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Journal of Cellular and Molecular... Feb 2024Blood vessels are essential for bone development and metabolism. Type H vessels in bone, named after their high expression of CD31 and Endomucin (Emcn), have recently... (Review)
Review
Blood vessels are essential for bone development and metabolism. Type H vessels in bone, named after their high expression of CD31 and Endomucin (Emcn), have recently been reported to locate mainly in the metaphysis, exhibit different molecular properties and couple osteogenesis and angiogenesis. A strong correlation between type H vessels and bone metabolism is now well-recognized. The crosstalk between type H vessels and osteoprogenitor cells is also involved in bone metabolism-related diseases such as osteoporosis, osteoarthritis, fracture healing and bone defects. Targeting the type H vessel formation may become a new approach for managing a variety of bone diseases. This review highlighted the roles of type H vessels in bone-related diseases and summarized the research attempts to develop targeted intervention, which will help us gain a better understanding of their potential value in clinical application.
Topics: Humans; Osteogenesis; Bone and Bones; Osteoporosis; Bone Diseases, Metabolic; Fracture Healing; Neovascularization, Physiologic
PubMed: 38353470
DOI: 10.1111/jcmm.18123 -
Journal of Nanobiotechnology Sep 2023Despite the recent advances in the development of bone graft substitutes, treatment of critical size bone defects continues to be a significant challenge, especially in... (Review)
Review
Despite the recent advances in the development of bone graft substitutes, treatment of critical size bone defects continues to be a significant challenge, especially in the elderly population. A current approach to overcome this challenge involves the creation of bone-mimicking scaffolds that can simultaneously promote osteogenesis and angiogenesis. In this context, incorporating multiple bioactive agents like growth factors, genes, and small molecules into these scaffolds has emerged as a promising strategy. To incorporate such agents, researchers have developed scaffolds incorporating nanoparticles, including nanoparticulate carriers, inorganic nanoparticles, and exosomes. Current paper provides a summary of the latest advancements in using various bioactive agents, drugs, and cells to synergistically promote osteogenesis and angiogenesis in bone-mimetic scaffolds. It also discusses scaffold design properties aimed at maximizing the synergistic effects of osteogenesis and angiogenesis, various innovative fabrication strategies, and ongoing clinical studies.
Topics: Aged; Humans; Osteogenesis; Tissue Engineering; Tissue Scaffolds; Biocompatible Materials; Bone Regeneration; Neovascularization, Physiologic
PubMed: 37770928
DOI: 10.1186/s12951-023-02115-7 -
Annals of the Rheumatic Diseases Feb 2024This study aimed to identify the types and heterogeneity of cells within the spinal enthesis and investigate the underlying mechanisms of osteogenesis.
OBJECTIVES
This study aimed to identify the types and heterogeneity of cells within the spinal enthesis and investigate the underlying mechanisms of osteogenesis.
METHODS
Single-cell RNA sequencing was used to identify cell populations and their gene signatures in the spinal enthesis of five patients with ankylosing spondylitis (AS) and three healthy individuals. The transcriptomes of 40 065 single cells were profiled and divided into 7 clusters: neutrophils, monocytic cells, granulomonocytic progenitor_erythroblasts, T cells, B cells, plasma cells and stromal cells. Real-time quantitative PCR, immunofluorescence, flow cytometry, osteogenesis induction, alizarin red staining, immunohistochemistry, short hairpin RNA and H&E staining were applied to validate the bioinformatics analysis.
RESULTS
Pseudo-time analysis showed two differentiation directions of stromal cells from the mesenchymal stem cell subpopulation MSC-C2 to two Cxcl12-abundant-reticular (CAR) cell subsets, Osteo-CAR and Adipo-CAR, within which three transcription factors, C-JUN, C-FOS and CAVIN1, were highly expressed in AS and regulated the osteogenesis of mesenchymal stem cells. A novel subcluster of early-stage neutrophils, CD99_G1, was elevated in AS. The proinflammatory characteristics of monocyte dendritic cell progenitor-recombinant adiponectin receptor 2 monocytic cells were explored. Interactions between Adipo-CAR cells, CD99_G1 neutrophils and other cell types were mapped by identifying ligand-receptor pairs, revealing the recruitment characteristics of CD99_G1 neutrophils by Adipo-CAR cells and the pathogenesis of osteogenesis induced in AS.
CONCLUSIONS
Our results revealed the dynamics of cell subpopulations, gene expression and intercellular interactions during AS pathogenesis. These findings provide new insights into the cellular and molecular mechanisms of osteogenesis and will benefit the development of novel therapeutic strategies.
