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Cell May 2024Clonal hematopoiesis of indeterminate potential (CHIP) arises from aging-associated acquired mutations in hematopoietic progenitors, which display clonal expansion and...
Clonal hematopoiesis of indeterminate potential (CHIP) arises from aging-associated acquired mutations in hematopoietic progenitors, which display clonal expansion and produce phenotypically altered leukocytes. We associated CHIP-DNMT3A mutations with a higher prevalence of periodontitis and gingival inflammation among 4,946 community-dwelling adults. To model DNMT3A-driven CHIP, we used mice with the heterozygous loss-of-function mutation R878H, equivalent to the human hotspot mutation R882H. Partial transplantation with Dnmt3a bone marrow (BM) cells resulted in clonal expansion of mutant cells into both myeloid and lymphoid lineages and an elevated abundance of osteoclast precursors in the BM and osteoclastogenic macrophages in the periphery. DNMT3A-driven clonal hematopoiesis in recipient mice promoted naturally occurring periodontitis and aggravated experimentally induced periodontitis and arthritis, associated with enhanced osteoclastogenesis, IL-17-dependent inflammation and neutrophil responses, and impaired regulatory T cell immunosuppressive activity. DNMT3A-driven clonal hematopoiesis and, subsequently, periodontitis were suppressed by rapamycin treatment. DNMT3A-driven CHIP represents a treatable state of maladaptive hematopoiesis promoting inflammatory bone loss.
PubMed: 38838669
DOI: 10.1016/j.cell.2024.05.003 -
ELife Jun 2024Ninein is a centrosome protein that has been implicated in microtubule anchorage and centrosome cohesion. Mutations in the human gene have been linked to Seckel...
Ninein is a centrosome protein that has been implicated in microtubule anchorage and centrosome cohesion. Mutations in the human gene have been linked to Seckel syndrome and to a rare form of skeletal dysplasia. However, the role of ninein in skeletal development remains unknown. Here, we describe a ninein knockout mouse with advanced endochondral ossification during embryonic development. Although the long bones maintain a regular size, the absence of ninein delays the formation of the bone marrow cavity in the prenatal tibia. Likewise, intramembranous ossification in the skull is more developed, leading to a premature closure of the interfrontal suture. We demonstrate that ninein is strongly expressed in osteoclasts of control mice, and that its absence reduces the fusion of precursor cells into syncytial osteoclasts, whereas the number of osteoblasts remains unaffected. As a consequence, ninein-deficient osteoclasts have a reduced capacity to resorb bone. At the cellular level, the absence of ninein interferes with centrosomal microtubule organization, reduces centrosome cohesion, and provokes the loss of centrosome clustering in multinucleated mature osteoclasts. We propose that centrosomal ninein is important for osteoclast fusion, to enable a functional balance between bone-forming osteoblasts and bone-resorbing osteoclasts during skeletal development.
Topics: Animals; Mice; Centrosome; Mice, Knockout; Nuclear Proteins; Osteoblasts; Osteoclasts; Osteogenesis
PubMed: 38836552
DOI: 10.7554/eLife.93457 -
JGH Open : An Open Access Journal of... Jun 2024Alendronate is used to treat Paget's bone disease, glucocorticoid-induced osteoporosis, and postmenopausal osteoporosis because it suppresses osteoclast activity to stop...
BACKGROUND
Alendronate is used to treat Paget's bone disease, glucocorticoid-induced osteoporosis, and postmenopausal osteoporosis because it suppresses osteoclast activity to stop bone resorption.
CASE REPORT
We present an exceptional case of esophagitis caused by alendronate. Blood tests and other data were normal when the patient was taken to the hospital, but an endoscopic examination revealed significant esophageal redness, erosion, and ulceration, along with pseudomembrane. The patient was given medicine after receiving a diagnosis of alendronate pill-induced esophagitis based on the pathological findings.
CONCLUSION
This case report is a timely reminder of the importance of thorough pharmacovigilance, patient education, and smart therapeutic decision-making in the context of alendronate use. To properly treat and prevent problems with the esophagus caused by alendronate, additional research is required.
PubMed: 38832136
DOI: 10.1002/jgh3.13080 -
Aging May 2024Currently, the repair of large bone defects still faces numerous challenges, with the most crucial being the lack of large bone grafts with good osteogenic properties....
