OBJECTIVE: To evaluate the effect of biodegradable magnesium alloy materials in promoting tendon-bone healing during rotator cuff tear repair and to investigate their potential underlying biological mechanisms. METHODS: Forty-eight 8-week-old Sprague Dawley rats were taken and randomly divided into groups A, B, and C. Rotator cuff tear models were created and repaired using magnesium alloy sutures in group A and Vicryl Plus 4-0 absorbable sutures in group B, while only subcutaneous incisions and sutures were performed in group C. Organ samples of groups A and B were taken for HE staining at 1 and 2 weeks after operation to evaluate the safety of magnesium alloy, and specimens from the supraspinatus tendon and proximal humerus were harvested at 2, 4, 8, and 12 weeks after operation. The specimens were observed macroscopically at 4 and 12 weeks after operation. Biomechanical tests were performed at 4, 8, and 12 weeks to test the ultimate load and stiffness of the healing sites in groups A and B. At 2, 4, and 12 weeks, the specimens were subjected to the following tests: Micro-CT to evaluate the formation of bone tunnels in groups A and B, HE staining and Masson staining to observe the regeneration of fibrocartilage at the tendon-bone interface after decalcification and sectioning, and Goldner trichrome staining to evaluate the calcification. Immunohistochemical staining was performed to detect the expressions of angiogenic factors, including vascular endothelial growth factor (VEGF) and bone morphogenetic protein 2 (BMP-2), as well as osteogenic factors at the tendon-bone interface. Additionally, immunofluorescence staining was used to examine the expressions of Arginase 1 and Integrin beta-2 to assess M1 and M2 macrophage polarization at the tendon-bone interface. The role of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway in tendon-bone healing was further analyzed using real-time fluorescence quantitative PCR. RESULTS: Analysis of visceral sections revealed that magnesium ions released during the degradation of magnesium alloys did not cause significant toxic effects on organs such as the heart, liver, spleen, lungs, and kidneys, indicating good biosafety. Histological analysis further demonstrated that fibrocartilage regeneration at the tendon-bone interface in group A occurred earlier, and the amount of fibrocartilage was significantly greater compared to group B, suggesting a positive effect of magnesium alloy material on tendon-bone interface repair. Additionally, Micro-CT analysis results revealed that bone tunnel formation occurred more rapidly in group A compared to group B, further supporting the beneficial effect of magnesium alloy on bone healing. Biomechanical testing showed that the ultimate load in group A was consistently higher than in group B, and the stiffness of group A was also greater than that of group B at 4 weeks, indicating stronger tissue-carrying capacity following tendon-bone interface repair and highlighting the potential of magnesium alloy in enhancing tendon-bone healing. Immunohistochemical staining results indicated that the expressions of VEGF and BMP-2 were significantly upregulated during the early stages of healing, suggesting that magnesium alloy effectively promoted angiogenesis and bone formation, thereby accelerating the tendon-bone healing process. Immunofluorescence staining further revealed that magnesium ions exerted significant anti-inflammatory effects by regulating macrophage polarization, promoting their shift toward the M2 phenotype. Real-time fluorescence quantitative PCR results demonstrated that magnesium ions could facilitate tendon-bone healing by modulating the PI3K/AKT signaling pathway. CONCLUSION Biodegradable magnesium alloy material accelerated fibrocartilage regeneration and calcification at the tendon-bone interface in rat rotator cuff tear repair by regulating the PI3K/AKT signaling pathway, thereby significantly enhancing tendon-bone healing.
Animals ; Rotator Cuff Injuries/metabolism* ; Rats, Sprague-Dawley ; Signal Transduction ; Wound Healing/drug effects* ; Alloys/pharmacology* ; Rats ; Proto-Oncogene Proteins c-akt/metabolism* ; Rotator Cuff/metabolism* ; Macrophages/metabolism* ; Magnesium/pharmacology* ; Phosphatidylinositol 3-Kinases/metabolism* ; Vascular Endothelial Growth Factor A/metabolism* ; Male ; Biocompatible Materials ; Bone Morphogenetic Protein 2/metabolism*