Topics: Humans; Cell Differentiation; Cells, Cultured; Mesenchymal Stem Cells; Neutrophils; Osteogenesis; Spondylitis, Ankylosing
PubMed: 37977819
DOI: 10.1136/ard-2023-224107 -
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 -
Journal of Translational Medicine Jan 2024As more is learned about lactate, it acts as both a product and a substrate and functions as a shuttle system between different cell populations to provide the energy... (Review)
Review
As more is learned about lactate, it acts as both a product and a substrate and functions as a shuttle system between different cell populations to provide the energy for sustaining tumor growth and proliferation. Recent discoveries of protein lactylation modification mediated by lactate play an increasingly significant role in human health (e.g., neural and osteogenic differentiation and maturation) and diseases (e.g., tumors, fibrosis and inflammation, etc.). These views are critically significant and first described in detail in this review. Hence, here, we focused on a new target, protein lactylation, which may be a "double-edged sword" of human health and diseases. The main purpose of this review was to describe how protein lactylation acts in multiple physiological and pathological processes and their potential mechanisms through an in-depth summary of preclinical in vitro and in vivo studies. Our work aims to provide new ideas for treating different diseases and accelerate translation from bench to bedside.
Topics: Humans; Osteogenesis; Lactic Acid; Cell Differentiation; Inflammation; Protein Processing, Post-Translational
PubMed: 38200523
DOI: 10.1186/s12967-023-04842-9 -
Frontiers in Immunology 2023Determining the transcriptomes and molecular mechanism underlying human degenerative nucleus pulposus (NP) is of critical importance for treating intervertebral disc...
BACKGROUND AND AIMS
Determining the transcriptomes and molecular mechanism underlying human degenerative nucleus pulposus (NP) is of critical importance for treating intervertebral disc degeneration (IDD). Here, we aimed to elucidate the detailed molecular mechanism of NP ossification and IDD using single-cell RNA sequencing.
METHODS
Single-cell RNA-seq and bioinformatic analysis were performed to identify NP cell populations with gene signatures, biological processes and pathways, and subpopulation analysis, RNA velocity analysis, and cell-to-cell communication analysis were performed in four IDD patients. We also verified the effects of immune cells on NP ossification using cultured NP cells and a well-established rat IDD model.
RESULTS
We identified five cell populations with gene expression profiles in degenerative NP at single-cell resolution. GO database analysis showed that degenerative NP-associated genes were mainly enriched in extracellular matrix organization, immune response, and ossification. Gene set enrichment analysis showed that rheumatoid arthritis signaling, antigen processing and presentation signaling were activated in the blood cell cluster. We revealed that stromal cells, which are progenitor cells, differentiated toward an ossification phenotype and delineated interactions between immune cells (macrophages and T cells) and stromal cells. Immune factors such as TNF-α, CD74 and CCL-3 promoted the differentiation of stromal cells toward an ossification phenotype . Blocking TNF-α with a specific inhibitor successfully reversed NP ossification and modified NP morphology .
CONCLUSION
Our study revealed an increase in macrophages and T cells in degenerative NP, which induced stromal cell differentiation toward an ossification phenotype, and contributed to the identification of a novel therapeutic target to delay IDD.
Topics: Humans; Animals; Rats; Nucleus Pulposus; Osteogenesis; Single-Cell Gene Expression Analysis; Tumor Necrosis Factor-alpha; Cell Differentiation
PubMed: 37638033
DOI: 10.3389/fimmu.2023.1224627 -
JCI Insight Aug 2023Reactive oxygen species (ROS) are natural products of mitochondrial oxidative metabolism and oxidative protein folding. ROS levels must be well controlled, since...
Reactive oxygen species (ROS) are natural products of mitochondrial oxidative metabolism and oxidative protein folding. ROS levels must be well controlled, since elevated ROS has been shown to have deleterious effects on osteoblasts. Moreover, excessive ROS is thought to underlie many of the skeletal phenotypes associated with aging and sex steroid deficiency in mice and humans. The mechanisms by which osteoblasts regulate ROS and how ROS inhibits osteoblasts are not well understood. Here, we demonstrate that de novo glutathione (GSH) biosynthesis is essential in neutralizing ROS and establish a proosteogenic reduction and oxidation reaction (REDOX) environment. Using a multifaceted approach, we demonstrate that reducing GSH biosynthesis led to acute degradation of RUNX2, impaired osteoblast differentiation, and reduced bone formation. Conversely, reducing ROS using catalase enhanced RUNX2 stability and promoted osteoblast differentiation and bone formation when GSH biosynthesis was limited. Highlighting the therapeutic implications of these findings, in utero antioxidant therapy stabilized RUNX2 and improved bone development in the Runx2+/- haplo-insufficient mouse model of human cleidocranial dysplasia. Thus, our data establish RUNX2 as a molecular sensor of the osteoblast REDOX environment and mechanistically clarify how ROS negatively impacts osteoblast differentiation and bone formation.