Currently, the repair of large bone defects still faces numerous challenges, with the most crucial being the lack of large bone grafts with good osteogenic properties. In this study, a novel bone repair implant (degradable porous zinc scaffold/BF Exo composite implant) was developed by utilizing laser melting rapid prototyping 3D printing technology to fabricate a porous zinc scaffold, combining it under vacuum conditions with highly bioactive serum exosomes (BF EXO) and Poloxamer 407 thermosensitive hydrogel. The electron microscope revealed the presence of tea saucer-shaped exosomes with a double-layered membrane structure, ranging in diameter from 30-150 nm, with an average size of 86.3 nm and a concentration of 3.28E+09 particles/mL. experiments demonstrated that the zinc scaffold displayed no significant cytotoxicity, and loading exosomes enhanced the zinc scaffold's ability to promote osteogenic cell activity while inhibiting osteoclast activity. experiments on rabbits indicated that the hepatic and renal toxicity of the zinc scaffold decreased over time, and the loading of exosomes alleviated the hepatic and renal toxic effects of the zinc scaffold. Throughout various stages of repairing radial bone defects in rabbits, loading exosomes reinforced the zinc scaffold's capacity to enhance osteogenic cell activity, suppress osteoclast activity, and promote angiogenesis. This effect may be attributed to BF Exo's regulation of p38/STAT1 signaling. This study signifies that the combined treatment of degradable porous zinc scaffolds and BF Exo is an effective and biocompatible strategy for bone defect repair therapy.
Topics: Animals; Exosomes; Printing, Three-Dimensional; Rabbits; Tissue Scaffolds; Radius; Zinc; Osteogenesis; Porosity; Bone Regeneration; Male
PubMed: 38829771
DOI: 10.18632/aging.205891 -
Experimental Biology and Medicine... 2024[This corrects the article DOI: 10.1177/15353702231211977.].
[This corrects the article DOI: 10.1177/15353702231211977.].
PubMed: 38826627
DOI: 10.3389/ebm.2024.10149 -
BioRxiv : the Preprint Server For... May 2024Malocclusions are common craniofacial malformations which cause quality of life and health problems if left untreated. Unfortunately, the current treatment for severe...
Malocclusions are common craniofacial malformations which cause quality of life and health problems if left untreated. Unfortunately, the current treatment for severe skeletal malocclusion is invasive surgery. Developing improved therapeutic options requires a deeper understanding of the cellular mechanisms responsible for determining jaw bone length. We have recently shown that neural crest mesenchyme (NCM) can alter jaw length by controlling recruitment and function of mesoderm-derived osteoclasts. Transforming growth factor beta (TGF-β) signaling is critical to craniofacial development by directing bone resorption and formation, and heterozygous mutations in TGF-β type I receptor ( are associated with micrognathia in humans. To identify what role TGF-β signaling in NCM plays in controlling osteoclasts during mandibular development, mandibles of mouse embryos deficient in the gene encoding specifically in NCM were analyzed. Our lab and others have demonstrated that mice display significantly shorter mandibles with no condylar, coronoid, or angular processes. We hypothesize that TGF-β signaling in NCM can also direct later bone remodeling and further regulate late embryonic jaw bone length. Interestingly, analysis of mandibular bone through micro-computed tomography and Masson's trichrome revealed no significant difference in bone quality between the mice and controls, as measured by bone perimeter/bone area, trabecular rod-like diameter, number and separation, and gene expression of Collagen type 1 alpha 1 () and Matrix metalloproteinase 13 (). Though there was not a difference in localization of bone resorption within the mandible indicated by TRAP staining, mice had approximately three-fold less osteoclast number and perimeter than controls. Gene expression of receptor activator of nuclear factor kappa-β () and , markers of osteoclasts and their activity, also showed a three-fold decrease in mandibles. Evaluation of osteoblast-to-osteoclast signaling revealed no significant difference between mandibles and controls, leaving the specific mechanism unresolved. Finally, pharmacological inhibition of signaling during the initiation of bone mineralization and resorption significantly shortened jaw length in embryos. We conclude that TGF-β signaling in NCM decreases mesoderm-derived osteoclast number, that TGF-β signaling in NCM impacts jaw length late in development, and that this osteoblast-to-osteoclast communication may be occurring through an undescribed mechanism.
PubMed: 38826301
DOI: 10.1101/2024.05.24.595783 -
The Science of the Total Environment Aug 2024Epidemic and animal studies have reported that perfluoroalkyl and polyfluoroalkyl substances (PFASs) are strongly associated with liver injury; however, to date, the...
