Periodontal Ligament Stem Cells (PDLSCs) and Dental Pulp Stem Cells (DPSCs) are mesenchymal stem cells with the ability to self-renew and differentiate into three lineages. One significant advantage of dental stem cells, such as PDLSCs and DPSCs, is their ease of harvest compared to other types of mesenchymal stem cells (MSCs). While MSCs are highly valued in bone tissue engineering, MSCs sourced from dental tissues, such as PDLSCs and DPSCs, offer promising options for periodontal regeneration because they are more easily accessible and can be collected through minimally invasive methods. Currently, PDLSCs and DPSCs exhibit a strong ability to undergo osteogenic differentiation when stimulated by factors such as growth factors, chemicals, and paracrine signaling. It has been shown that aspirin (ASA) can enhance the osteoblastic potential of PDLSCs and DPSCs, although the exact mechanism remains unclear. This article examines the origin and features of mesenchymal stem cells, the bone regeneration potential of DPSCs and PDLSCs, the factors that enhance their osteogenic differentiation, and a comparison of PDLSCs and DPSCs regarding their proliferation and differentiation abilities. Additionally, we will examine the effects of aspirin on PDLSCs and DPSCs. In conclusion, PDLSCs show a greater effect on osteoblast differentiation.

Idiopathic pulmonary fibrosis (IPF), a progressive interstitial lung disease of unknown etiology, remains a therapeutic challenge with limited treatment options. This study investigates the therapeutic potential and molecular mechanisms of Tryptanthrin, a bioactive indole quinazoline alkaloid derived from Isatis tinctoria L., in pulmonary fibrosis. In a bleomycin-induced murine IPF model, Tryptanthrin administration (5 and 10 mg/kg/day for 28 days) significantly improved pulmonary function parameters and attenuated histological evidence of fibrosis. Mechanistic analysis revealed dual pathway modulation: Tryptanthrin suppressed MAPK/NF-κB signaling through inhibition of phosphorylation events, subsequently reducing pulmonary levels of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6). Concurrently, it attenuated TGF-β1/Smad pathway activation by decreasing TGF-β1 expression and Smad2/3 phosphorylation, thereby downregulating fibrotic markers including COL1A1, α-smooth muscle actin (α-SMA), and fibronectin in lung tissues. Complementary in vitro studies using Lipopolysaccharide (LPS) or TGF-β1-stimulated NIH3T3 fibroblasts confirmed these anti-inflammatory and anti-fibrotic effects through analogous pathway inhibition. Our findings demonstrate that Tryptanthrin exerts therapeutic effects against pulmonary fibrosis via coordinated modulation of both inflammatory (MAPK/NF-κB) and fibrotic (TGF-β1/Smad) signaling cascades, suggesting its potential as a novel multi-target therapeutic agent for IPF management.

Unraveling the intricacies of osteoblast differentiation is crucial for advancing our comprehension of bone biology. This study investigated the complicated molecular events orchestrating osteoblast differentiation in MC3T3-E1 cells, a well-established in vitro culture model. Employing longitudinal RNA-sequencing analysis, we explored transcriptomic changes at the pivotal time points of 0, 1, 4, 7, 10, 14, and 21 days and categorized osteogenic differentiation into proliferation, matrix maturation, and mineralization stages. Notably, we observed a simultaneous increase in matrix mineralization and cell proliferation during the mineralization stage, accompanied by a positive correlation between proliferation-associated genes and those enriched in ossification. Additionally, we identified the presence of proliferating cells over the mineralizing matrix layers. These results could serve as a model for understanding the principles by which bone lining cells are formed on the calcified bone matrix and the mechanism by which new osteoblasts are recruited during the bone remodeling process.

RNA binding Fox-1 homolog 2 (RBFOX2) is an RNA-binding protein that has been extensively studied in heart disease. Its downstream target, Jph2, has also been primarily investigated in relation to heart disease. However, their roles in osteoblast differentiation remain unexplored. This study aimed to investigate the regulatory role of RBFOX2 in osteoblast differentiation through its relationship with Jph2 in the MC3T3-E1 preosteoblast cell line.

The expression levels of RBFOX2, Jph2, and osteoblast differentiation markers (Dlx5 and Runx2) were analyzed using RT-PCR, qPCR, and Western blotting. Alkaline phosphatase (ALP) activity and extracellular matrix mineralization were evaluated using ALP and Alizarin Red S staining. Transient overexpression and siRNA-mediated knockdown were performed to assess the functional roles of RBFOX2 and Jph2 in osteoblast differentiation. Overexpression of RBFOX2 significantly increased Dlx5 and Runx2 expression at both mRNA and protein levels (p < 0.05) and enhanced mineralization in MC3T3-E1 cells. Conversely, knockdown of RBFOX2 or Jph2 resulted in decreased expression of these markers and reduced mineralization. Notably, RBFOX2 was found to upregulate Jph2, and this interaction promoted osteoblast differentiation via modulation of Dlx5 and Runx2.

These findings suggest that RBFOX2 regulates osteoblast differentiation through Jph2, making it a potential therapeutic target for bone diseases. Further studies are warranted to explore the detailed molecular mechanisms and clinical implications of this regulatory pathway.

Osteogenesis is the process of bone formation mediated by the osteoblasts, participating in various bone-related physiological processes including bone development, bone homeostasis and fracture healing. It exhibits temporal and spatial interconnectivity with angiogenesis, constructed by multiple forms of cell communication occurring between bone and vascular endothelial cells. Molecular regulation among different cell types is crucial for coordinating osteogenesis and angiogenesis to facilitate bone remodeling, fracture healing, and other bone-related processes. The transmission of signaling molecules and the activation of their corresponding signal pathways are indispensable for various forms of cell communication. This communication acts as a "bridge" in coupling osteogenesis to angiogenesis. This article reviews the modes and processes of cell communication in osteogenesis-angiogenesis coupling over the past decade, mainly focusing on interactions among bone-related cells and vascular endothelial cells to provide insights into the mechanism of cell communication of osteogenesis-angiogenesis coupling in different bone-related contexts. Moreover, clinical relevance and applications are also introduced in this review.

