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Small (Weinheim An Der Bergstrasse,... Oct 2023In the system of magnesium-loaded scaffolds, the effect of magnesium ions (Mg ) on the osteogenesis induction is restricted due to the low transmembrane transport...
In the system of magnesium-loaded scaffolds, the effect of magnesium ions (Mg ) on the osteogenesis induction is restricted due to the low transmembrane transport efficiency of Mg into the cell, which limits the application for bone defect repair. Inspired by the fact that magnetic field can regulate ion channel proteins on the cell membrane, magnetite nanoparticle is introduced into the poly (l-lactic acid) /magnesium oxide composite in this study, and a magnetic magnesium-loaded bone scaffold is prepared via selective laser sintering . Notably, the activities of the Mg channel protein (MAGT1) on the membrane of bone marrow mesenchymal stem cells (rBMSCs) are enhanced via magnetic torque effect (via integrin αV β3/actin), under the action of static magnetic field (SMF), which promoted rBMSCs to capture Mg in the microenvironment and induced osteogenesis. In vitro experiments showed that the magnetic magnesium-loaded scaffold, under the action of SMF, can accelerate the inflow of Mg from surrounding microenvironment, which improved cellular activities, osteogenesis-related gene expression (ALP, Runx2, OCN, and OPN), and mineralization. Besides, in vivo skull defect repair experiments showed that the scaffolds possessed good ability to promote bone differentiation and new bone regeneration.
Topics: Magnesium; Tissue Scaffolds; Osteogenesis; Bone Regeneration; Skull; Cell Differentiation; Ions; Magnetic Fields; Tissue Engineering
PubMed: 37271895
DOI: 10.1002/smll.202301426 -
Bone Apr 2024Bone formation and homeostasis are controlled by environmental factors and endocrine regulatory cues that initiate intracellular signaling pathways capable of modulating... (Review)
Review
Bone formation and homeostasis are controlled by environmental factors and endocrine regulatory cues that initiate intracellular signaling pathways capable of modulating gene expression in the nucleus. Bone-related gene expression is controlled by nucleosome-based chromatin architecture that limits the accessibility of lineage-specific gene regulatory DNA sequences and sequence-specific transcription factors. From a developmental perspective, bone-specific gene expression must be suppressed during the early stages of embryogenesis to prevent the premature mineralization of skeletal elements during fetal growth in utero. Hence, bone formation is initially inhibited by gene suppressive epigenetic regulators, while other epigenetic regulators actively support osteoblast differentiation. Prominent epigenetic regulators that stimulate or attenuate osteogenesis include lysine methyl transferases (e.g., EZH2, SMYD2, SUV420H2), lysine deacetylases (e.g., HDAC1, HDAC3, HDAC4, HDAC7, SIRT1, SIRT3), arginine methyl transferases (e.g., PRMT1, PRMT4/CARM1, PRMT5), dioxygenases (e.g., TET2), bromodomain proteins (e.g., BRD2, BRD4) and chromodomain proteins (e.g., CBX1, CBX2, CBX5). This narrative review provides a broad overview of the covalent modifications of DNA and histone proteins that involve hundreds of enzymes that add, read, or delete these epigenetic modifications that are relevant for self-renewal and differentiation of mesenchymal stem cells, skeletal stem cells and osteoblasts during osteogenesis.
Topics: Osteogenesis; Transcription Factors; Lysine; Nuclear Proteins; Cell Differentiation; Epigenesis, Genetic; Osteoblasts; Transferases
PubMed: 38341164
DOI: 10.1016/j.bone.2024.117043 -
Genetics in Medicine : Official Journal... Aug 2023Bone morphogenic proteins (BMPs) regulate gene expression that is related to many critical developmental processes, including osteogenesis for which they are named. In...
PURPOSE
Bone morphogenic proteins (BMPs) regulate gene expression that is related to many critical developmental processes, including osteogenesis for which they are named. In addition, BMP2 is widely expressed in cells of mesenchymal origin, including bone, cartilage, skeletal and cardiac muscle, and adipose tissue. It also participates in neurodevelopment by inducing differentiation of neural stem cells. In humans, BMP2 variants result in a multiple congenital anomaly syndrome through a haploinsufficiency mechanism. We sought to expand the phenotypic spectrum and highlight phenotypes of patients harboring monoallelic missense variants in BMP2.