OBJECTIVE: To review the role and research progress of mechanotransduction signaling pathway in distraction osteogenesis, so as to provide theoretical basis and reference for clinical treatment. METHODS: The role and research progress of mechanotransduction signaling pathway in distraction osteogenesis were summarized by extensive review of relevant literature at home and abroad. RESULTS: The mechanotransduction signaling pathway plays a central role of "sensation-transformation-execution" in distraction osteogenesis, and activates a series of molecular mechanisms to promote the regeneration and remodeling of bone tissue by integrating external mechanical signals. Mechanical stimuli are converted into mechanotransduction signals through the perception of integrins, Piezo1 ion channels and bone cell networks. Activate downstream molecules are transduce through signal pathways such as Wnt/β-catenin, transforming growth factor β/bone morphogenetic protein-Smad, mitogen-activated protein kinase, protein kinase Hippo-Yes-associated protein/transcriptional coactivator with PDZ-binding motif, and phosphatidylinositol 3-kinase/ protein kinase B, so as to achieve the effects of promoting osteoblasts proliferation, accelerating endochondral ossification, regulating bone resorption and the like, thereby promoting the regeneration of new bone in the distraction area. The study of mechanotransduction signaling pathways in distraction osteogenesis is expected to optimize the mechanical parameters of distraction osteogenesis and provide targeted intervention strategies for accelerating new bone regeneration and mineralization in the distraction zone. However, the specific mechanism of mechanotransduction signaling pathway in distraction osteogenesis remains to be further elucidated, and artificial intelligence and multi-omics analysis may be the future development direction of mechanotransduction signaling pathway. CONCLUSION In distraction osteogenesis, mechanotransduction signal transduction is the core mechanism of bone regeneration in the distraction zone, which regulates cell behavior and tissue regeneration by converting mechanical stimulation into biochemical signals.
Mechanotransduction, Cellular/physiology* ; Osteogenesis, Distraction/methods* ; Humans ; Signal Transduction ; Bone Regeneration ; Animals ; Osteoblasts/metabolism* ; Osteogenesis ; Transforming Growth Factor beta/metabolism* ; Ion Channels/metabolism* ; Integrins/metabolism* ; beta Catenin/metabolism* ; Bone Morphogenetic Proteins/metabolism* ; Smad Proteins/metabolism*

OBJECTIVES: This study investigated the effects of a polycaprolactone (PCL)-polyethylene glycol (PEG) scaffold incorporated with concentrated growth factor (CGF) on the adhesion, proliferation, and osteogenic differentiation of human periodontal ligament stem cells (hPDLSCs). METHODS: The PCL-PEG-CGF composite scaffold was fabricated using an immersion and freeze-drying technique. Its microstructure, mechanical properties, and biocompatibility were systematically characterized. The hPDLSCs were isolated through enzymatic digestion, and the hPDLSCs were identified through flow cytometry. Third-passage hPDLSCs were seeded onto the composite scaffolds, and their adhesion, proliferation and osteogenic differentiation were assessed using CCK-8 assays, 4',6-diamidino-2-phenylindole (DAPI) staining, alkaline phosphatase (ALP) staining, alizarin red staining, and Western blot analysis of osteogenesis-related proteins [Runt-related transcription factor 2 (Runx2), ALP, and morphogenetic protein 2 (BMP2)]. RESULTS: Scanning electron microscopy revealed that the PCL-PEG-CGF composite scaffold exhibited a honeycomb-like structure with heterogeneous pore sizes. The composite scaffold exhibited excellent hydrophilicity, as evidenced by a contact angle (θ) approaching 0° within 6 s. Its elastic modulus was measured at (4.590 0±0.149 3) MPa, with comparable hydrophilicity, fracture tensile strength, and fracture elongation to PCL-PEG scaffold. The hPDLSCs exhibited significantly improved adhesion to the PCL-PEG-CGF composite scaffold compared with the PCL-PEG scaffold (P<0.01). Additionally, cell proliferation was markedly improved in all the experimental groups on days 3, 5, and 7 (P<0.01), and statistically significant differences were found between the PCL-PEG-CGF group and other groups (P<0.01). The PCL-PEG-CGF group showed significantly elevated ALP activity (P<0.05), increased mineralization nodule formation, and upregulated expression of osteogenic-related proteins (Runx2, BMP2 and ALP; P<0.05). CONCLUSIONS The PCL-PEG-CGF composite scaffold exhibited excellent mechanical properties and biocompatibility, enhancing the adhesion and proliferation of hPDLSCs and promoting their osteogenic differentiation by upregulating osteogenic-related proteins.
Humans ; Polyesters/chemistry* ; Periodontal Ligament/cytology* ; Polyethylene Glycols/chemistry* ; Stem Cells/cytology* ; Tissue Scaffolds ; Cell Proliferation ; Osteogenesis ; Cell Differentiation ; Cell Adhesion ; Bone Morphogenetic Protein 2/metabolism* ; Cells, Cultured ; Alkaline Phosphatase/metabolism* ; Core Binding Factor Alpha 1 Subunit/metabolism* ; Intercellular Signaling Peptides and Proteins/pharmacology* ; Tissue Engineering/methods*

