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Genomics Sep 2023To investigate EGR1-mediated METTL3/m6A/CHI3L1 axis in osteoporosis.
OBJECTIVE
To investigate EGR1-mediated METTL3/m6A/CHI3L1 axis in osteoporosis.
METHODS
Ovariectomy (OVX) was performed on mice to induce osteoporosis, followed by μ-CT scanning of femurs, histological staining, immunohistochemistry analysis of MMP9 and NFATc1, and ELISA of serum BGP, ALP, Ca, and CTXI. The isolated mouse bone marrow mononuclear macrophages (BMMs) were differentiated into osteoclasts under cytokine stimulation. TRAP staining was performed to quantify osteoclasts. The levels of Nfatc1, c-Fos, Acp5, and Ctsk in osteoclasts, m6A level, and the relationships among EGR1, METTL3, and CHI3L1 were analyzed.
RESULTS
The EGR1/METTL3/CHI3L1 levels and m6A level were upregulated in osteoporotic mice and the derived BMMs. EGR1 was a transcription factor of METTL3. METTL3 promoted the post-transcriptional regulation of CHI3L1 by increasing m6A methylation. EGR1 downregulation reduced BMMs-differentiated osteoclasts and alleviated OVX-induced osteoporosis by regulating the METTL3/m6A/CHI3L1 axis.
CONCLUSION
EGR1 promotes METTL3 transcription and increases m6A-modified CHI3L1 level, thereby stimulating osteoclast differentiation and osteoporosis development.
Topics: Animals; Female; Mice; Cell Differentiation; Macrophages; NFATC Transcription Factors; Osteoclasts; Osteogenesis; Osteoporosis; Proto-Oncogene Proteins c-fos
PubMed: 37558013
DOI: 10.1016/j.ygeno.2023.110696 -
BioMed Research International 2015
Topics: Biocompatible Materials; Dentistry; Humans; Osteogenesis
PubMed: 25950004
DOI: 10.1155/2015/945320 -
Current Opinion in Biotechnology Aug 2022In recent years it has been increasingly appreciated that blood vessels are not simply suppliers of nutrients and oxygen, but actually play an exquisite regulatory role... (Review)
Review
In recent years it has been increasingly appreciated that blood vessels are not simply suppliers of nutrients and oxygen, but actually play an exquisite regulatory role in bone development and repair. A specialized kind of endothelium, named type H because of its high expression of CD31 and Endomucin, constitutes anatomically defined vessels in proximity of the epiphyseal growth plate. Type H endothelium regulates the proliferation and differentiation of both osteoblasts and osteoclasts through the secretion of angiocrine signals and is a hub for the bidirectional molecular crosstalk between the different cell populations of the osteogenic microenvironment. Type H vessels are a key target for current translational approaches aiming at coupling angiogenesis and osteogenesis for bone repair. Open questions remain about their presence and features in notstereotyped tissues, like engineered osteogenic grafts, and the opportunities for their clinical stimulation by pharmacological treatments.
Topics: Bone Regeneration; Cell Differentiation; Osteogenesis; Signal Transduction
PubMed: 35841865
DOI: 10.1016/j.copbio.2022.102750 -
The Journal of the American Academy of... Jul 2022Bone marrow stromal cells are regulated by the chemical and physical features of a biomaterial surface. When grown on titanium (Ti) and Ti alloy surfaces, such as...
Bone marrow stromal cells are regulated by the chemical and physical features of a biomaterial surface. When grown on titanium (Ti) and Ti alloy surfaces, such as titanium-aluminum-vanadium, with specific topographies that mimic the microscale, mesoscale, and nanoscale features of an osteoclast resorption pit, they undergo a rapid change in cell shape to assume a columnar morphology typical of a secretory osteoblast. These cells exhibit markers associated with an osteoblast phenotype, including osteocalcin and osteopontin, and they secrete factors associated with osteogenesis, including bone morphogenetic protein 2, vascular endothelial growth factor, and neurotrophic semaphorins. The pathway involves a shift in integrin expression from α5β1 to α2β1 and signaling by Wnt5a rather than Wnt3a. Conditioned media from these cultures can stimulate vasculogenesis by human endothelial cells and osteoblastic differentiation of marrow stromal cells not grown on the biomimetic substrate, suggesting that the surface could promote osteogenesis in vivo through similar mechanisms. In vivo studies using a variety of animal models confirm that implants with biomimetic surfaces result in improved osseointegration compared with Ti implants with smooth surfaces, as do meta-analyses comparing clinical performance of implant surface topographies.