Topics: Mice; Humans; Animals; Osteogenesis; Reactive Oxygen Species; Core Binding Factor Alpha 1 Subunit; Oxidation-Reduction; Glutathione
PubMed: 37432749
DOI: 10.1172/jci.insight.166888 -
A Bioinspired Gelatin-Amorphous Calcium Phosphate Coating on Titanium Implant for Bone Regeneration.Advanced Healthcare Materials Aug 2023Biocompatible and bio-active coatings can enhance and accelerate osseointegration via chemical binding onto substrates. Amorphous calcium phosphate (ACP) has been shown...
Biocompatible and bio-active coatings can enhance and accelerate osseointegration via chemical binding onto substrates. Amorphous calcium phosphate (ACP) has been shown as a precursor to achieve mineralization in vertebrates and invertebrates under the control of biological macromolecules. This work presents a simple bioinspired Gelatin-CaPO (Gel-CaP) composite coating on titanium surfaces to improve osseointegration. The covalently bound Gel-CaP composite is characterized as an ACP-Gel compound via SEM, FT-IR, XRD, and HR-TEM. The amorphous compound coating exhibits a nanometer range thickness and improved elastic modulus, good wettability, and nanometric roughness. The amount of grafted carboxyl groups and theoretical thickness of the coatings are also investigated. More importantly, MC3T3 cells, an osteoblast cell line, show excellent cell proliferation and adhesion on the Gel-CaP coating. The level of osteogenic genes is considerably upregulated on Ti with Gel-CaP coatings compared to uncoated Ti, demonstrating that Gel-CaP coatings possess a unique osteogenic ability. To conclude, this work offers a new perspective on functional, bioactive titanium coatings, and Gel-CaP composites can be a low-cost and promising candidate in bone regeneration.
Topics: Animals; Gelatin; Titanium; Spectroscopy, Fourier Transform Infrared; Coated Materials, Biocompatible; Osseointegration; Osteogenesis; Surface Properties
PubMed: 36944062
DOI: 10.1002/adhm.202203411 -
Oral Diseases Apr 2024Periodontitis is the major cause of tooth loss in adults and is mainly characterized by alveolar bone destruction. Elucidating the mesenchymal stem cell (MSC)/progenitor... (Review)
Review
Periodontitis is the major cause of tooth loss in adults and is mainly characterized by alveolar bone destruction. Elucidating the mesenchymal stem cell (MSC)/progenitor populations of alveolar bone formation will provide valuable insights into regenerative approaches to clinical practice, such as endogenous regeneration and stem-cell-based tissue engineering therapies. Classically, MSCs residing in the bone marrow, periosteum, periodontal ligament (PDL), and even the gingiva are considered to be osteogenic progenitors. Furthermore, the contributions of MSCs expressing specific markers, including Gli1, Axin2, PTHrP, LepR, and α-SMA, to alveolar bone formation have been studied using cell lineage tracing and gene knockout models. In this review, we describe the MSCs/progenitors of alveolar bone and the biological properties of different subpopulations of MSCs involved in alveolar bone development, remodeling, injury repair, and regeneration.
Topics: Humans; Mesenchymal Stem Cells; Periodontium; Osteogenesis; Periodontitis; Periodontal Ligament; Animals
PubMed: 36648363
DOI: 10.1111/odi.14507 -
Small Methods Oct 2023Current artificial designs of the periosteum focus on osteogenic or angiogenic properties, while ignoring the filling and integration with bone microcracks, which...
Current artificial designs of the periosteum focus on osteogenic or angiogenic properties, while ignoring the filling and integration with bone microcracks, which trigger a prolonged excessive inflammatory reaction and lead to failure of bone regeneration. In this study, seamless adhesive biomimetic periosteum patches (HABP/Sr-PLA) were prepared to fill microcracks in defective bone via interfacial self-assembly induced by Sr ions mediated metal-ligand interactions among pamidronate disodium-modified hyaluronic acid (HAPD), black phosphorus (BP), and hydrophilic polylactic acid (PLA). In vitro, HABP/Sr-PLA exhibited excellent self-healing properties, seamlessly filled bone microcracks, and significantly enhanced osteogenesis and angiogenesis. Furthermore, in a rat cranial defect model, HABP/Sr-PLA was demonstrated to significantly promote the formation of blood vessels and new bone under mild 808 nm photothermal stimulation (42.8 °C), and the highest protein expression of CD31 and OPN was five times higher than that of the control group and other groups. Therefore, the proposed seamless microcrack-filled bionic periosteum patch is a promising clinical strategy for promoting bone repair.
Topics: Rats; Animals; Periosteum; Bionics; Osteogenesis; Bone Regeneration; Polyesters
PubMed: 37356079
DOI: 10.1002/smtd.202300370