarthritis progression, assessed its cartilage-protective effects, and elucidated the underlying mechanisms. Methods: Male Sprague–Dawley rats were randomly allocated to six experimental groups. One group received an intra-articular saline injection as the normal control (NC), while the remaining five groups were injected with monosodium iodoacetate (MIA) and consisted of an MIA control group (MC), a positive control group treated with celecoxib (PC, 3 mg/kg), and three groups treated with CP (31.25, 62.5, or 125 mg/kg). Results: Compared with the MC group, CP administration significantly improved pain-related behavior, as assessed by weight-bearing measurements. Micro-computed tomography and histological analyses demonstrated that CP administration mitigated subchondral bone erosion and preserved cartilage integrity. Additionally, the CP treatment significantly reduced markers associated with cartilage degradation, including matrix metalloproteinases and cartilage oligomeric matrix proteins; downregulated the expression of matrix-degrading enzymes; and restored aggrecan expression. Serum levels of inflammatory mediators, including nitric oxide; prostaglandin E₂; C-reactive protein; and pro-inflammatory cytokines, including interleukin (IL)-6, tumor necrosis factor (TNF)-α, and IL-1β, were reduced following CP administration. Furthermore, CP decreased the activation of nuclear factor kappa B (NF-κB) signaling. Conclusions: These findings suggest that CP may be a promising functional agent for osteoarthritis, demonstrating beneficial effects on pain-related outcomes and cartilage integrity, potentially mediated by its anti-inflammatory activity. Full article

Tooth development or odontogenesis is a complex morphogenetic process that requires tightly regulated interactions between the oral epithelium and mesenchyme of neural crest origin. In this narrative review, we compile existing knowledge regarding gene regulatory networks and epigenetic factors throughout tooth development from initiation to eruption. Signaling between the epithelium and mesenchyme is mediated by four conserved pathways—Wnt/β-catenin, bone morphogenetic protein (BMP), fibroblast growth factor (FGF), and Sonic hedgehog (Shh)—which operate iteratively and interact through extensive crosstalk at each developmental stage. Transcription factors, such as PAX9, MSX1, PITX2, and LEF1, interpret these signals to control cell fate decisions and differentiation. Epigenetic modifications, including DNA methylation, histone modifications, and microRNA-mediated regulation, provide additional layers of control that fine-tune gene expression programs. Unlike existing reviews that address these regulatory mechanisms separately, here we integrate signaling pathways, transcription factor networks, epigenetic regulation, human genetic disorders, dental stem cell biology, and recent single-cell transcriptomic insights into a unified framework. We discuss opportunities to apply developmental biology knowledge towards regenerative dentistry goals, including iPSC-derived dental models and spatially resolved multi-omics approaches, while acknowledging the considerable gap between preclinical findings and clinical applications. Full article

FAM3A, FAM3B, FAM3C and FAM3D are members of the “family with sequence similarity 3” (FAM3) gene family, an emerging class of cytokine-like proteins with a unique structural globular β-β-α fold and distinct biological functions. With widespread expression in tissue, organs and in many cell types, their specific roles in human diseases have been the focus of much research. FAM3A acts as a positive regulator of metabolic health, typically activating canonical pro-survival and metabolic pathways. FAM3B, also called PANDER (PANcreatic DERived Factor), exerts critical physiological functions in the regulation of glycemic levels via promotion of hepatic glucose production and pancreatic β-cell insulin secretion. FAM3C, also named ILEI (Interleukin-like EMT inducer), is involved as an inducer of epithelial–mesenchymal transition (EMT) and cancer metastasis, as well as osteoblast differentiation and bone mineralization. FAM3D is a gut-secreted protein and potential regulator of gastrointestinal homeostasis and microbiota-induced inflammation. Here we provide an overview of previous studies supporting that FAM3 proteins act through putative membrane receptors and co-partners, including fibroblast growth factor receptor (FGFR), leukemia inhibitory factor receptor (LIFR), formyl peptide receptor (FPR1/2), to activate diverse downstream signaling pathways on different cellular contexts. Basic and clinical studies suggest that the FAM3 family influences both obesity, diabetes, and other metabolic disorders; thus, its expression may have diagnostic potential. The differential and often cancer-specific expression patterns make members of the FAM3 family promising candidates for biomarkers and therapeutic targets of some types of neoplasia. Full article

The prevalence of osteoporosis, a skeletal disorder characterized by reduced bone mass, microarchitectural deterioration, and increased fracture risk, poses a substantial global healthcare burden. Although animal models and two-dimensional cell cultures have been used to advance bone research, they do not completely replicate the multicellular interactions, extracellular matrix organization, and biomechanical environment of human bone, limiting their translational relevance. This review provides a critical synthesis of recent advances in bone organoid technology, emphasizing biological complexity, technical innovation, and relevance to osteoporosis modeling. Beyond summarizing progress, we distinguish validated capabilities from aspirational claims and identify the methodological gaps that must be addressed before bone organoids can reliably support drug screening, regenerative medicine, and precision approaches. Advances in stem cell biology, tissue engineering, and three-dimensional culture systems have enabled the use of self-organizing, multicellular organoids that reproduce key physiological and pathological features of bone. These systems model estrogen-deficiency-induced bone loss, glucocorticoid-associated osteoporosis, aging-related degeneration, and genetic susceptibility. By integrating osteogenic and endothelial components within biomimetic matrices, bone organoids can support mechanistic studies and pharmacological testing. However, their incomplete vascularization, limited mechanical fidelity, instability, and lack of standardized benchmarks restrict their translational readiness. Overcoming these barriers requires technological refinement, quantitative metrics, and regulatory alignment. Full article