Bone defects have historically represented a significant challenge in clinical practice, with traditional surgical intervention remaining the gold standard for their management. However, due to the problem of the origin of autologous and allogeneic bone and the complex and diverse bone defects, traditional surgical methods sometimes cannot meet the treatment needs and expectations of patients. The development of bone tissue engineering and 3D printing technology provides new ideas for bone defect repair. Ideal bioscaffold materials must have good mechanical properties, biocompatibility, osteoinduction and bone conduction capabilities. Additionally, factors such as degradation rate, appropriate porosity and a sustained antibacterial effect must be taken into account. The combination of 3D printing technology and synthetic composite biomaterial scaffolds has become a well-established approach in the treatment of complex bone defects, offering innovative solutions for bone defect repair. The combined application of seed cells, signalling factors and biological scaffolds is also beneficial to improve the therapeutic effect of complex bone defects. This article will therefore examine some of the most commonly used 3D printing technologies for biological scaffolds and the most prevalent bioscaffold materials suitable for 3D printing. An analysis will be conducted on the mechanical and biological properties of these materials to elucidate their respective advantages and limitations.

High-quality repair of critical bone defects without exogenous cells remains a major clinical challenge worldwide. Herein, we fabricated a nanocomposite hydrogel scaffold (ASA/MSNs/CSH) by incorporating aspirin (ASA)-loaded mesoporous silica nanoparticles (MSNs) into genipin-cross-linked chitosan hydrochloride (CSH). The resulting scaffold was designed to provide immunomodulatory support during the process of bone regeneration. ASA-loaded MSNs were encapsulated in CSH, forming a composite hydrogel capable of sustained drug release for over 35 days. This composite hydrogel was able to meet key criteria for physicochemical properties, mechanical strength, biocompatibility, and cell affinity. The study showed that the scaffolds could create a beneficial immune microenvironment through reducing inflammation and inducing macrophages toward M2-polarized phenotype in vitro. The scaffold also enhanced the osteogenesis of bone marrow mesenchymal stromal cells, as demonstrated by enhancing the alkaline phosphatase activity and the formation of calcium nodules. Meanwhile, the TGF-β/Smad pathway was identified as an important regulatory mechanism via Western blot analysis. Moreover, the critical size defect models were established in rat skulls, and the results demonstrated that the ASA/MSNs/CSH nanocomposite scaffolds exhibited adequate biocompatibility, superior anti-inflammatory effect, and an admirable capacity for bone regeneration in vivo.

This study explores a series of twenty-four newly synthesized pyrzole-dihydropyrimidinone hybrids as potential bone anabolic agents. Initially, an alkaline phosphatase assay, a common marker of bone formation, was used to screen all compounds for their ability to stimulate osteogenic potential. Initial screening identified three promising candidates (5f, 5u and 5w) that were subsequently confirmed to be non-toxic to osteoblasts. Further investigation revealed that compound 5w displayed the most potent osteoanabolic effect, promoting osteoblast differentiation and upregulating mRNAs expression of osteogenic gene. Based on the promising in vitro and in vivo activity, structure-activity relationship (SAR) analysis revealed a furan ring on the dihydropyrimidinone unit and electron-donating groups on the N-phenyl ring of the pyrazole moiety to be crucial for osteogenic activity. Additionally, molecular docking, favorable pharmacokinetic properties and In silico ADME predictions suggest potential oral bioavailability. These findings establish the pyrazole-dihydropyrimidinone scaffold as a promising hit for developing a new class of orally active bone anabolic agents.

Patients with chronic kidney disease (CKD) frequently develop uremic cardiomyopathy, characterized by mitochondrial dysfunction as one of its pathologically significant mediators. Given that PM2.5 specifically targets cardiac mitochondria, exacerbating toxicity, this study addresses the potential alterations in the severity of PM2.5 toxicity in the context of CKD conditions. Female Wistar rats were exposed to PM2.5 at a concentration of 250 μg/m3 daily for 3 h for 21 days after which an adenine-induced CKD model was developed. While both PM2.5 exposure and the induction of CKD in rats lead to cardiomyopathy, the CKD animals exposed to PM2.5 exhibited a notably severe extent of myocardial hypertrophy and fibrosis. ECG recordings in CKD+ PM2.5 animals revealed a depressed ST segment and prolonged QRS interval, with both PM2.5 and CKD animals displaying an elevated ST segment. Subcellular level analysis confirmed a significantly low mitochondrial copy number and a severe decline in mitochondrial bioenergetic function in the CKD+ PM2.5 group. The prominent decline in PGC1-α further affirmed the severe mitochondrial functional deterioration in CKD+ PM2.5 animals compared to other experimental groups. Additionally, myocardial calcification was enhanced in CKD+ PM2.5 animals, heightening the susceptibility of CKD animals to PM2.5 toxicity. In summary, our findings suggest that the increased vulnerability of CKD myocardium to PM2.5-induced toxicity may be attributed to severe mitochondrial damage and increased calcification in the myocardium.

Type VII osteogenesis imperfecta (OI), caused by recessive CRTAP mutations, is predominantly lethal in the first year of life. Due to its early lethality, little is known about bone dysplasia mechanism. RNA-seq analysis of differentiated osteoblasts of siblings with a non-lethal homozygous CRTAP-null variant showed an enrichment of gene ontology terms involved in DNA replication and cell cycle compared to control. BrdU incorporation confirmed a ≈2-fold increase in proliferation in non-lethal proband osteoblasts in comparison to control cells. In addition, the expression of cyclin dependent kinase inhibitor 2A (CDKN2A), encoding a protein involved in cell cycle inhibition, was significantly reduced (>50%) in CRTAP-null osteoblasts, while cyclin B1 (CCNB1), encoding a promoter of the cell cycle, was enhanced. Ossification and bone and cartilage development gene ontology pathways were enriched among upregulated genes throughout osteoblast differentiation, as was protein secretion. Ingenuity pathway analysis indicated an upregulation of BMP2 signaling, supported by increase in both BMP2 and MSX2, an early BMP2-responsive gene, by qPCR. Throughout differentiation, CRTAP-null osteoblasts showed a decrease in transcripts related to cell adhesion and extracellular matrix organization pathways. We propose that increased proliferation and osteogenesis of type VII OI osteoblasts may be stimulated through upregulation of BMP2 signaling, altering bone homeostasis, and leading to weaker bones.

The evolutionary process of intermuscular bones (IBs) is complex, the molecular regulatory mechanisms of their development are not clear, and even the genes involved in the evolution and development of IBs are poorly understood. In this study, comparative genomic analysis of four fish species with IBs and eleven fish species without IBs identified 106 genes that are more conservatively evolved in fish species with IBs, but highly variable in fish species without IBs. These genes are mainly involved in swimming behavior and BMP signaling pathways. We performed single-cell transcriptome sequencing of IBs origin tissues in zebrafish before and after IBs formation and found that osteoblasts and mesenchymal stem cells (MSCs) increased significantly after IBs formation. RNA velocity analysis showed that osteoblasts in IBs differentiate from MSCs, and the differentiation trajectory of MSCs into osteoblasts was successfully constructed by pseudo-time analysis. Combined with the results of multi-omics analysis, seven candidate genes associated with IBs development were screened and knocked out in zebrafish. It was found that foxn3 mutation resulted in a delay in IB development, whereas bmp6 mutation resulted in a total loss of IB. By comparing the transcriptome of IBs tissues between bmp6+/+ zebrafish and bmp6-/- zebrafish, we found that bmp6 deletion may inhibit the differentiation of MSCs into osteoblasts while promoting the formation of osteoclasts and ultimately inhibiting the formation of IBs. This study provides new insights into the molecular regulatory mechanisms and evolutionary processes of IB development.

