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*

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

OBJECTIVES: To evaluate the repairing ability of nano-pearl powder bone substitute in rabbit with defect of distal femur bone. METHODS: Thirty-two New Zealand rabbits were randomly divided into four groups: a nano-pearl powder/recombinant human bone morphogenetic protein 2 (rhBMP-2)/hyaluronic acid group, a nano-pearl powder/hyaluronic acid group, a nano-pearl powder group and a blank control group (=8 in each group). A defect with the diameter of 7 mm and height of 10 mm was prepared at the distal femoral metaphysis line of the rabbit.Different bone substitutes were planted, and the effect of repair was evaluated by macroscopic observation, imaging examination, and histopathological examination. RESULTS: The results of imageology showed that: the bone repairing effect in the nano-pearl powder/rhBMP-2/hyaluronic acid group was better than that in the pure pearl powder group and the nano-pearl powder/hyaluronic acid group, and which in the 3 experimental groups was better than that in the blank control group; The results of histology showed that: at the 4th, 8th and 12th weeks after the modeling operation, the speed of bone repair in the nano-pearl powder/rhBMP-2/hyaluronic acid group was faster than that in the pure pearl powder group and the nano-pearl powder/hyaluronic acid group, and which in the blank control group was far slower than that in the 3 experimental groups. The results of immunohistochemistry staining for osteocalcin antibody showed that: the osteogenic effect in the nano-pearl powder/rhBMP-2/hyaluronic acid group was better than that in the pure pearl powder group and the nano-pearl powder/hyaluronic acid group (both <0.05); there was no significant difference between the nano-pearl powder/hyaluronic acid group and the pure pearl powder group (>0.05); however, there was significant difference between the pure pearl powder group and the blank control group (<0.05). According to the staining results of Type I collagen antibody, there was no significant difference in the osteogenic effect between the nano-pearl powder/rhBMP-2/hyaluronic acid group and the nano-pearl powder/hyaluronic acid group (>0.05), but the osteogenic effect in the nano-pearl powder/hyaluronic acid group was better than that in the pure pearl powder group and the blank control group (both <0.05). CONCLUSIONS Nano-pearl powder and its bone substitute can promote the repair of bone defect, and the nano-pearl powder which contains rhBMP-2 has better osteogenic and repairing effect on defect.
Animals ; Bone Morphogenetic Protein 2 ; Bone Substitutes ; Collagen ; Femur ; Humans ; Osteogenesis ; Powders ; Rabbits ; Recombinant Proteins ; Transforming Growth Factor beta

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*

STUDY DESIGN: Prospective observational cohort study. PURPOSE: This study aims to evaluate the safety and efficacy of bone morphogenetic protein-2 (BMP-2) in transforaminal lumbar interbody fusion (TLIF) with regard to postoperative radiculitis. OVERVIEW OF LITERATURE: Bone morphogenetic protein (BMP) is being used increasingly as an alternative to iliac crest autograft in spinal arthrodesis. Recently, the use of BMP in TLIF has been examined, but concerns exist that the placement of BMP close to the nerve roots may cause postoperative radiculitis. Furthermore, prospective studies regarding the use of BMP in TLIF are lacking. METHODS: This prospective study included 77 patients. The use of BMP-2 was determined individually, and demographic and operative characteristics were recorded. Leg pain was assessed using the Visual Analog Scale (VAS) for pain and the Sciatica Bothersome Index (SBI) with several secondary outcome measures. The outcome data were collected at each follow-up visit. RESULTS: Among the 77 patients, 29 were administered with BMP. Postoperative leg pain significantly improved according to VAS leg and SBI scores for the entire cohort, and no clinically significant differences were observed between the BMP and control groups. The VAS back, Oswestry Disability Index, and Short-Form 36 scores also significantly improved. A significantly increased 6-month fusion rate was noted in the BMP group (82.8% vs. 55.3%), but no significant differences in fusion rate were observed at the 12- and 24-month follow-up. Heterotopic ossification was observed in seven patients: six patients and one patient in the BMP and control groups, respectively (20.7% vs. 2.1%). However, no clinical effect was observed. CONCLUSIONS: In this prospective observational trial, the use of BMP in TLIF did not lead to significant postoperative radiculitis, as measured by VAS leg and SBI scores. Back pain and other functional outcome scores also improved, and no differences existed between the BMP and control groups. The careful use of BMP in TLIF appears to be both safe and effective.
Arthrodesis ; Autografts ; Back Pain ; Bone Morphogenetic Proteins ; Cohort Studies ; Follow-Up Studies ; Humans ; Leg ; Lumbosacral Region ; Ossification, Heterotopic ; Outcome Assessment (Health Care) ; Prospective Studies ; Radiculopathy ; Sciatica ; Spinal Fusion ; Spine ; Visual Analog Scale

