Search Results (160)

Multiple myeloma (MM) is an incurable hematological malignancy. SOX7, located within the recurrently deleted 8p23.1 region in MM, is suggested to act as a tumor suppressor. We characterized SOX7 through genetic, epigenetic, and functional analyses in MM cell lines. SOX7 was frequently silenced due to deletion and/or promoter hypermethylation. Ectopic SOX7 expression in KMS-18 and MM.1S cell lines caused a progressive decline in SOX7-transduced cells and induced G1 cell cycle arrest and/or apoptosis. Although SOX7 re-expression did not enhance bortezomib efficacy, treatment with the pan-histone deacetylase inhibitor panobinostat induced G1 arrest, promoted apoptosis, and increased SOX7 expression in MM.1S cells. Whole-transcriptome sequencing identified G1/S progression-related Wnt/β-catenin pathway genes as major SOX7-regulated targets, while ChIP-Seq analysis revealed widespread genomic SOX7 occupancy in MM.1S. Flow cytometric analysis of permeabilized bone marrow tumor cells from newly diagnosed and relapsed MM patients demonstrated generally low SOX7 protein expression. Collectively, these results indicate that SOX7 functions as a tumor suppressor in MM, and its inactivation promotes cell cycle progression. The anti-myeloma effects of panobinostat in MM.1S cells may be partially mediated through SOX7 induction. Full article

Attapulgite (ATP; palygorskite) is a fibrous magnesium aluminum silicate that can reinforce hydrated polymer networks, provide a surface for molecular interactions, and participate in formulation-dependent ion or drug delivery. Although ATP has been studied most extensively in bone-oriented composites, its more distinctive role in cartilage repair may be as a spatially controlled regulator of the scaffold microenvironment rather than as a uniformly distributed bioactive filler. This review therefore examines ATP from a cartilage-first perspective. Direct ATP evidence, effects of modified ATP, performance of complete drug-loaded formulations, and cross-material extrapolations are considered separately. Current cartilage data support injectability, shear-thinning, photocrosslinking, mechanical reinforcement, and sustained intra-articular delivery but do not yet establish durable hyaline cartilage regeneration. In osteochondral constructs, ATP is more plausibly restricted to the calcified-cartilage interface or subchondral region, where reinforcement and mineral-associated functions may be beneficial, while high or uniform cartilage-side loading could increase stiffness, hypertrophy, or ectopic mineralization. This interpretation leads to testable design rules: define the ATP material fingerprint, map dose and spatial distribution, distinguish the true carrier phase, and assess cartilage matrix quality, lubrication, anti-hypertrophic stability, interface mechanics, persistence, and synovial safety. ATP should thus be developed as a dose-controlled and spatially restricted component whose value depends on material–tissue matching and direct mechanistic validation. Full article