Topics: Animals; Cell Differentiation; Endothelial Cells; Humans; Osseointegration; Osteogenesis; Surface Properties; Titanium; Vascular Endothelial Growth Factor A
PubMed: 35383608
DOI: 10.5435/JAAOS-D-21-00523 -
International Journal of Nanomedicine 2020Prosthesis-associated infections and aseptic loosening are major causes of implant failure. There is an urgent need to improve the antibacterial ability and... (Review)
Review
Prosthesis-associated infections and aseptic loosening are major causes of implant failure. There is an urgent need to improve the antibacterial ability and osseointegration of orthopedic implants. Zinc oxide nanoparticles (ZnO-NPs) are a common type of zinc-containing metal oxide nanoparticles that have been widely studied in many fields, such as food packaging, pollution treatment, and biomedicine. The ZnO-NPs have low toxicity and good biological functions, as well as antibacterial, anticancer, and osteogenic capabilities. Furthermore, ZnO-NPs can be easily obtained through various methods. Among them, green preparation methods can improve the bioactivity of ZnO-NPs and strengthen their potential application in the biological field. This review discusses the antibacterial abilities of ZnO-NPs, including mechanisms and influencing factors. The toxicity and shortcomings of anticancer applications are summarized. Furthermore, osteogenic mechanisms and synergy with other materials are introduced. Green preparation methods are also briefly reviewed.
Topics: Animals; Anti-Bacterial Agents; Antineoplastic Agents; Chondrogenesis; Green Chemistry Technology; Humans; Metal Nanoparticles; Osteogenesis; Prostheses and Implants; Zinc Oxide
PubMed: 32903812
DOI: 10.2147/IJN.S262876 -
Anatomical Record (Hoboken, N.J. : 2007) Apr 2017The human pelvis has evolved over time into a remarkable structure, optimised into an intricate architecture that transfers the entire load of the upper body into the... (Review)
Review
The human pelvis has evolved over time into a remarkable structure, optimised into an intricate architecture that transfers the entire load of the upper body into the lower limbs, while also facilitating bipedal movement. The pelvic girdle is composed of two hip bones, os coxae, themselves each formed from the gradual fusion of the ischium, ilium and pubis bones. Unlike the development of the classical long bones, a complex timeline of events must occur in order for the pelvis to arise from the embryonic limb buds. An initial blastemal structure forms from the mesenchyme, with chondrification of this mass leading to the first recognisable elements of the pelvis. Primary ossification centres initiate in utero, followed post-natally by secondary ossification at a range of locations, with these processes not complete until adulthood. This cascade of events can vary between individuals, with recent evidence suggesting that fetal activity can affect the normal development of the pelvis. This review surveys the current literature on the ontogeny of the human pelvis. Anat Rec, 300:643-652, 2017. © 2017 Wiley Periodicals, Inc.
Topics: Humans; Osteogenesis; Pelvic Bones; Pelvis
PubMed: 28297183
DOI: 10.1002/ar.23541 -
International Journal of Molecular... Dec 2020This article provides a brief review of the pathophysiology of osteoarthritis and the ontogeny of chondrocytes and details how physical exercise improves the health of... (Review)
Review
This article provides a brief review of the pathophysiology of osteoarthritis and the ontogeny of chondrocytes and details how physical exercise improves the health of osteoarthritic joints and enhances the potential of autologous chondrocyte implants, matrix-induced autologous chondrocyte implants, and mesenchymal stem cell implants for the successful treatment of damaged articular cartilage and subchondral bone. In response to exercise, articular chondrocytes increase their production of glycosaminoglycans, bone morphogenic proteins, and anti-inflammatory cytokines and decrease their production of proinflammatory cytokines and matrix-degrading metalloproteinases. These changes are associated with improvements in cartilage organization and reductions in cartilage degeneration. Studies in humans indicate that exercise enhances joint recruitment of bone marrow-derived mesenchymal stem cells and upregulates their expression of osteogenic and chondrogenic genes, osteogenic microRNAs, and osteogenic growth factors. Rodent experiments demonstrate that exercise enhances the osteogenic potential of bone marrow-derived mesenchymal stem cells while diminishing their adipogenic potential, and that exercise done after stem cell implantation may benefit stem cell transplant viability. Physical exercise also exerts a beneficial effect on the skeletal system by decreasing immune cell production of osteoclastogenic cytokines interleukin-1β, tumor necrosis factor-α, and interferon-γ, while increasing their production of antiosteoclastogenic cytokines interleukin-10 and transforming growth factor-β. In conclusion, physical exercise done both by bone marrow-derived mesenchymal stem cell donors and recipients and by autologous chondrocyte donor recipients may improve the outcome of osteochondral regeneration therapy and improve skeletal health by downregulating osteoclastogenic cytokine production and upregulating antiosteoclastogenic cytokine production by circulating immune cells.