Bone morphogenetic proteins (BMPs) are multifunctional growth factors of the transforming growth factor β (TGF-β) superfamily. They regulate steroid secretion from mammalian granulosa cells, promote granulosa cell survival and proliferation, and inhibit follicular atresia, luteinization, and granulosa cell apoptosis, thereby promoting the development and maturation of mammalian follicles. At the same time, BMPs play an important role in embryonic morphogenesis, induction of uterine receptivity, and blastocyst attachment. This paper describes the effects of BMPs on mammalian follicular and embryonic development and the roles of BMPs in female reproduction, focusing on the process in which BMPs promote follicular maturation by regulating steroid secretion from granulosa cells during mammalian oocyte maturation. This review aims to provide a reference for further research on mammalian oocyte culture and improvement of reproductive efficiency in female animals.
Animals ; Embryonic Development/drug effects* ; Female ; Bone Morphogenetic Proteins/pharmacology* ; Reproduction/physiology* ; Humans ; Granulosa Cells/cytology* ; Oocytes

The seat of human intelligence is the human cerebral cortex, which is responsible for our exceptional cognitive abilities. Identifying principles that lead to the development of the large-sized human cerebral cortex will shed light on what makes the human brain and species so special. The remarkable increase in the number of human cortical pyramidal neurons and the size of the human cerebral cortex is mainly because human cortical radial glial cells, primary neural stem cells in the cortex, generate cortical pyramidal neurons for more than 130 days, whereas the same process takes only about 7 days in mice. The molecular mechanisms underlying this difference are largely unknown. Here, we found that bone morphogenic protein 7 (BMP7) is expressed by increasing the number of cortical radial glial cells during mammalian evolution (mouse, ferret, monkey, and human). BMP7 expression in cortical radial glial cells promotes neurogenesis, inhibits gliogenesis, and thereby increases the length of the neurogenic period, whereas Sonic Hedgehog (SHH) signaling promotes cortical gliogenesis. We demonstrate that BMP7 signaling and SHH signaling mutually inhibit each other through regulation of GLI3 repressor formation. We propose that BMP7 drives the evolutionary expansion of the mammalian cortex by increasing the length of the neurogenic period.
Animals ; Mice ; Humans ; Ependymoglial Cells/metabolism* ; Hedgehog Proteins/metabolism* ; Ferrets/metabolism* ; Cerebral Cortex ; Neurogenesis ; Mammals/metabolism* ; Neuroglia/metabolism* ; Bone Morphogenetic Protein 7/metabolism*

Vascular calcification significantly increases the incidence of cardiovascular disease and all-cause mortality patients with chronic kidney disease(CKD), severely affecting their health and lifespan. However, the mechanisms underlying vascular calcification in CKD remain incompletely understood, and the available therapeutic agents are limited. Research has found that the transformation of vascular smooth muscle cells(VSMCs) from a contractile phenotype to an osteoblast-like phenotype is a key step in CKD-related vascular calcification. As research on the pathogenesis of calcification progresses, it has been demonstrated that bone morphogenetic protein(BMP) and silent information regulator(SIRT) signaling pathways can participate in the process of vascular calcification by regulating the osteogenic transdifferentiation of VSMCs. Traditional Chinese medicine(TCM) has accumulated a wealth of valuable experience in the prevention and treatment of kidney diseases over centuries. Modern research indicates that TCM, with its multi-pathway, multi-target, and low-toxicity properties, has shown certain advantages in the prevention and treatment of CKD-related vascular calcification and in improving patients' quality of life. Therefore, in this study, we will introduce the latest research progress of TCM in preventing and treating CKD-related vascular calcification, particularly focusing on the BMP and SIRT signaling pathways, with the aim of providing ideas for the clinical diagnosis and treatment of CKD-related vascular calcification with TCM and related basic research.
Humans ; Vascular Calcification/genetics* ; Renal Insufficiency, Chronic/genetics* ; Signal Transduction/drug effects* ; Bone Morphogenetic Proteins/genetics* ; Drugs, Chinese Herbal/therapeutic use* ; Animals ; Sirtuins/genetics* ; Medicine, Chinese Traditional