Solute Carrier Family 13 Member 5 (SLC13A5) encodes the sodium-dependent citrate cotransporter NaCT, which mediates citrate transport across cell membranes. Pathogenic variants in SLC13A5 cause developmental and epileptic encephalopathy 25 with amelogenesis imperfecta, DEE25; OMIM #615905, a debilitating autosomal recessive disorder. To better define the role of NaCT in ameloblast function and enamel mineralization, we used CRISPR/Cas9 genome editing to generate Slc13a5^R337* knock-in mice that terminate NaCT translation at the Arg337 codon, which is homologous to the human SLC13A5^R333* variant associated with DEE25. We compared enamel phenotypes among wild-type, Slc13a5^+/+; heterozygous, Slc13a5^+/R337*; and homozygous, Slc13a5^R337*/R337* mice using light microscopy, in situ hybridization, immunohistochemistry, backscattered scanning electron microscopy (bSEM); and focused ion beam–scanning electron microscopy (FIB-SEM) with quantitative imaging of organelles and matrix. Citrate bioassays were performed on serum, long bones, such as the femur and tibia, and developing mouse first molars, including enamel organ epithelium, mineralized tooth matrix, and pulp mesenchyme, to assess citrate levels during the presecretory, secretory, and maturation stages of enamel formation. In addition, first molars collected at postnatal days 0, 3, 5, and 12 were analyzed to characterize glycolytic and TCA cycle-related metabolic signatures. Homozygous Slc13a5^R337*/R337* mice exhibited severe defects during the secretory and maturation stages of amelogenesis. Most notably, Slc13a5^R337*/R337* ameloblasts failed to develop a Tomes’ process, detached from the enamel matrix surface, and produced a thin, poorly mineralized crust on the dentin surface rather than organized enamel ribbons. Despite the absence of normal enamel deposition, ameloblasts initially appeared viable and did not become dysplastic until the late secretory stage. Cellular and subcellular analyses revealed increased secondary lysosomes and intracellular accumulation of enamel matrix proteins, consistent with impaired matrix processing or secretion. Citrate concentrations were elevated in serum and long bones at both 7 and 35 weeks of age. Citrate was elevated in secretory-stage Slc13a5^R337*/R337* molars at days 0 and 3, the enamel organ epithelium (including ameloblasts), the pulp mesenchyme (including odontoblasts), and mineralizing dentin and enamel matrices. These levels gradually declined at day 5 and into the enamel maturation stage (day 12). GC-MS-based analysis of central carbon metabolites revealed increased intracellular accumulation of citrate, malate, and pyruvate, suggesting altered energy metabolism and reduced metabolic efficiency in Slc13a5^R337*/R337* mice. Together, these findings indicate that loss of NaCT function in the ameloblasts causes citrate accumulation, which impairs hydroxyapatite formation. Consequently, only a thin, structurally defective mineral crust forms on the dentin surface, while mineral nodules develop ectopically within the maturation-stage enamel organ epithelium. We conclude that regulating citrate concentration is essential for proper appositional growth of enamel. Full article

Osteosarcopenia—defined as the coexistence of sarcopenia and osteoporosis—is increasingly recognized as a clinically important geriatric syndrome associated with falls, fractures, frailty, disability, and mortality. Beyond the simple coexistence of bone and muscle loss, emerging data suggest that osteosarcopenia may reflect systemic dysregulation of the bone–muscle–immune–metabolic network. In this narrative review, we synthesize evidence linking inflammaging, immune-cell polarization, mitochondrial dysfunction, nutrient metabolic dyshomeostasis, and gut-derived metabolites to the pathogenesis of osteosarcopenia. Multiple pathological processes—including chronic low-grade inflammation, Th17/Treg imbalance, macrophage polarization, oxidative stress, impaired mitophagy, insulin resistance, ectopic fat accumulation, and altered microbial metabolites—may converge to disrupt bone–muscle crosstalk. Notably, direct evidence from osteosarcopenic populations remains limited, and many mechanistic insights are extrapolated from osteoporosis, sarcopenia, and aging models. We further discuss current and emerging therapeutic strategies, including exercise, nutritional interventions, anti-osteoporotic agents, metabolic modulators, mitochondrial-targeted therapies, and gut-directed approaches. Longitudinal cohorts, multi-omics studies, and randomized controlled trials are urgently required to validate immunometabolic biomarkers and develop integrated interventions for osteosarcopenia. Full article

The ubiquitin ligase protein tripartite-motif containing 56 (TRIM56) positively regulates Toll-like receptor-3 (TLR3) signaling by forming a complex with Toll-Interleukin-1 receptor domain-containing adapter protein inducing interferon (IFN)-beta (TRIF), independent of its E3 ligase activity. Whether TRIM56 modulates other TLR pathways in innate antiviral immunity, however, is unclear. Herein, we show ectopic expression of TRIM56 augments activation of IFN regulatory factor-3 (IRF3)-dependent promoters following stimulation by lipopolysaccharide (LPS) in HEK293-TLR4-MD2-CD14 cells while leaving activation of NF-κB-dependent promoter unaffected, suggesting TRIM56 specifically promotes immune signaling through the TLR4-TRIF axis but not the MYD88 arm downstream of this TLR. Confirming its impact on endogenous antiviral responses in immune sentinel cells naturally harboring the TLR4 pathway, we demonstrated enforced expression of TRIM56 enhanced LPS-induced expression of IFN-beta and IFN-stimulated genes (ISGs) and establishment of an antiviral state in bone marrow-derived macrophages. Importantly, depletion of endogenous TRIM56 impaired LPS-induced antiviral gene expression and cellular antiviral defense. Altogether, these data add to understanding of the role of TRIM56 in TLR-mediated innate immune responses. Given that TRIM56 is an ISG and that many immune adjuvants and some viral proteins activate TLR4, the findings of this study could have implications for designing immunotherapies, especially those against viral infections. Full article