Topics: Animals; Cartilage, Articular; Chondrocytes; Cytokines; Exercise; Glycosaminoglycans; Humans; Mesenchymal Stem Cells; Metalloproteases; Osteoarthritis; Osteogenesis; Physical Conditioning, Animal; Regeneration; Stem Cell Transplantation
PubMed: 33322825
DOI: 10.3390/ijms21249471 -
International Journal of Molecular... Mar 2022Bone is crucial for the support of muscles and the protection of vital organs, and as a reservoir of calcium and phosphorus. Bone is one of the most metabolically active... (Review)
Review
Bone is crucial for the support of muscles and the protection of vital organs, and as a reservoir of calcium and phosphorus. Bone is one of the most metabolically active tissues and is continuously renewed to adapt to the changes required for healthy functioning. To maintain normal cellular and physiological bone functions sufficient oxygen is required, as evidence has shown that hypoxia may influence bone health. In this scenario, this review aimed to analyze the molecular mechanisms involved in hypoxia-induced bone remodeling alterations and their possible clinical consequences. Hypoxia has been associated with reduced bone formation and reduced osteoblast matrix mineralization due to the hypoxia environment inhibiting osteoblast differentiation. A hypoxic environment is involved with increased osteoclastogenesis and increased bone resorptive capacity of the osteoclasts. Clinical studies, although with contradictory results, have shown that hypoxia can modify bone remodeling.
Topics: Bone Remodeling; Cell Differentiation; Humans; Hypoxia; Osteoblasts; Osteoclasts; Osteogenesis
PubMed: 35328654
DOI: 10.3390/ijms23063233 -
Histology and Histopathology Oct 2021Hypertrophic chondrocytes are the master regulators of endochondral ossification; however, their ultimate cell fates cells remain largely elusive due to their transient... (Review)
Review
Hypertrophic chondrocytes are the master regulators of endochondral ossification; however, their ultimate cell fates cells remain largely elusive due to their transient nature. Historically, hypertrophic chondrocytes have been considered as the terminal state of growth plate chondrocytes, which are destined to meet their inevitable demise at the primary spongiosa. Chondrocyte hypertrophy is accompanied by increased organelle synthesis and rapid intracellular water uptake, which serve as the major drivers of longitudinal bone growth. This process is delicately regulated by major signaling pathways and their target genes, including growth hormone (GH), insulin growth factor-1 (IGF-1), indian hedgehog (Ihh), parathyroid hormone-related protein (PTHrP), bone morphogenetic proteins (BMPs), sex determining region Y-box 9 (Sox9), runt-related transcription factors (Runx) and fibroblast growth factor receptors (FGFRs). Hypertrophic chondrocytes orchestrate endochondral ossification by regulating osteogenic-angiogenic and osteogenic-osteoclastic coupling through the production of vascular endothelial growth factor (VEGF), receptor activator of nuclear factor kappa-B ligand (RANKL) and matrix metallopeptidases-9/13 (MMP-9/13). Hypertrophic chondrocytes also indirectly regulate resorption of the cartilaginous extracellular matrix, by controlling formation of a special subtype of osteoclasts termed "chondroclasts". Notably, hypertrophic chondrocytes may possess innate potential for plasticity, reentering the cell cycle and differentiating into osteoblasts and other types of mesenchymal cells in the marrow space. We may be able to harness this unique plasticity for therapeutic purposes, for a variety of skeletal abnormalities and injuries. In this review, we discuss the morphological and molecular properties of hypertrophic chondrocytes, which carry out important functions during skeletal growth and regeneration.
Topics: Animals; Cell Size; Chondrocytes; Chondrogenesis; Growth Plate; Humans; Osteogenesis
PubMed: 34137454
DOI: 10.14670/HH-18-355 -
Frontiers in Endocrinology 2021Bone regeneration is a complex process that requires the coordination of osteogenesis and osteoclastogenesis. The balance between osteogenesis and adipogenesis of bone...
Bone regeneration is a complex process that requires the coordination of osteogenesis and osteoclastogenesis. The balance between osteogenesis and adipogenesis of bone marrow mesenchymal stem cells (BMSCs) plays a major role in the process of bone formation. Recently, intercellular communication between bone cells and surrounding cells has been gradually recognized, and macrophages on the surface of bone have been proven to regulate bone metabolism. However, the underlying mechanisms have not been fully elucidated. Recent studies have indicated that exosomes are vital messengers for cell-cell communication in various biological processes. In this experiment, we found that exosomes derived from M2 macrophages (M2D-Exos) could inhibit adipogenesis and promote osteogenesis of BMSCs. M2D-Exo intervention increased the expression of miR-690, IRS-1, and TAZ in BMSCs. Additionally, miR-690 knockdown in M2 macrophages with a miR-690 inhibitor partially counteracted the effect of M2D-Exos on BMSC differentiation and the upregulation of IRS-1 and TAZ expression. Taken together, the results of our study indicate that exosomes isolated from M2 macrophages could facilitate osteogenesis and reduce adipogenesis through the miR-690/IRS-1/TAZ axis and might be a therapeutic tool for bone loss diseases.
Topics: Adipogenesis; Animals; Exosomes; Interleukin-4; Macrophages; Mesenchymal Stem Cells; Mice; Osteogenesis
PubMed: 34295306
DOI: 10.3389/fendo.2021.680328