The failure rate of dental implantation in patients with well-controlled type 2 diabetes mellitus (T2DM) is higher than that in non-diabetic patients. This due, in part, to the impaired function of bone marrow mesenchymal stem cells (BMSCs) from the jawbone marrow of T2DM patients (DM-BMSCs), limiting implant osseointegration. RNA N6-methyladenine (m6A) is important for BMSC function and diabetes regulation. However, it remains unclear how to best regulate m6A modifications in DM-BMSCs to enhance function. Based on the "m6A site methylation stoichiometry" of m6A single nucleotide arrays, we identified 834 differential m6A-methylated genes in DM-BMSCs compared with normal-BMSCs (N-BMSCs), including 43 and 790 m6A hypermethylated and hypomethylated genes, respectively, and 1 gene containing hyper- and hypomethylated m6A sites. Differential m6A hypermethylated sites were primarily distributed in the coding sequence, while hypomethylated sites were mainly in the 3'-untranslated region. The largest and smallest proportions of m6A-methylated genes were on chromosome 1 and 21, respectively. MazF-PCR and real-time RT-PCR results for the validation of erythrocyte membrane protein band 4.1 like 3, activity-dependent neuroprotector homeobox (ADNP), growth differentiation factor 11 (GDF11), and regulator of G protein signalling 2 agree with m6A single nucleotide array results; ADNP and GDF11 mRNA expression decreased in DM-BMSCs. Furthermore, gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses suggested that most of these genes were enriched in metabolic processes. This study reveals the differential m6A sites of DM-BMSCs compared with N-BMSCs and identifies candidate target genes to enhance BMSC function and improve implantation success in T2DM patients.
Humans ; Bone Marrow/metabolism* ; Bone Morphogenetic Proteins/metabolism* ; Dental Implants/adverse effects* ; Diabetes Mellitus, Type 2/metabolism* ; Growth Differentiation Factors/metabolism* ; Mesenchymal Stem Cells/metabolism* ; RNA/metabolism* ; RNA Processing, Post-Transcriptional

OBJECTIVES: To investigate the effect of recombinant human fibroblast growth factor 21 (rhFGF21) on the proliferation and mineralization of cementoblasts and its mechanism. METHODS: Hematoxylin eosin, immunohistochemical staining, and immunofluorescence were used to detect the expression and distribution of fibroblast growth factor 21 (FGF21) in rat periodontal tissues and cementoblasts (OCCM-30), separately. Cell Counting Kit-8 was used to detect the proliferation of OCCM-30 under treatment with rhFGF21. Alkaline phosphatase staining and Alizarin Red staining were used to detect the mineralization state of OCCM-30 after 3 and 7 days of mineralization induction. The transcription and protein expression of the osteogenic-related genes Runx2 and Osterix were detected by real-time quantitative polymerase chain reaction (PCR) and Western blot analysis. The expression levels of genes of transforming growth factor β (TGFβ)/bone morphogenetic protein (BMP) signaling pathway in OCCM-30 were detected through PCR array analysis. RESULTS: FGF21 was expressed in rat periodontal tissues and OCCM-30. Although rhFGF21 had no significant effect on the proliferation of OCCM-30, treatment with 50 ng/mL rhFGF21 could promote the mineralization of OCCM-30 cells after 7 days of mineralization induction. The transcriptional levels of Runx2 and Osterix increased significantly at 3 days of mineralization induction and decreased at 5 days of mineralization induction. Western blot analysis showed that the protein expression levels of Runx2 and Osterix increased during mineralization induction. rhFGF21 up-regulated Bmpr1b protein expression in cells. CONCLUSIONS rhFGF21 can promote the mineralization ability of OCCM-30. This effect is related to the activation of the TGFβ/BMP signaling pathway.
Humans ; Rats ; Animals ; Dental Cementum ; Core Binding Factor Alpha 1 Subunit/metabolism* ; Cell Differentiation ; Bone Morphogenetic Proteins/metabolism* ; Transforming Growth Factor beta/pharmacology*