Bone healing is a complex process regulated by intricate biological and mechanical factors and spatially varied regions over time. This scoping review synthesizes current computational models that incorporate cytokines and growth factors, examining their role in bone healing. Through a systematic analysis of 71 studies, this review identifies and categorizes the modeling methodologies used, including mathematical, finite element, agent-based, mechanobiological, pharmacobiological, and hybrid approaches. The findings highlight the predominant use of mathematical models while noting a recent shift toward more sophisticated techniques like finite element and agent-based models. Key cytokines and growth factors, such as TGF-β, RANK-RANKL-OPG, and PTH, are repeatedly used, underscoring their essential roles in regulating cellular processes. This review also analyzes parameter selection and validation strategies, identifying gaps in current practices and emphasizing the need for high-quality experimental validation to improve model reliability. Some bibliometric analyses provide insights into citation networks and keyword co-occurrence, illustrating influential studies in the field and central themes. The findings offer a foundation for future research to enhance model accuracy, aiming toward more predictive and clinically relevant models accounting for biology and mechanics in bone healing.

Periodontal disease is a risk factor for many systemic diseases such as Alzheimer's disease and adverse pregnancy outcomes. Cleft palate (CP), the most common congenital craniofacial defect, has a multifaceted etiology influenced by complex genetic and environmental risk factors such as maternal bacterial or virus infection. A prior case-control study revealed a surprisingly strong association between maternal periodontal disease and CP in offspring. However, the precise relationship remains unclear. In this study, the relationship between maternal oral pathogen and CP in offspring was studied by sonicated P. gingivalis injected intravenously and orally into pregnant mice. We investigated an obvious increasing CP (12.5%) in sonicated P. gingivalis group which had inhibited osteogenesis in mesenchyme and blocked efferocytosis in epithelium. Then glycolysis and H4K12 lactylation (H4K12la) were detected to elevate in both mouse embryonic palatal mesenchyme (MEPM) cells and macrophages under P. gingivalis exposure which further promoted the transcription of metallopeptidase domain17 (ADAM17), subsequently mediated the shedding of transforming growth factor-beta receptor 1 (TGFBR1) in MEPM cells and mer tyrosine kinase (MerTK) in macrophages and resulted in the suppression of efferocytosis and osteogenesis in palate, eventually caused abnormalities in palate fusion and ossification. The abnormal efferocytosis also led to a predominance of M1 macrophages, which indirectly inhibited palatal osteogenesis via extracellular vesicles. Furthermore, pharmacological ADAM17 inhibition could ameliorate the abnormality of P. gingivalis-induced abnormal palate development. Therefore, our study extends the knowledge of how maternal oral pathogen affects fetal palate development and provides a novel perspective to understand the pathogenesis of CP.

Skeletal mesenchymal stem cells (MSCs) possess self-renewal capacities and play a leading role in the craniofacial system. However, their engagement in controlling cranial bone development and regeneration remains largely unidentified. Herein, we discovered the neurofibromin 2 (Nf2)-encoded regulator Merlin, demonstrating indispensableness in the craniofacial system. Mice lacking Nf2 in MSCs exhibit malformed cranial bones, diminished proliferation, increased apoptosis, and more severe osteogenesis impairment. Mechanically, we substantiate that Nf2 physically interacts with focal adhesion kinase (FAK) to preferentially mediate Erk1/2 and PI3K catalytic p110 subunit/Akt signaling. Meanwhile, Nf2-FAK disturbance in MSCs results in deficient migration, cytoskeletal organization and focal adhesion dynamics, and develops retarded regeneration of cranial bone defects. Collectively, our findings underscore an unrecognized scaffolding role for Nf2-FAK as upstream element in regulating PI3K/Akt and Erk1/2 action in osteoblasts, and illuminate its essentialness in coordinating cell migration, osteogenic lineage development, cranial bone ossification and regeneration.

Nowadays, custom-made subperiosteal implants are emerging as a solution in all those cases where there is lack of healthy bone tissue to support endosseous implants. The development of innovative techniques has allowed the production of grids that precisely match the patient's anatomy. Elucidating the impact of laser-melted Ti6Al4V grids on both hard and soft tissues with which they come into contact is, therefore, mandatory. In this study, we analyzed the effects of five different surface treatments on a human osteoblast-like cell line (MG-63). In particular, the cell proliferation and osteogenic response were evaluated. Taken together, our data demonstrate that in our in vitro setting, the new surface treatment developed by Al Ti color could enhance osteogenesis and improve the stabilization of the implant to the residual bone by stimulating the best osteogenic response in MG-63 cells. Although further studies are required to validate our data in an in vivo model, our results provide the basis for future advances in implantology for the long-term maintenance of osseointegration.

Osteoarthritis (OA) is a prevalent chronic degenerative joint disorder characterized by cartilage degeneration, joint inflammation, and pain. The pathogenesis of OA still remains unclear. Among the various factors contributing to OA, the role of extracellular matrix (ECM) proteins, particularly thrombospondins (TSPs), has garnered significant attention. TSPs, a family of multifunctional extracellular matrix glycoproteins, are known to participate in numerous physiological and pathological processes, including cell adhesion, migration, differentiation, angiogenesis, and synaptogenesis through cell-cell and cell-matrix interactions. In this review, we provide a summary of the current understanding of TSP proteins in the pathogenesis of OA, including their effects on cartilage homeostasis, synovial inflammation, and subchondral bone remodeling and arthritic pain. We also review the evidence supporting the potential of TSP proteins as diagnostic biomarkers and therapeutic targets, with a focus on recent advances in cartilage regeneration, gene delivery therapy and pain management. Considering the multifaceted roles of TSP proteins in maintaining articular homeostasis, TSP proteins emerge as promising therapeutic targets for OA.