We previously showed that TCEA1 deficiency in myeloid cells promotes proliferation, impairs differentiation and inhibits apoptosis, but its role and underlying mechanism in acute myeloid leukemia (AML) are unknown. Here, in NB-4 cells, an M3 subtype of AML, TCEA1 overexpression suppressed proliferation (p < 0.001), induced S-phase arrest (from 35.35% to 19.47%, p < 0.001), increased apoptosis (from 10.37% to 23.5%, p < 0.001), and promoted differentiation. Mechanistically, TCEA1 overexpression upregulated C/EBPε and IRF8 at the mRNA and protein levels; conversely, TCEA1 knockdown downregulated both. Rescue experiments in TCEA1 knockdown 32Dcl3 cells showed that ectopic C/EBPε or IRF8 reversed the uncontrolled proliferation, blocked apoptosis, and impaired differentiation. In xenograft mouse models, TCEA1 overexpression reduced leukemic infiltration in the bone marrow, spleen, and liver; extended overall survival; and elevated C/EBPε and IRF8 expression in vivo. Analysis of public APL datasets revealed that high TCEA1 expression is associated with a favorable prognosis (HR = 0.43, 95% CI: 0.2–0.93, logrank p = 0.028). Collectively, our findings demonstrate that TCEA1 suppresses proliferation, promotes apoptosis and differentiation, and attenuates disease progression by upregulating C/EBPε and IRF8, positioning this regulatory mechanism as a potential therapeutic target and prognostic biomarker for this disease. Full article

Background/Objectives: GLP-1-based obesity pharmacotherapy has shifted clinical attention from the magnitude of weight loss to the quality of weight loss. This review evaluates whether body composition changes during treatment with GLP-1-based agents represent clinically meaningful muscle loss and identifies nutrition, supplementation, exercise, and monitoring strategies that may help preserve lean mass, function, bone health, and nutritional adequacy. Methods: A comprehensive narrative review was performed using focused searches of PubMed, publisher-hosted journal platforms, and reference lists of key primary studies and recent evidence syntheses through March and May 2026. Evidence was organized around body composition, muscle quality and function, dietary protein and micronutrient adequacy, exercise, supplementation, bioelectrical impedance analysis, imaging, and emerging biomarkers. Results: Semaglutide and tirzepatide preferentially reduce fat mass, including visceral and ectopic adiposity, while producing smaller but consistent reductions in lean mass or lean soft tissue. However, DXA-derived lean mass and BIA-derived fat-free mass are not equivalent to skeletal muscle, and lean tissue loss does not necessarily indicate impaired strength or physical performance. The most defensible supportive care model combines food-first nutritional counseling, adequate protein intake, structured resistance exercise, management of gastrointestinal adverse effects, and risk-based monitoring of micronutrient inadequacy. Protein supplementation and nutritionally complete meal replacements may be useful when intake is insufficient, whereas creatine, essential amino acids or leucine, beta-hydroxy-beta-methylbutyrate, fiber, probiotics, omega-3 fatty acids, and multi-ingredient products remain adjunctive options supported mainly by indirect or phenotype-specific evidence. Conclusions: Future GLP-1 trials and clinical care should move beyond body weight and total lean mass toward integrated assessment of muscle quantity, muscle quality, function, bone, and nutritional adequacy, and standardized BIA-based clinical monitoring where advanced imaging is not feasible. Full article