METHODS
We used retrospective chart review to examine phenotypes from an international cohort of 18 individuals and compared these with published cases. Patient-derived missense variants were modeled in zebrafish to examine their effect on the ability of bmp2b to promote embryonic ventralization.
RESULTS
The presented cases recapitulated existing descriptions of BMP2-related disorders, including craniofacial, cardiac, and skeletal anomalies and exhibit a wide phenotypic spectrum. We also identified patients with neural tube defects, structural brain anomalies, and endocrinopathies. Missense variants modeled in zebrafish resulted in loss of protein function.
CONCLUSION
We use this expansion of reported phenotypes to suggest multidisciplinary medical monitoring and management of patients with BMP2-related skeletal dysplasia spectrum.
Topics: Animals; Humans; Zebrafish; Retrospective Studies; Cell Differentiation; Osteogenesis; Bone Morphogenetic Proteins; Osteochondrodysplasias; Bone Morphogenetic Protein 2
PubMed: 37125634
DOI: 10.1016/j.gim.2023.100863 -
International Journal of Biological... Nov 2023In designing and fabricating scaffolds to fill the bone defects and stimulate new bone formation, the biomimetics of the construct is a crucial factor in invoking the... (Review)
Review
In designing and fabricating scaffolds to fill the bone defects and stimulate new bone formation, the biomimetics of the construct is a crucial factor in invoking the bone microenvironment to promote osteogenic differentiation. Regarding structural traits, changes in porous characteristics of the scaffolds, such as pore size, pore morphology, and percentage porosity, may patronize or jeopardize their other physicochemical and biological properties. Chitosan (CS), a biodegradable naturally occurring polymer, has recently drawn considerable attention as a scaffolding material in tissue engineering and regenerative medicine. CS-based microporous scaffolds have been reported to aid osteogenesis under both in vitro and in vivo conditions by supporting cellular attachment and proliferation of osteoblast cells and the formation of mineralized bone matrix. This related notion may be found in numerous earlier research, even though the precise mechanism of action that encourages the development of new bone still needs to be understood completely. This article presents the potential correlations and the significance of the porous properties of the CS-based scaffolds to influence osteogenesis and angiogenesis during bone regeneration. This review also goes over resolving the mechanical limitations of CS by blending it with other polymers and ceramics.
Topics: Chitosan; Tissue Engineering; Tissue Scaffolds; Porosity; Humans; Animals; Osteogenesis; Bone Regeneration; Bone and Bones; Biocompatible Materials
PubMed: 37567529
DOI: 10.1016/j.ijbiomac.2023.126238 -
Frontiers in Endocrinology 2023Bone metabolism is the basis for maintaining the normal physiological state of bone, and imbalance of bone metabolism can lead to a series of metabolic bone diseases. As... (Review)
Review
Bone metabolism is the basis for maintaining the normal physiological state of bone, and imbalance of bone metabolism can lead to a series of metabolic bone diseases. As a member of the IL-6 family, IL-11 acts primarily through the classical signaling pathway IL-11/Receptors, IL-11 (IL-11R)/Glycoprotein 130 (gp130). The regulatory role of IL-11 in bone metabolism has been found earlier, but mainly focuses on the effects on osteogenesis and osteoclasis. In recent years, more studies have focused on IL-11's roles and related mechanisms in different bone metabolism activities. IL-11 regulates osteoblasts, osteoclasts, BM stromal cells, adipose tissue-derived mesenchymal stem cells, and chondrocytes. It's involved in bone homeostasis, including osteogenesis, osteolysis, bone marrow (BM) hematopoiesis, BM adipogenesis, and bone metastasis. This review exams IL-11's role in pathology and bone tissue, the cytokines and pathways that regulate IL-11 expression, and the feedback regulations of these pathways.
Topics: Interleukin-11; Cell Differentiation; Bone and Bones; Osteoclasts; Osteogenesis
PubMed: 38352248
DOI: 10.3389/fendo.2023.1290130 -
Acta Biomaterialia Dec 2023Angiogenesis is critical for successful bone repair, and interestingly, miR-210 and miR-16 possess counter-active targets involved in both angiogenesis and osteogenesis:...