Large bone defects caused by trauma, infection, tumor excision, and non-union fractures are challenging to treat. Mechanical stability, appropriate osteoconductive bone grafts, and osteoinductive growth factors are necessary for bone regeneration in long bone diaphyseal defects. This study aimed to investigate the efficiency of a hybrid bone scaffold formed using hydroxyapatite (HAp) and bone morphogenetic protein (BMP)-2-containing alginate beads, combined with a barrier membrane, in promoting new bone formation in a rabbit radial segmental defect model.

Nine rabbits were divided into two groups depending on the type of implant: Alginate beads containing HAp microparticles in phosphate-buffered saline (n=5) or BMP-2 (n=4). A 10-mm radial segmental defect was stabilized using a bone plate and screws, wrapped with an absorbable collagen membrane, and filled with alginate beads. Bone healing at the defect site was assessed via radiography, micro-computed tomography, and histological analysis after 12 weeks.

The BMP-2/HAp alginate bead group showed significantly increased bone volume, polar moment of inertia, and periosteal callus ossification, along with a decreased fibrous infiltration at the defect site. Conversely, the BMP-2-unloaded HAp bead group exhibited membrane degradation, with no hard callus formation at the defect site. Therefore, HAp- and BMP-2-encapsulating alginate beads provided sufficient osteoconductive and osteoinductive support for long bone defect repair.

BMP-2/HAp alginate beads, combined with an appropriate collagen membrane and proper internal fixation, may be an effective treatment strategy for long bone segmental defects.

This study aimed to decipher the temporal and spatial signaling code for clinical cartilage and bone regeneration. We investigated the effects of continuous equal dosages of a single, dual, or triplicate growth factor combination of bone morphogenetic protein (BMP)-2, transforming growth factor (TGF)-β3, and/or BMP-7 on muscle tissue over a culturing period. The hypothesis was that specific growth factor combinations at specific time points direct tissue transformation toward endochondral bone or cartilage formation.

The harvested muscle tissues from F-344 adult male rats were cultured in 96-well plates maintained in a specific medium and cultured at specific conditions. And the multidimensional and multi-time point analyses were performed at both the genetic and protein levels.

The results insinuate that the application of growth factor stimulates a chaotic tissue response that does not follow a chronological signaling cascade. Both osteogenic and chondrogenic genes showed upregulation after induction, a similar result was also observed in the semiquantitative analysis after immunohistochemical staining against different antigens.

The study showed that multiple TGF-β superfamily proteins applied to tissue stimulate developmental tissue processes that do not follow current tissue formation rules. The findings contribute to the understanding of the chronological order of signals and expression patterns needed to achieve chondrogenesis, articular chondrogenesis, or osteogenesis, which is crucial for the development of treatments that can regrow bone and articular cartilage clinically.

The skeletal system provides vital importance to support organ development and functions. The Notch signaling pathway possesses well-established functions in organ development and cellular homeostasis. The Notch signaling pathway comprises five typical ligands (JAG1, JAG2, DLL1, DLL3, and DLL4), four receptors (Notch1-4), and four intracellular domains (NICD1-4). Each component of the Notch signaling pathway has been demonstrated to be fundamental in osteoblast differentiation and bone formation. The dysregulation in the Notch signaling pathway is highly linked with skeletal disorders or diseases at the developmental and postnatal stages. Recent studies have highlighted the importance of the elements of the Notch signaling pathway in the skeletal system, as well as its interaction with signaling, such as Wnt/β-catenin, BMP, TGF-β, FGF, autophagy, and hedgehog (Hh) to construct a potential gene regulatory network to orchestrate osteogenesis and ossification. Our review has provided a comprehensive summary of the Notch signaling pathway in the skeletal system, as well as the insights targeting Notch signaling for innovative potential drug discovery targets or therapeutic interventions to treat bone disorders, such as osteoporosis and osteoarthritis. An in-depth molecular mechanistic strategy to modulate the Notch signaling pathway and its associated signaling pathway will be encouraged for consideration to trigger enhanced therapeutic approaches for bone disorders by defining Notch-regulating drugs for clinical use.

Zinc finger protein 687 (ZNF687), a transcription factor implicated in osteoblast/osteoclast differentiation and linked to Paget's disease of bone, has unclear mechanisms in bone metabolism. Epigenetic disruptions can affect bone cell activity and contribute to bone-related diseases. This work aimed to elucidate the regulatory role of epigenetics in modulating Zfp687 expression throughout osteoblast differentiation and bone growth/aging in mice. Differentiation of the mouse-derived osteoblast precursor cell line (MC3T3-E1) showed increased expression of osteogenic markers and decreased Zfp687 expression. In the hindlimb bones of C57BL/6J mice, the expression of most bone-forming genes decreased from youth to adulthood, while Zfp687 and Runx2 expression was maintained, being only significantly reduced in old mice in comparison to young mice. Bisulfite sequencing revealed hypomethylation of the Zfp687 promoter during MC3T3-E1 differentiation and bone growth/aging. Bioinformatics predicted miR-142a-3p, miR-122b-5p, and miR-124-3p binding sites in Zfp687 3'UTR, and RT-qPCR analysis showed higher expression of these miRNAs in mature osteoblasts. Transfection of a miR-142-3p mimic reduced luciferase activity in the wildtype Zfp687 3'UTR but not the mutant 3'UTR and downregulated the Zfp687 gene and protein levels. In conclusion, miR-142a-3p directly targets the Zfp687 3'UTR, promoting its downregulation during osteoblastogenesis. Furthermore, DNA methylation does not appear to regulate Zfp687 during osteoblast differentiation or bone development in mice.

HRAS is a ubiquitously expressed protein and functions as a central regulator of cellular homeostasis. In somatic cells, mutations in this gene cause cancer, while germline mutations trigger a developmental disorder known as Costello syndrome (CS). Among numerous pathologies, adult CS patients develop osteoporosis. Previous studies revealed that HRAS is implicated in bone homeostasis by controlling osteoblast differentiation, adaptation to mechanical strain and repression of RANKL expression in mature osteoblasts, and by regulating osteoclast differentiation. However, the impact of HRAS on osteoblast differentiation is still debatable. In this study, we created stable doxycycline inducible cell lines overexpressing HRAS G12 mutants in MC3T3-E1 preosteoblast cell line and analyzed their impact on osteoblast differentiation. We demonstrated an inhibitory role of HRAS G12S and HRAS G12V mutants on osteogenic differentiation and identified an increased expression of Opn in an HRAS-dependent manner, which directly correlated with impaired osteogenesis, and was rescued by the farnesyl transferase inhibitor Tipifarnib. At the molecular level, Tipifarnib was not able to block HRAS activation, but impaired HRAS localization to the plasma membrane, and inhibited MAPK activation and Opn expression. Thus, HRAS abundance/activation and its potential crosstalk with OPN may be more critical for osteogenic differentiation than previously assumed.