Trauma-induced heterotopic ossification (tHO) is characterized by aberrant ectopic bone formation in soft tissue following high-energy trauma, affecting >60% of combat-related amputees and >50% of major burn patients. Current prophylactic strategies (including NSAIDs, bisphosphonates, and low-dose radiation) lack mechanistic specificity, carry significant side effects, and surgical excision carries a 27% recurrence rate. This review reframes tHO pathogenesis through the neural–immune axis, arguing that ectopic bone formation is a downstream consequence of dysregulated neuroimmune signaling rather than a primary osteogenic event. Following trauma, nociceptor activation drives nociception-induced neural inflammation (NINI), releasing substance P (SP) and calcitonin gene-related peptide (CGRP), which disrupts the blood–nerve barrier, mobilizes neural crest-derived progenitor cells, and, alongside BMP-2/SMAD1/5/8 signaling and M1-polarized macrophage activation, establishes a permissive osteogenic microenvironment. A BMP-2/CGRP positive feedback loop sustains aberrant osteogenesis, converging on osteogenic transcription factors Runx2, SOX5/6/9, and Osterix. Dysregulated noncoding RNAs represent promising pre-radiographic biomarkers. This neural–immune framework motivates mechanism-based therapeutic strategies targeting CGRP (fremanezumab, erenumab), SP/NK1 signaling (aprepitant), and macrophage polarization (metformin, palovarotene, rapamycin), with multi-node combination approaches tailored to the temporal stages of tHO offering the most promise for precision prophylaxis. Full article

Large bone defects resulting from trauma, tumor resection, infection, or degenerative diseases pose a major clinical challenge in orthopedic surgery and regenerative medicine. Despite advances in biomaterials and surgical techniques, successful outcomes are often compromised by poor vascularization, limited osteoinduction, and donor-site morbidity associated with autografts or allografts. However, conventional delivery systems suffer from burst release, rapid clearance, off-target effects, and supraphysiologic dosing, which can lead to undesirable complications such as ectopic ossification and inflammation, with some reports raising concerns about the long-term tumorigenic risk. Heparin, a naturally highly sulfated glycosaminoglycan structurally related to heparan sulfate, has emerged as a particularly attractive candidate for affinity-based biomaterial systems. It naturally binds over 300 growth factors, including bone morphogenetic proteins. By protecting these proteins from enzymatic degradation, enhancing their bioavailability, and mediating receptor clustering, heparin provides both biochemical stability and biofunctional modulation. This review provides a comprehensive overview of heparin-based delivery strategies in bone tissue engineering. We begin by describing the biological functions of heparin in modulating growth factor activity. We then discuss in detail the different heparin-based biomaterials designed to sustain the release of growth factors for bone tissue engineering, including the heparin–polycation coacervate system; heparin-based supramolecules; and heparin-based hydrogels, nanoparticles, and microspheres for sustained release of bone morphogenic proteins and other growth factors for bone tissue engineering. Finally, we assess the clinical and translational relevance of heparin-based systems, identify key challenges, and outline future perspectives, highlighting the potential of these biomaterials for providing safer and more effective therapies for bone regeneration. Full article

(1) Heterotopic ossification (HO) is a pathological process characterized by ectopic bone formation in soft tissues, often following trauma or neurological injury, and is associated with spasticity and chronic inflammation. Mesenchymal stem cells (MSCs) play a central role in HO by differentiating into osteoblasts through endochondral or intramembranous ossification, while alternative fates such as adipogenesis are suppressed. In this study, we investigated the effects of two commonly used antispastic drugs, baclofen and tizanidine, on MSC differentiation under adipogenic and inflammatory conditions in vitro. (2) Mouse C3H10T1/2 MSCs were cultured and induced toward adipogenesis in the presence of baclofen or tizanidine, and inflammatory stimuli (Interleukin-1β or lipopolysaccharides) were applied where indicated. Gene expressions of adipogenic and osteochondrogenic markers were assessed by RT-qPCR, while osteopontin protein levels were quantified by Simple Western. (3) Baclofen treatment significantly inhibited adipogenic gene expression and promoted osteochondrogenic markers and osteopontin protein under basal conditions, whereas tizanidine had minimal effects. Under inflammatory conditions, baclofen partially suppressed adipogenesis but did not strongly induce osteochondrogenesis. (4) These findings indicate that baclofen can directly modulate MSC fate, potentially contributing to HO risk, while tizanidine may offer a safer alternative for spasticity management in patients at risk of ectopic bone formation. Full article