PURPOSE: To compare the efficacy and safety of recombinant human bone morphogenetic protein (rhBMP) and iliac crest autograft in the fusion treatment of lumbar spondylolisthesis. METHODS: The studies using randomized controlled trials to compare the rhBMP with iliac crest autograft in the treatment of lumbar spondylolisthesis were retrieved from Embase, Pubmed, ProQuest dissertations & theses (PQDT), China national knowledge infrastructure (CNKI), Chinese Biomedical Database, Wanfang Data, Cochrane Library (from March 1998 to March 2018). Postoperative fusion rate, clinical success rate, postoperative intervertebral height, complications, operation time, blood loss and duration of hospitalization were chosen as the outcome indicators. Methodological quality of the trials was critically assessed, and relevant data were extracted. Statistical software Revman 5.3 was used for data-analysis. RESULTS: Eleven articles were included in the meta-analysis. The results showed that, comparing the efficacy of rhBMP with iliac crest autograft, statistical significance was found in the 24-month fusion rate post operation [95% CI (1.38, 24.70), p = 0.02] and operation time [95% CI (-14.22, -2.08), p = 0.008]. There is not sufficient evidence for statistical differences in the remaining indicators. CONCLUSION The current literature shows rhBMP is a safe and effective grafting material in the treatment of lumbar spondylolisthesis. Further evidence is dependent on the emergence of more randomized controlled trials with higher quality and larger sample sizes in the future.
Autografts ; Bone Morphogenetic Proteins ; administration & dosage ; Databases, Bibliographic ; Humans ; Ilium ; transplantation ; Lumbar Vertebrae ; surgery ; Randomized Controlled Trials as Topic ; Recombinant Proteins ; administration & dosage ; Spinal Fusion ; methods ; Spondylolisthesis ; surgery ; Time Factors ; Treatment Outcome

OBJECTIVE: To investigate the effects of low-dose decitabine on levels of soluble CD44 and GDF11, and hematopoietic function in elderly patients with myelodysplastic syndrome (MDS). METHODS: Ninety-nine patients with senile myelodysplastic syndrome (MDS) admitted to our hospital from October 2015 to October 2017 were divided into group A, B and C according to their treatment, each with 33 cases.The patients in group A were treated with low-dose decitabine, the patients in group B were treated with usual dose of decitabine, and the patients in group C were treated with low-dose decitabine plus G-GSF, cytarabine, and aclarithromycin. The changes of soluble CD44, GDF11 levels and hematopoietic function (sTfR/E) were compared before and after treatment. The clinical remission rate and adverse reaction rate in 3 groups were analyzed. RESULTS: Before treatment, the levels of CD44, GDF11 and sTfR/E were not significantly different between the 3 groups (P＞0.05). After treatment, the levels of CD44 and GDF11 were significantly decreased in these groups, while the serum levels of sTfR/E were significantly increased, and there was no significant difference between the 3 groups (P＞0.05). After treatment, the total effective rates of A, B, and C 3 group were 82.3%, 81.8%, and 78.8%, respectively, without statistically significant difference (P＞0.05). During the treatment, the incidence of non-hemotoxic adverse reactions in group A was 8.8%, significantly lower than that in group B and C (30.3%, 27.3%) (P＜0.05, P＜0.05), the incidence of hemotoxic adverse reactions in group A was 39.4%, significantly lower than that 63.6% and 66.7% in group B and C (P＜0.05, P＜0.05). CONCLUSION Low-dose decitabine alone is effective in treating elderly patients with MDS as compared with conventional dose and combination therapy, moreover can significantly reduce the levels of CD44 and GDF11, improve hematopoietic function and low the adverse reactions. Thereby the low dose of decitabine may be a new choice for clinical treatment of MDS.
Aged ; Antineoplastic Combined Chemotherapy Protocols ; Azacitidine ; Bone Morphogenetic Proteins ; Decitabine ; administration & dosage ; therapeutic use ; Growth Differentiation Factors ; Hematopoietic Stem Cell Transplantation ; Humans ; Hyaluronan Receptors ; Myelodysplastic Syndromes ; drug therapy ; Treatment Outcome

OBJECTIVE: The purpose of this study is to investigate the potential effects of sclerostin (SOST) on the biological funtions and related mechanisms of cementoblasts under mechanical stress. METHODS: OCCM-30 cells were treated with varying doses of SOST (0, 25, 50, and 100 ng·mL⁻¹) and were loaded with uniaxial compressive stress (2 000 μ strain with a frequency of 0.5 Hz) for six hours. Western blot was utilized to detect the expressions of β-catenin, p-smad1/5/8, and smad1/5/8 proteins. Alkaline phosphatase (ALP) activity was determined, and reverse transcription polymerase chain reaction was used to measure the expressions of runt-related transcription factor 2 (Runx-2), osteocalcin (OCN), bone sialoproteins (BSP), receptor activator of NF-κB ligand (RANKL) and osteoprotegerin (OPG) mRNA. RESULTS: The expression of p-smad
1/5/8 was significantly downregulated with increasing SOST. β-catenin and smad1/5/8 exhibited no difference. ALP activity decreased under mechanical compressive stress with increasing SOST concentrations. Runx-2 expression was reduced with increasing SOST concentrations, and a similar trend was observed for the BSP and OCN expressions. When the SOST concentration was enhanced, RANKL expression gradually increased, whereas the expression of OPG decreased. CONCLUSIONS Under mechanical comprehensive stress, SOST can adjust the bone morphogenetic protein (BMP) /smad signal pathway. Osteosclerosis inhibits the mineralization of cementoblasts under mechanical compressive stress, which may be achieved by inhibiting the expressions of osteogenesis factors (Runx2, OCN, BSP, and others) and by promoting the ratio of cementoclast-related factors (RANKL/OPG) through BMP signal pathways.
Bone Morphogenetic Proteins ; metabolism ; Core Binding Factor Alpha 1 Subunit ; Dental Cementum ; Osteocalcin ; Smad Proteins ; metabolism ; Stress, Mechanical