Aims: Osteoarthritis (OA) represents the prevailing form of degenerative joint pathology. Recent investigations have revealed a heightened expression of interleukin 26 (IL-26) in various inflammatory arthritic conditions, including OA. However, the specific impacts and functions of IL-26 on osteoblasts (OBs) within the context of OA remain inadequately elucidated. This study aims to clarify the effects and underlying mechanisms of IL-26 by examining its influence on osteoblasts isolated from OA patients and a murine osteoblast cell line. Methods: Human primary osteoblasts and mouse pre-osteoblast cells were subjected to treatment with β-glycerophosphate or concurrent treatment with IL-26 to observe the effects on osteoblast differentiation. The differentiation of osteoblasts was assessed through the expression of relevant genes using reverse transcription-polymerase chain reaction (RT-PCR). Key molecular mechanisms of downstream signaling pathways were examined through immunoblotting assays. Results: Our results reveal that IL-26 mitigates osteoblast differentiation and reduces the expression of the marker alkaline phosphatase. Furthermore, the NF-κB downstream OB proliferated marker iNOS and inhibition OB differentiated marker LCN2 messenger RNA are up-regulated in IL-26 treated group. Also, phosphorylation and nuclear translocation of NF-κB p65 occur following IL-26 stimulation. Additionally, IL-26 enhances the downstream transcription factor cyclooxygenase-2 (COX2), a major player associated with iNOS. STAT1, the canonical receptor signaling pathway of IL-26 is activated. Conclusion: In summary, our findings substantiate the role of IL-26 in osteoarthritis and identify it as a potential therapeutic target for intervention in osteoarthritic pathology.

This study presents the development of an innovative injectable bioactive material, BG-ETa, for bone regeneration. Porcine-derived dermal extracellular matrix (dECM) was decellularized and combined with beta-tri calcium phosphate (β-TCP) and porous bio-glass (BG) beads, followed by freeze-drying to produce surface-modified BG beads. Incorporating sodium alginate (SA) enhanced injectability of the system, enabling effective delivery to defect sites. Bio-glass promotes osteogenic support and osteogenesis. dECM, rich in essential proteins and growth factors, mimics the bone microenvironment to improve cell adhesion, proliferation, and differentiation. The bioactive dECM/β-TCP coating on the bead surface offers neovascularization and early mineralization properties which ultimately facilitates new bone formation. In vitro assays demonstrated BG-ETa's biocompatibility, antimicrobial properties, and potential for osteogenic differentiation, with significant results in alkaline phosphatase (ALP) activity, alizarin red staining (ARS), immunocytochemistry (ICC), and gene expression through real-time PCR. In vivo implantation in rabbit femoral defects revealed promising degradation and significant bone regeneration after 4 and 8 weeks, as observed by histological analysis and micro-CT imaging. This injectable BG-ETa system holds promise as an effective alternative to traditional grafts, providing bioactive environment for enhanced bone regeneration with the potential to overcome limitations associated with autologous or allogeneic grafting.

The regeneration of bone tissue is a critical challenge in oral and maxillofacial surgery, with the success of such procedures often depending on the ability to promote osteogenesis while managing the soft tissue environment. The role of gingival fibroblasts in modulating the osteogenic potential of mandible mesenchymal stem cells (MMSCs) mediated by bone substitute materials (BSMs) is not fully understood. This study aimed to investigate the impact of gingival fibroblasts on the osteogenic differentiation of MSCs in the presence of BSMs and to elucidate the underlying mechanisms, focusing on the WNT/β-catenin signaling pathway.

Gingival fibroblasts and BSMs co-culture conditioned medium was used to culture MMSCs, and the expression and activity of alkaline phosphatase (ALP), as well as osteogenic and fibrogenic gene and protein expression, were evaluated. Additionally, the expression of key factors of WNT/β-catenin signaling pathway were investigated. In vivo animal experiments were conducted to assess the effect of gingival fibroblasts on BSM-mediated bone regeneration.

Gingival fibroblasts and BSMs co-culture environment did not affect MMSCs proliferation but significantly inhibited ALP expression and activity, as well as osteogenic gene and protein expression, while promoting expression of fibrogenic markers. This suppression was associated with the downregulation of key factors in the WNT/β-catenin signaling pathway. In vivo, increased suppression of bone defect repair was observed with higher amounts of gingival fibroblasts, confirming the in vitro findings.

Our study demonstrates that gingival fibroblasts can suppress the osteogenic potential of BSMs by inhibiting the autocrine WNT expression and the activation of the WNT/β-catenin signaling pathway in MMSCs. These findings highlight the importance of considering the cellular microenvironment in tissue engineering and regenerative medicine and suggest potential targets for modulating MMSCs behavior to enhance bone regeneration.

Hemifacial microsomia (HFM) is a rare congenital craniofacial deformity that significantly impacts the appearance and hearing. The genetic etiology of HFM remains largely unknown, although genetic factors are considered to be primary contributors. We previously identified CTDSP2 as a potential causative gene in HFM cases. Utilizing CRISPR/Cas9, we knocked out ctdsp2 in zebrafish and analyzed the spatiotemporal expression of ctdsp2 and neural crest cell (NCC) markers through in situ hybridization (ISH). Craniofacial cartilage and chondrocyte phenotypes were visualized using Alcian blue and wheat germ agglutinin (WGA) staining. Cell proliferation and apoptosis were assessed via immunofluorescence with PH3 and TUNEL. RNA sequencing was performed on ctdsp2-/- embryos and control siblings, followed by rescue experiments. Knockout of ctdsp2 in zebrafish resulted in craniofacial defects characteristic of HFM. We observed abnormalities in NCC apoptosis and proliferation in the pharyngeal arches, as well as impaired differentiation of chondrocytes in ctdsp2-/- embryos. RNA-Seq analysis revealed significantly higher expression of genes in the p53 signaling pathway in mutants. Furthermore, ctdsp2 mRNA injection and tp53 knockout significantly rescued pharyngeal arch cartilage dysplasia. Our findings suggest that ctdsp2 knockout induces zebrafish craniofacial dysplasia, primarily by disrupting pharyngeal chondrocyte differentiation and inhibiting NCC proliferation through p53 signaling pathway activation.