During aging, bone marrow stromal (a.k.a. mesenchymal stem) cells (BMSCs) shift their lineage commitment away from osteogenesis and towards adipogenesis, resulting in bone loss and marrow fat accumulation. We previously reported that during osteogenesis, BMSCs activate mitochondrial oxidative phosphorylation (OXPHOS) at least in part by downregulating cyclophilin D (CypD) expression and, consequently, mitochondrial permeability transition pore (MPTP) activity. We also reported that in contrast, during adipogenesis, BMSCs upregulate CypD and MPTP, activate glycolysis and inhibit OXPHOS. To further study the role of CypD in BMSC bioenergetics, adipogenesis and bone marrow fat accumulation, we used CypD loss-of-function (LOF) or gain-of-function (GOF) models in osteo-adipoprogenitors in vitro and in vivo. We found that CypD LOF and GOF are associated with impaired and enhanced BMSC adipogenesis, respectively, both in vitro and in ectopic bone grafts in vivo. In addition, bioenergetic profiling and metabolomic analyses show evidence of corresponding metabolic reprogramming in CypD LOF and GOF cells. In summary, our study demonstrates the role of CypD-regulated mitochondrial metabolism during BMSC adipogenesis, facilitating the understanding of stem cell fate determination and the molecular mechanism of age-related bone loss as well as bone marrow fat accumulation. Full article

Background/Objectives: Cells derived from direct chemical reprogramming into osteoblasts represent a promising source for bone regeneration, but the efficiency needs improvement. Here, we systematically evaluated whether the natural compound psoralen (Psr) could enhance this process and explored its therapeutic potential and mechanism of action. Methods: Mouse embryonic fibroblasts (MEFs) were treated with a cocktail of forskolin and phenamil (FP), supplemented with Psr. In vitro differentiation was assessed by alkaline phosphatase and Alizarin Red S staining, reverse transcription quantitative PCR, immunofluorescence and Western blot. The bone-regenerative potential of the derived chemically induced osteoblast-like cells (ciOBs) was evaluated in critical-sized calvarial defects, femoral cortical defects and a subcutaneous ectopic implantation model, using micro-computed tomography and histology. Mechanistic insights of Psr were gained by analyzing the adenylyl cyclase 9 (ADCY9)/cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)/cAMP response element-binding protein (CREB) axis using inhibitor SQ22536. Results: Psr acted synergistically with the FP cocktail to drive efficient osteogenic reprogramming of MEFs. At an optimal concentration of 25 μM, Psr enabled the most robust induction of early osteogenic markers and generation of mature, mineralizing ciOBs in vitro. In vivo, FP + Psr-induced ciOBs repaired critical-sized calvarial and femoral cortical defects and generated substantial, vascularized bone tissue in ectopic sites. Mechanistically, Psr co-treatment potently activated the ADCY9/cAMP/PKA/CREB pathway, and pharmacological inhibition of this pathway completely abolished the pro-osteogenic effects of Psr. Conclusions: Psr acts as a potent synergistic enhancer of direct chemical reprogramming, generating functional osteoblast-like cells with robust bone-regenerative capacity via activation of the ADCY9/cAMP/PKA/CREB pathway. Full article