OBJECTIVE: To investigate the effect of intramedullary nail fixation (IMN) and minimally invasive percutaneous plate internal fixation (MIPPO) techniques on tibiofibular fractures and their effect on platelet activation and serum transforming growth factor-β1 (TGF-β1) and bone morphogenetic protein-2 (BMP-2). METHODS: Total of 105 patients with tibiofibular fractures from February 2019 to February 2020 were selected and divided into 53 cases in the MIPPO group and 52 cases in the IMN group. There were 29 males and 24 females with an average age of (41.74±6.05) years old in MIPPO group;in IMN group, 31 males and 21 females with an average age of (40.59±5.26) years old. The perioperative surgical indexes, postoperative complications, ankle function recovery at 12 months postoperatively, platelet activation indexes at 3 and 7 days preoperatively and postoperatively, and serum TGF-β1 and BMP-2 levels at 4 and 8 weeks preoperatively and postoperatively were compared between the two groups. RESULTS: The operating time and fracture healing time in the MIPPO group were shorter than those in the IMN group(P<0.05); Compared with the preoperative period, the levels of GMP-140, PAC-1, CD63, and CD61 increased in both groups at 3 and 7 days after surgery, but were lower in the MIPPO group than in the IMN group(P<0.05);the levels of serum TGF-β1 and BMP-2 increased in both groups at 4 and 8 weeks after surgery compared with the preoperative period, and the postoperative complication rate in the MIPPO group was lower than that in the IMN group(P<0.05);the difference was not statistically significant in the excellent rate of ankle function recovery at 12 months follow-up after surgery between two groups(P>0.05). CONCLUSION Both intramedullary nail fixation and MIPO technique for treatment of tibia and fibula fractures can improve ankle joint function, but the latter has the advantages of short operation time, fast fracture healing, fewer complications, and light platelet activation. Serum TGF-β1, BMP-2 level improves quickly.
Male ; Female ; Humans ; Adult ; Middle Aged ; Tibia/injuries* ; Transforming Growth Factor beta1 ; Fracture Fixation, Intramedullary/methods* ; Tibial Fractures/surgery* ; Fracture Fixation, Internal/methods* ; Bone Plates ; Fracture Healing ; Postoperative Complications ; Fractures, Multiple ; Treatment Outcome ; Bone Morphogenetic Proteins ; Minimally Invasive Surgical Procedures/methods* ; Retrospective Studies

Understanding limb development not only gives insights into the outgrowth and differentiation of the limb, but also has clinical relevance. Limb development begins with two paired limb buds (forelimb and hindlimb buds), which are initially undifferentiated mesenchymal cells tipped with a thickening of the ectoderm, termed the apical ectodermal ridge (AER). As a transitional embryonic structure, the AER undergoes four stages and contributes to multiple axes of limb development through the coordination of signalling centres, feedback loops, and other cell activities by secretory signalling and the activation of gene expression. Within the scope of proximodistal patterning, it is understood that while fibroblast growth factors (FGFs) function sequentially over time as primary components of the AER signalling process, there is still no consensus on models that would explain proximodistal patterning itself. In anteroposterior patterning, the AER has a dual-direction regulation by which it promotes the sonic hedgehog (Shh) gene expression in the zone of polarizing activity (ZPA) for proliferation, and inhibits Shh expression in the anterior mesenchyme. In dorsoventral patterning, the AER activates Engrailed-1 (En1) expression, and thus represses Wnt family member 7a (Wnt7a) expression in the ventral ectoderm by the expression of Fgfs, Sp6/8, and bone morphogenetic protein (Bmp) genes. The AER also plays a vital role in shaping the individual digits, since levels of Fgf4/8 and Bmps expressed in the AER affect digit patterning by controlling apoptosis. In summary, the knowledge of crosstalk within AER among the three main axes is essential to understand limb growth and pattern formation, as the development of its areas proceeds simultaneously.
Animals ; Apoptosis ; Body Patterning ; Bone Morphogenetic Proteins/biosynthesis* ; Developmental Biology ; Ectoderm/metabolism* ; Extremities/embryology* ; Fibroblast Growth Factor 10/metabolism* ; Fibroblast Growth Factors/biosynthesis* ; Gene Expression Regulation ; Hedgehog Proteins/biosynthesis* ; Homeodomain Proteins/biosynthesis* ; Mesoderm/metabolism* ; Mice ; Signal Transduction ; Wnt Proteins/biosynthesis*