Prevalence of osteoarthritis has been increasing in aging populations, which has necessitated the use of advanced biomedical treatments. These involve grafts or delivering drug molecules entrapped in scaffolds. However, such treatments often show suboptimal therapeutic effects due to poor half-life and off-target effects of drug molecules. As a countermeasure, a 3D printable robust hydrogel-based tissue-repair platform is developed containing decellularized extracellular matrix (dECM) from differentiated mammalian cells as the therapeutic cargo. Here, pre-osteoblastic and pre-chondrogenic murine cells are differentiated in vitro, decellularized, and incorporated into methacrylated gelatin (GelMA) solutions to form osteogenic (GelO) and chondrogenic (GelC) hydrogels, respectively. Integrating the bioactive dECM from differentiated cell sources allows GelO and GelC to induce differentiation in human adipose-derived stem cells (hASCs) toward osteogenic and chondrogenic lineages. Further, GelO and GelC can be covalently adhered using a carbodiimide coupling reaction, forming a multi-layered hydrogel with potential application as a bioactive osteochondral plug. The designed multi-layered hydrogel can also induce differentiation of hASCs in vitro. In conclusion, the bioactive dECM carrying 3D printed robust hydrogel offers a promising new drug and cell-free therapeutic strategy for bone and cartilage repair and future osteoarthritis management.

This research is intended to evaluate the correlations of serum IL-6 and TGF-β1 concentrations with bone density and turnover markers as well as their diagnostic value in elderly male patients with osteoporosis (OP).

A retrospective analysis was conducted on 335 elderly men (≥ 60 years; 90 with normal bone mass, 120 osteopenia cases, and 125 OP cases). Lumbar spine/femoral neck BMD values were measured using dual-energy X-ray absorptiometry. Correlations of serum IL-6 and TGF-β1 concentrations with bone density and bone turnover markers in OP patients were analyzed utilizing Pearson or Spearman correlation coefficients. Independent influencing factors for OP were identified by logistic multivariate regression analysis. The diagnostic value of serum IL-6 and TGF-β1 was assessed with ROC curves and MedCalc software.

Smoking history, drinking history, lumbar spine BMD, femoral neck BMD, PINP, and β-CTX markedly differed among the normal bone mass, osteopenia, and OP groups. Elevated IL-6 and reduced TGF-β1 concentrations were observed in serum samples of OP. Serum IL-6 concentrations was inversely associated with bone density markers but positively lined to bone turnover markers. Conversely, serum TGF-β1 was positively related to bone density markers but negatively associated with bone turnover markers. Smoking history, PINP, and IL-6, were identified as independent risk factors while lumbar spine BMD, femoral neck BMD, and TGF-β1 were independent protective markers for OP. The combined assessment of serum IL-6 and TGF-β1 showed superior diagnostic performance for OP.

Serum IL-6 in combination with TGF-β1 exhibits good diagnostic performance for OP.

Diagnostic: individual cross-sectional studies with consistently applied reference standard and blinding.

Due to the contradictory and temporally variable effects of transforming growth factor-β (TGF-β) and the Wnt/β-catenin pathways on osteogenic differentiation in different stem cell types, we sought to examine the activity of these pathways as well as their interaction during the osteogenic differentiation of the osteo-induced adiposederived mesenchymal stem cells (AD-MSCs).

The osteo-induced AD-MSCs were treated with TGF-β1 (1 ng/mL) either alone or together with its antagonist SB- 431542 (10 μM) or that of the Wnt antagonist, inhibitor of Wnt production 2 (IWP2) (3 μM), every 3 days for 21 days. Cells were then analyzed for calcium deposit, bone matrix production, and the osteogenic markers gene expression.

Our results showed firstly that, either of the pathways is active since the mRNA expressions of their respective target genes, PAI-1 and Cyclin D1 were detectable although the latter was at a very low level. Secondly that, treatment with TGF-β1 decreased levels of calcium deposit, bone matrix production and the osteogenic markers gene expression. Accordingly, osteogenesis was induced in those treated with SB either alone or together with the TGF-β1, pointing to inhibitory effect of TGF-β pathway on osteogenic differentiation. Thirdly that following treatment with IWP2 and TGF-β1, the inhibitory effect of TGF-β1 on bone matrix production was reversed. Fourthly, there was constantly low expression of Wnt3amRNA but progressively increasing that of its endogenous antagonist Dkk-1mRNA throughout.

Together these results suggest that TGF-β1 requires the active Wnt/β-catenin signaling pathway to exert its inhibitory effects on osteogenic differentiation of AD-MSCs.

Echolocation represents one of the most rapid adaptive sensorimotor modulation behaviors observed in mammals, establishing bats as one of the most evolutionarily successful mammals. Bats rely on high-frequency hearing for survival, but our understanding of its cellular molecular basis is scattered and segmented. Herein, we constructed the first single-cell transcriptomic landscape of the cochlea in Hipposideros armiger, a CF-FM bat, using a PacBio-optimized genome and compared it with the results obtained from unoptimized original genomes. Sixteen distinct cell types were distributed across five spatial regions of the cochlea. Notably, through hematoxylin and eosin staining and fluorescence in situ hybridization, we identified new types of spiral ganglion neuron (SGN) cells in the cochlea of H. armiger. These SGN cells are likely critical for auditory perception and may have driven the adaptive evolution of high-frequency hearing in this species. Furthermore, we uncovered the differentiation relationships of among specific cell types, such as the transition from supporting cells to hair cells. Using the cochlear cell atlas as a reference, cell types susceptible to deafness-associated genes (in the human) were also identified. In summary, this study provides novel insights into the cellular and molecular mechanisms underlying the adaptive high-frequency hearing in bats and highlights potential candidate cell types and genes for therapeutic interventions in hearing loss.

Ferroptosis is a type of non-apoptotic regulated cell death characterized by iron accumulation and lipid peroxidation. Cisplatin is an effective chemotherapy drug with several serious side effects including acute kidney injury (AKI). Asprosin is a peptide contributing to metabolism regulation and metabolic disorders. This study aimed to determine the role and mechanism of asprosin in AKI. Cisplatin was used to induce cell damage in mouse renal tubular epithelial (TCMK-1) cells and AKI in C57BL/6 mice. Cisplatin caused asprosin upregulation in cisplatin-treated TCMK-1 cells and mice. In TCMK-1 cells, asprosin overexpression led to iron overload and lipid peroxidation, while asprosin knockdown attenuated cisplatin-induced iron overload, lipid peroxidation and ferroptosis. Exogenous asprosin promoted cell damage and ferroptosis, which were attenuated by ferroptosis inhibitors. Asprosin-induced iron overload, lipid peroxidation, cell damage and SMAD1/5/8 phosphorylation were prevented by bone morphogenetic protein (BMP) type I receptor inhibitor. Integrin antagonist prevented asprosin-induced SMAD1/5/8 phosphorylation, and asprosin can specifically bind to integrin β3. Inhibition of integrin β3 reduced the asprosin-induced increases in Fe2+ and MDA levels. Asprosin knockdown relieved cisplatin-induced hepcidin upregulation, while hepcidin knockdown attenuated asprosin-induced iron overload, lipid peroxidation and ferroptosis. In cisplatin-induced AKI mice, specific knockdown of asprosin in the kidney not only attenuated renal dysfunction and damage, but also alleviated iron overload, lipid peroxidation and ferroptosis. These results indicated that excessively increased asprosin promotes TCMK-1 cells ferroptosis and damage via integrin β3/BMP/hepcidin-mediated iron overload and lipid peroxidation. Silencing of asprosin attenuates renal injury and dysfunction in cisplatin-induced AKI by inhibiting ferroptosis.