Background/Objectives: In humans, diseases such as oral cancer may require surgical amputation of the jaw. This severe disruption causes impairments in eating, swallowing, and speech, leading to a significant decline in quality of life. In contrast, newts, a group of urodele amphibians, can regenerate their jaws even in adulthood. This study explored how adult newts reconstruct lower jaws after substantial loss and clarified how this process contributes to rapid functional recovery when feeding becomes impossible. Methods: Adult Japanese fire-bellied newts (Cynops pyrrhogaster) underwent surgical amputation of the anterior half of their lower jaws. Regeneration was monitored for 64 weeks using histological analyses of bone, cartilage, and dental tissues and micro-computed tomography (micro-CT)-based osteomorphometry to quantify structural changes in the regenerating lower jaw. Results: Histological observations and osteomorphometry revealed the following: epithelial coverage of the amputation margin; ectopic cartilage formation, growth, and regression; bone resorption at the amputation margin prior to bone regeneration; anterior extension of the lower jaw bone along the original dentition position, followed by its thickening; and dental lamina invagination with tooth germ formation. Through these processes, the lower jaw bone, Meckel’s cartilage, and dentition were restored by 64 weeks post-amputation to their pre-amputation states. Conclusions: This study delineates the full sequence of lower jaw regeneration in adult newts, demonstrating complete restoration of bone, cartilage, and teeth after substantial lower jaw loss. These findings provide a detailed framework for understanding urodele jaw regeneration and may inform future strategies for promoting jaw reconstruction in humans. Full article

Background: Silicone chin implants have been widely used is plastic and esthetic surgery of the face being considered as safe and efficient way for chin augmentation. However, complications such as bone resorption, displacement or ectopic bone formation may occur. Methods: The objective of this study was to evaluate complications associated with silicone chin implants and revision surgery protocols. Results: Among 98 patients who received silicone chin implants, 24 (11 males, 13 females) exhibited complications. The most commonly diagnosed issues were displacement (n = 3), bone resorption (n = 9), both conditions (n = 3), and patient dissatisfaction (n = 7). All patients were qualified for revision surgery, which included silicone implant removal followed by sliding genioplasty (n = 7), orthognathic surgery (n = 4), custom-made chin implant placement (n = 7), and repositioning and fixation (n = 1). After revision surgery, no complications occurred. Conclusions: Observations from this revision cohort suggest that careful patient selection and consideration of orthognathic or customized implant-based approaches may reduce the risk of dissatisfaction and revision surgery in patients with dentofacial deformities, or those seeking gender confirmation surgeries, compared to stock silicone implants. Full article

Background: Delayed or non-union fractures comprise 5–10% of cases, indicating the need for biologic interventions. Recombinant human bone morphogenetic protein-2 (rhBMP-2) is a potent osteoinductive agent; yet, collagen carrier-based uncontrolled release causes adverse events. We evaluated the safety and efficacy of a hydroxyapatite (HA) carrier-based rhBMP-2 delivery system for acute traumatic upper and lower fractures exhibiting bone defects. Methods: This prospective, multicenter, single-arm clinical trial enrolled 90 patients who underwent surgery using a hydroxyapatite (HA) carrier-based rhBMP-2 delivery system (Novosis^TM). Radiographically validated union at 6 and 12 months post-surgery and treatment success (union without additional surgery) were used to assess efficacy. The incidence, type, and severity of all device-related adverse events during follow-up were monitored by investigators to evaluate safety. Results: Of the 90 patients enrolled, 81 were included in the full analysis set. The mean age was 58.5 years, and 18.6% (15/81) had open fractures. At 6 months post-surgery, radiographically validated union was achieved in 81.5% (66/81) of patients, increasing to 96.2% (77/81) at 12 months after surgery. Treatment success was 95.0% (76/81). Adverse events were rare (1/81, 1.2%). No ectopic ossification, systemic complications, or severe inflammatory responses were observed. Conclusions: HA-based rhBMP-2 intervention demonstrated favorable union rates and safety with minimal complications in acute upper and lower fractures with bone defects. The biocompatibility and controlled-release properties of HA likely improved efficacy and reduced complications. Results should be interpreted as feasibility data from a heterogeneous case series without a control group. Larger randomized controlled comparative trials are warranted for optimal dosing and evaluating efficacy and cost-effectiveness. Full article