Angiogenesis is critical for successful bone repair, and interestingly, miR-210 and miR-16 possess counter-active targets involved in both angiogenesis and osteogenesis: miR-210 acts as an activator by silencing EFNA3 & AcvR1b, while miR-16 inhibits both pathways by silencing VEGF & Smad5. It was thus hypothesized that dual delivery of both a miR-210 mimic and a miR-16 inhibitor from a collagen-nanohydroxyapatite scaffold system may hold significant potential for bone repair. Therefore, this systems potential to rapidly accelerate bone repair by directing enhanced angiogenic-osteogenic coupling in host cells in a rat calvarial defect model at a very early 4 week timepoint was assessed. In vitro, the treatment significantly enhanced angiogenic-osteogenic coupling of human mesenchymal stem cells, with enhanced calcium deposition after just 10 days in 2D and 14 days on scaffolds. In vivo, these dual-miRNA loaded scaffolds showed more than double bone volume and vessel recruitment increased 2.3 fold over the miRNA-free scaffolds. Overall, this study demonstrates the successful development of a dual-miRNA mimic/inhibitor scaffold for enhanced in vivo bone repair for the first time, and the possibility of extending this 'off-the-shelf' platform system to applications beyond bone offers immense potential to impact a myriad of other tissue engineering areas. STATEMENT OF SIGNIFICANCE: miRNAs have potential as a new class of bone healing therapeutics as they can enhance the regenerative capacity of bone-forming cells. However, angiogenic-osteogenic coupling is critical for successful bone repair. Therefore, this study harnesses the delivery of miR-210, known to be an activator of both angiogenesis and osteogenesis, and miR-16 inhibitor, as miR-16 is known to inhibit both pathways, from a collagen-nanohydroxyapatite scaffold system to rapidly enhance osteogenesis in vitro and bone repair in vivo in a rat calvarial defect model. Overall, it describes the successful development of the first dual-miRNA mimic/inhibitor scaffold for enhanced in vivo bone repair. This 'off-the-shelf' platform system offers immense potential to extend beyond bone applications and impact a myriad of other tissue engineering areas.
Topics: Humans; Rats; Animals; Osteogenesis; Tissue Scaffolds; MicroRNAs; Bone and Bones; Tissue Engineering; Collagen; Bone Regeneration; Cell Differentiation
PubMed: 37797708
DOI: 10.1016/j.actbio.2023.09.049 -
Bone Research Aug 2023Endochondral ossification requires proper control of chondrocyte proliferation, differentiation, survival, and organization. Here we show that knockout of α-parvin, an...
Endochondral ossification requires proper control of chondrocyte proliferation, differentiation, survival, and organization. Here we show that knockout of α-parvin, an integrin-associated focal adhesion protein, from murine limbs causes defects in endochondral ossification and dwarfism. The mutant long bones were shorter but wider, and the growth plates became disorganized, especially in the proliferative zone. With two-photon time-lapse imaging of bone explant culture, we provide direct evidence showing that α-parvin regulates chondrocyte rotation, a process essential for chondrocytes to form columnar structure. Furthermore, loss of α-parvin increased binucleation, elevated cell death, and caused dilation of the resting zones of mature growth plates. Single-cell RNA-seq analyses revealed alterations of transcriptome in all three zones (i.e., resting, proliferative, and hypertrophic zones) of the growth plates. Our results demonstrate a crucial role of α-parvin in long bone development and shed light on the cellular mechanism through which α-parvin regulates the longitudinal growth of long bones.
Topics: Animals; Mice; Bone Development; Cell Death; Chondrocytes; Growth Plate; Osteogenesis
PubMed: 37607905
DOI: 10.1038/s41413-023-00284-7 -
Journal of Biomolecular Structure &... Nov 2023Osteoblasts, cells derived from mesenchymal stem cells (MSCs) in the bone marrow, are cells responsible for bone formation and remodeling. The differentiation of... (Review)
Review
Osteoblasts, cells derived from mesenchymal stem cells (MSCs) in the bone marrow, are cells responsible for bone formation and remodeling. The differentiation of osteoblasts from MSCs is triggered by the expression of specific genes, which are subsequently controlled by pro-osteogenic pathways. Mature osteoblasts then differentiate into osteocytes and are embedded in the bone matrix. Dysregulation of osteoblast function can cause inadequate bone formation, which leads to the development of bone disease. Various key molecules are involved in the regulation of osteoblastogenesis, which are transcription factors. Previous studies have heavily examined the role of factors that control gene expression during osteoblastogenesis, both in vitro and in vivo. However, the systematic relationship of these transcription factors remains unknown. The involvement of ncRNAs in this mechanism, particularly miRNAs, lncRNAs, and circRNAs, has been shown to influence transcriptional factor activity in the regulation of osteoblast differentiation. Here, we discuss nine essential transcription factors involved in osteoblast differentiation, including Runx2, Osx, Dlx5, β-catenin, ATF4, Ihh, Satb2, and Shn3. In addition, we summarize the role of ncRNAs and their relationship to these essential transcription factors in order to improve our understanding of the transcriptional regulation of osteoblast differentiation. Adequate exploration and understanding of the molecular mechanisms of osteoblastogenesis can be a critical strategy in the development of therapies for bone-related diseases.Communicated by Ramaswamy H. Sarma.