Mesenchymal stem cell (MSC)-based bone tissue regeneration has gained significant attention due to the excellent differentiation capacity and immunomodulatory activity of MSCs. Enhancing osteogenesis regulation is crucial for improving the therapeutic efficacy of MSC-based regeneration. By utilizing the regenerative capacity of bone ECM and the functionality of nanoparticles, we recently engineered bone-based nanoparticles (BNPs) from decellularized porcine bones. The effects of internalization of BNPs on MSC viability, proliferation, and osteogenic differentiation were first investigated and compared at different time points. The phenotypic behaviors, including cell number, proliferation, and differentiation were characterized and compared. By incorporating a LNA/DNA nanobiosensor and MSC live cell imaging, we monitored and compared Notch ligand delta-like 4 (Dll4) expression dynamics in the cytoplasm and nucleus during osteogenic differentiation. Pharmacological interventions are used to inhibit Notch signaling to examine the mechanisms involved. The results suggest that Notch inhibition mediates the osteogenic process, with reduced expression of early and late stage differentiation markers (ALP and calcium mineralization). The internalization of BNPs led to an increase in Dll4 expression, exhibiting a time-dependent pattern that aligned with enhanced cell proliferation and differentiation. Our findings indicate that the observed changes in BNP-treated cells during osteogenic differentiation could be associated with elevated levels of Dll4 mRNA expression. In summary, this study provides new insights into MSC osteogenic differentiation and the molecular mechanisms through which BNPs stimulate this process. The results indicate that BNPs influence osteogenesis by modulating Notch ligand Dll4 expression, demonstrating a potential link between Notch signaling and the proteins present in BNPs.

Nucleic acid-based therapeutics represent a revolutionary approach in treating genetic disorders, offering unprecedented potential for addressing pathologies at their molecular level. However, effective cellular delivery remains a critical challenge hindering their clinical implementation. While existing delivery systems, including viral vectors and lipid nanoparticles, have shown utility, they face limitations in immunogenicity, cargo capacity, and manufacturing complexity. Natural protein-based nanoparticles, derived from proteins such as albumin, ferritin, and elastin, have emerged as promising alternative delivery systems. These carriers offer distinct advantages including reduced immunogenicity, enhanced biocompatibility, and optimal biodegradation profiles. Their engineerable nature enables precise control over particle size, surface charge, and ligand conjugation, facilitating selective cellular targeting and improved pharmacokinetics. Recent technological advances have expanded the application of protein nanoparticles across various nucleic acid modalities, including mRNA, siRNA, and plasmid DNA. Extensive research has characterized these systems through rigorous in vitro and in vivo studies, advancing our understanding of their biological behavior and clinical potential. Advanced engineering methodologies have further enhanced their optimization for specific therapeutic applications. This review examines the development and potential of protein-based nanoparticles in nucleic acid delivery, highlighting their advantages and addressing current challenges. By analyzing recent advances and clinical progress, we underscore their significant potential to enhance the safety, specificity, and efficacy of nucleic acid therapeutics, potentially revolutionizing the treatment of genetic disorders.

Bronchial asthma (asthma) is a respiratory disease characterized by chronic inflammation, airway hyperresponsiveness, and airway remodeling. Numerous studies have delved into asthma's pathogenesis, among which epithelial mesenchymal transition (EMT) is considered one of the important mechanisms in the pathogenesis of asthma. EMT refers to the transformation of epithelial cells, which lose their original features and acquire a migratory and invasive stromal phenotype. EMT contributes to normal physiological functions like growth, development, and wound healing. However, EMT is also involved in the occurrence and development of many diseases. Currently, the precise regulatory mechanism linking EMT and asthma remain obscure. Increasing evidence suggests that airway EMT contributes to asthma pathogenesis via dysregulation of associated control mechanisms. This review explores EMT's significance in asthma and the regulatory networks associated with EMT in this context.

Treating the surfaces of dental implants in an alkaline medium allows us to obtain microstructures of sodium titanate crystals that favor the appearance of apatite in the physiological environment, producing osteoconductive surfaces. In this research, 385 discs made of titanium used in dental implants underwent different NaOH treatments with a 6M concentration at 600 °C and cooling rates of 20, 50, 75, and 115 °C/h. Using high-resolution electron microscopy, the microstructures were observed, and the different crystal sizes were determined and compared with control samples (those without biomimetic treatment). Roughness, wettability, surface energy and the sodium content of the surface were determined. The different surfaces were cultured with human osteoblastic cells; cell adhesion was determined at 3 and 14 days, and the degree of mineralization was determined at 14 days via alkaline phosphatase levels. Variations in the microstructure and size of sodium titanate crystals in NaOH solutions rich (1 g/L) or low in calcium (approximately 100 ppm) were determined. The results show that as the cooling rate increases, the size of the crystals decreases (from 0.4 μm to 0.8 μm) except for the case of 115 °C/h, when the rate is too fast for crystalline nucleation to occur on the surface of the titanium. The thermochemical treatment does not influence the roughness or the cooling rate since a Sa of 0.21 μm is maintained. However, the presence of titanate causes a decrease in the contact angle from 70° to 42° and, in turn, causes an increase in the total surface energy from 35 to 49.5 mJ/m2, with the polar component standing out in this energy increase. No variations were observed in the thermochemical treatments in the presence of sodium, which was around 1200 ppm. It was observed that as the size of the crystals decreases, cell adhesion increases at 3 days and decreases at 14 days. This is because finer crystals on the surface are already in the mineralization process, as demonstrated using the level of alkaline phosphatase that is maximal for the cooling rate of 75 °C/h. It was possible to confirm that the variations in the concentrated NaOH solutions with different calcium contents did not affect the crystal sizes or the microstructure of the surface. This research makes it possible to obtain dental implants with different mineralization speeds depending on the cooling rate applied.