Topics: Transcription Factors; Cell Differentiation; Osteoblasts; Gene Expression Regulation; Osteogenesis
PubMed: 36420663
DOI: 10.1080/07391102.2022.2148749 -
Cellular and Molecular Life Sciences :... Sep 2023The tightly controlled balance between osteogenic and adipogenic differentiation of human bone marrow-derived stromal cells (BMSCs) is critical to maintain bone...
BACKGROUND
The tightly controlled balance between osteogenic and adipogenic differentiation of human bone marrow-derived stromal cells (BMSCs) is critical to maintain bone homeostasis. Age-related osteoporosis is characterized by low bone mass with excessive infiltration of adipose tissue in the bone marrow compartment. The shift of BMSC differentiation from osteoblasts to adipocytes could result in bone loss and adiposity.
METHODS
TNS3 gene expression during osteogenic and adipogenic differentiation of BMSCs was evaluated by qPCR and Western blot analyses. Lentiviral-mediated knockdown or overexpression of TNS3 was used to assess its function. The organization of cytoskeleton was examined by immunofluorescent staining at multiple time points. The role of TNS3 and its domain function in osteogenic differentiation were evaluated by ALP activity, calcium assay, and Alizarin Red S staining. The expression of Rho-GTP was determined using the RhoA pull-down activation assay.
RESULTS
Loss of TNS3 impaired osteogenic differentiation of BMSCs but promoted adipogenic differentiation. Conversely, TNS3 overexpression hampered adipogenesis while enhancing osteogenesis. The expression level of TNS3 determined cell shape and cytoskeletal reorganization during osteogenic differentiation. TNS3 truncation experiments revealed that for optimal osteogenesis to occur, all domains proved essential. Pull-down and immunocytochemical experiments suggested that TNS3 mediates osteogenic differentiation through RhoA.
CONCLUSIONS
Here, we identify TNS3 to be involved in BMSC fate decision. Our study links the domain structure in TNS3 to RhoA activity via actin dynamics and implicates an important role for TNS3 in regulating osteogenesis and adipogenesis from BMSCs. Furthermore, it supports the critical involvement of cytoskeletal reorganization in BMSC differentiation.
Topics: Humans; Actins; Adipogenesis; Cell Differentiation; Osteogenesis; Tensins
PubMed: 37668682
DOI: 10.1007/s00018-023-04930-5 -
Advanced Materials (Deerfield Beach,... Jun 2024Bone implants for different body parts require varying mechanical properties, dimensions, and biodegradability rates. Currently, it is still challenging to produce...
Bone implants for different body parts require varying mechanical properties, dimensions, and biodegradability rates. Currently, it is still challenging to produce artificial bones with perfect compatibility with human bones. In this study, a silk-fabric reinforced silk material (SFS) composed of pure silk with exceptional biocompatibility, osteogenesis, and biodegradability is reported, and demonstrates its outstanding performance as a bone implant material. The SFS is fabricated using a simple hot-pressing technique, with degummed silk fabric as the reinforcement and silk fibroin as the matrix. The SFS as a self-reinforced composite, has exceptional mechanical properties due to the almost perfect interface between the matrix and reinforcement. More importantly, its mechanical properties, biodegradability rates, and density can be tailored by adjusting the reinforcement structure and the ratio of the reinforcement to the matrix to align with the requirements for bone implantation in different parts of the human body. Besides, the SFS can improve osteoblastic proliferation and increase osteogenic activity, which is not the case with clinically used titanium alloy artificial bone. Therefore, the SFS holds significant potential to replace conventional metal or ceramic implants in the field of medical fracture repair.
Topics: Silk; Osteogenesis; Animals; Materials Testing; Bone Substitutes; Cell Proliferation; Humans; Osteoblasts; Biocompatible Materials; Mice; Fibroins; Bone and Bones
PubMed: 38404231
DOI: 10.1002/adma.202308748