Osseointegration is essential for successful implant treatment. However, the underlying molecular mechanisms remain unclear. In this study, we focused on decorin (DCN), which was hypothesized to be present in the proteoglycan (PG) layer at the interface between bone and the titanium oxide (TiOx) surface. We utilized DCN RNA interference in human bone marrow mesenchymal stem cells (hBMSCs) to investigate its effects on PG layer formation, proliferation, initial adhesion, cell extension, osteogenic capacity, fibrotic markers, and immunotolerance to TiOx in vitro. After 14 days of cultivation, we observed no PG layer was detected, and the osteogenic capacity was suppressed in DCN-depleted hBMSCs. Furthermore, the conditioned medium upregulated the expression of M1 macrophage markers in human macrophages. These results suggest that endogenous DCN plays a crucial role in PG layer formation and that the PG layer alters inflammation around Ti materials.

Bone defects are becoming a true challenge in global health care due to the aging population and higher prevalence of musculoskeletal disorders. The interest in using plant-origin compounds and plant-derived biomaterials in bone tissue engineering (BTE) has been increased due to their availability (abundance), safety, biocompatibility, biodegradability, and low cost. Plant-origin compounds have supportive effects on bone tissue healing, and cell-laden plant-derived biomaterials can be applied in formulating bioinks for three-dimensional (3D) bioprinting to facilitate the preparation of native bone tissue-mimicking structures and customized bone scaffolds. Such plant-derived materials also have the capacity to improve cell viability and support osteoconductive and osteoinductive properties of a bone construct. In this article, we review the ethnomedical aspects related to the use of medicinal plants and plant-origin bioactive compounds in bone healing and the recent developments in the 3D bioprinting of bone constructs with plant-derived biomaterials for advancing BTE. The commonly used 3D-bioprinting techniques, the properties of plant-origin compounds and biomaterials (for bone 3D bioprinting), and the selective examples of bone scaffolds fabricated using plant-derived biomaterials are discussed with a special reference set on applicability, performance, advantages, limitations, and challenges. Plant-origin compounds, biomaterials, and biomimetic 3D-bioprinted constructs could be the basis for a next-generation BTE.

Ankylosing spondylitis (AS) is an autoimmune rheumatic disease that primarily affects the axial joints, with its etiology complex and still not fully understood. The unknown pathogenesis of AS limits the development of treatment strategies, so keeping up-to-date with the current research on AS can help in searching for potential therapeutic targets. In addition to the classic HLA-B27 genetic susceptibility and Th17-related inflammatory signals, increasing research is focusing on the influence of autoantigen-centered autoimmune responses and bone stromal cells on the onset of AS. Autoantigens derived from gut microbiota and preferential TCR both exacerbate the autoimmune response in patients with AS. Furthermore, dysregulated bone metabolism also promotes pathological new bone formation in AS. Current treatments approved for AS almost focus on the management of inflammation with inconsistent treatment results due to the heterogeneity of patients. In this review, we systematically summarized various pathogenesis and management of AS, meanwhile discussed the underlying risk factors and potential therapeutic targets.

Osteoporosis is characterized by the microstructural depletion of bone tissue and decreased bone density, leading to an increased risk of fractures. Cotoneaster wilsonii Nakai, an endemic species of the Korean Peninsula, grows wild in Ulleungdo. In this study, we aimed to investigate the effects of C. wilsonii and its components on osteoporosis.

The alkaline phosphatase (ALP) activity of C. wilsonii extracts and fractions was evaluated in MC3T3-E1 pre-osteoblasts, and the n-hexane fraction (CWH) showed the best properties for ALP activity. The effects of the CWH on bone formation were assessed in MC3T3-E1 cells and ovariectomized mice. Biochemical assays and histological analyses focused on the signaling activation of osteoblast differentiation and osteogenic markers, such as ALP, collagen, and osterix. The CWH significantly activated TGF-β and Wnt signaling, enhancing osteoblast differentiation and bone matrix formation. Notably, CWH treatment improved micro-CT indices, such as femoral bone density, and restored serum osteocalcin levels compared to OVX controls.

These results highlight the potential of the C. wilsonii Nakai n-hexane fraction as a promising therapeutic agent for managing osteoporosis.

Osteoporosis induces severe oxidative stress and disrupts bone metabolism, complicating the treatment of bone defects. Current therapies often have side effects and require lengthy bone regeneration periods. Hydrogels, known for their flexible mechanical properties and degradability, are promising carriers for drugs and bioactive factors in bone tissue engineering. However, they lack the ability to regulate the local pathological environment of osteoporosis and expedite bone repair. Polyphenols, with antioxidative, anti-inflammatory, and bone metabolism-regulating properties, have emerged as a solution. Combining hydrogels and polyphenols, polyphenol-based hydrogels can regulate local bone metabolism and oxidative stress while providing mechanical support and tissue adhesion, promoting osteoporotic bone regeneration. This review first provides a brief overview of the types of polyphenols and the mechanisms of polyphenols in facilitating adhesion, antioxidant, anti-inflammatory, and bone metabolism modulation in modulating the pathological environment of osteoporosis. Next, this review examines recent advances in hydrogels for the treatment of osteoporotic bone defects, including their use in angiogenesis, oxidative stress modulation, drug delivery, and stem cell therapy. Finally, it highlights the latest research on polyphenol hydrogels in osteoporotic bone defect regeneration. Overall, this review aims to facilitate the clinical application of polyphenol hydrogels for the treatment of osteoporotic bone defects.

Diabetic wounds represent a significant complication of diabetes and present a substantial challenge to global public health. Macrophages are crucial effector cells that play a pivotal role in the pathogenesis of diabetic wounds, through their polarization into distinct functional phenotypes. The field of epigenetics has emerged as a rapidly advancing research area, as this phenomenon has the potential to markedly affect gene expression, cellular differentiation, tissue development and susceptibility to disease. Understanding epigenetic mechanisms is crucial to further exploring disease pathogenesis. A growing body of scientific evidence has highlighted the pivotal role of epigenetics in the regulation of macrophage phenotypes. Various epigenetic mechanisms, such as DNA methylation, histone modification and non‑coding RNAs, are involved in the modulation of macrophage phenotype differentiation in response to the various environmental stimuli present in diabetic wounds. The present review provided an overview of the various changes that take place in macrophage phenotypes and functions within diabetic wounds and discussed the emerging role of epigenetic modifications in terms of regulating macrophage plasticity in diabetic wounds. It is hoped that this synthesis of information will facilitate the elucidation of diabetic wound pathogenesis and the identification of potential therapeutic targets.