Epidemic and animal studies have reported that perfluoroalkyl and polyfluoroalkyl substances (PFASs) are strongly associated with liver injury; however, to date, the effects of PFASs on the hepatic microenvironment remain largely unknown. In this study, we established perfluorooctane sulfonic acid (PFOS)-induced liver injury models by providing male and female C57BL/6 mice with water containing PFOS at varying doses for 4 weeks. Hematoxylin and eosin staining revealed that PFOS induced liver injury in both sexes. Elevated levels of serum aminotransferases including those of alanine aminotransferase and aspartate transaminase were detected in the serum of mice treated with PFOS. Female mice exhibited more severe liver injury than male mice. We collected the livers from female mice and performed single-cell RNA sequencing. In total, 36,529 cells were included and grouped into 10 major cell types: B cells, granulocytes, T cells, NK cells, monocytes, dendritic cells, macrophages, endothelial cells, fibroblasts, and hepatocytes. Osteoclast differentiation was upregulated and the T cell receptor signaling pathway was significantly downregulated in PFOS-treated livers. Further analyses revealed that among immune cell clusters in PFOS-treated livers, Tcf7CD4T cells were predominantly downregulated, whereas conventional dendritic cells and macrophages were upregulated. Among the fibroblast subpopulations, hepatic stellate cells were significantly enriched in PFOS-treated female mice. CellphoneDB analysis suggested that fibroblasts interact closely with endothelial cells. The major ligand-receptor pairs between fibroblasts and endothelial cells in PFOS-treated livers were Dpp4_Cxcl12, Ackr3_Cxcl12, and Flt1_complex_Vegfa. These genes are associated with directing cell migration and angiogenesis. Our study provides a general framework for understanding the microenvironment in the livers of female mice exposed to PFOS at the single-cell level.
Topics: Animals; Fluorocarbons; Alkanesulfonic Acids; Female; Mice; Mice, Inbred C57BL; Male; Chemical and Drug Induced Liver Injury; Transcriptome; Liver; Single-Cell Analysis; Environmental Pollutants
PubMed: 38825197
DOI: 10.1016/j.scitotenv.2024.173562 -
Journal of Advanced Research May 2024Sympathetic hyperinnervation plays an important role in modulating the vascular smooth muscle cell (VSMC) phenotype and vascular diseases, but its role in abdominal...
INTRODUCTION
Sympathetic hyperinnervation plays an important role in modulating the vascular smooth muscle cell (VSMC) phenotype and vascular diseases, but its role in abdominal aortic aneurysm (AAA) is still unknown.
OBJECTIVES
This study aimed to investigate the role of sympathetic hyperinnervation in promoting AAA development and the underlying mechanism involved.
METHODS
Western blotting and immunochemical staining were used to detect sympathetic hyperinnervation. We performed sympathetic denervation through coeliac ganglionectomy (CGX) and 6-OHDA administration to understand the role of sympathetic hyperinnervation in AAA and investigated the underlying mechanisms through transcriptome and functional studies. Sema4D knockout (Sema4D) mice were utilized to determine the involvement of Sema4D in inducing sympathetic hyperinnervation and AAA development.
RESULTS
We observed sympathetic hyperinnervation, the most important form of sympathetic neural remodeling, in both mouse AAA models and AAA patients. Elimination of sympathetic hyperinnervation by CGX or 6-OHDA significantly inhibited AAA development and progression. We further revealed that sympathetic hyperinnervation promoted VSMC phenotypic switching in AAA by releasing extracellular ATP (eATP) and activating eATP-P2rx4-p38 signaling. Moreover, single-cell RNA sequencing revealed that Sema4D secreted by osteoclast-like cells induces sympathetic nerve diffusion and hyperinnervation through binding to Plxnb1. We consistently observed that AAA progression was significantly ameliorated in Sema4D-deficient mice.
CONCLUSIONS
Sympathetic hyperinnervation driven by osteoclast-like cell-derived Sema4D promotes VSMC phenotypic switching and accelerates pathological aneurysm progression by activating the eATP/P2rx4/p38 pathway. Inhibition of sympathetic hyperinnervation emerges as a potential novel therapeutic strategy for preventing and treating AAA.
PubMed: 38821358
DOI: 10.1016/j.jare.2024.05.028 -
Annals of Medicine Dec 2024Intervertebral disc degeneration (IDD) is an important cause of low back pain. The aim of this study is to identify the potential molecular mechanism of abnormal...
Comprehensive analysis of abnormal methylation modification differential expression mRNAs between low-grade and high-grade intervertebral disc degeneration and its correlation with immune cells.
BACKGROUND
Intervertebral disc degeneration (IDD) is an important cause of low back pain. The aim of this study is to identify the potential molecular mechanism of abnormal methylation-modified DNA in the progression of IDD, hoping to contribute to the diagnosis and management of IDD.
METHODS
Low-grade IDD (grade I-II) and high-grade IDD (grade III-V) data were downloaded from GSE70362 and GSE129789 datasets. The abnormally methylated modified differentially expressed mRNAs (DEmRNAs) were identified by differential expression analysis (screening criteria were < .05 and |logFC| > 1) and differential methylation analysis (screening criteria were < .05 and |δβ| > 0.1). The classification models were constructed, and the receiver operating characteristic analysis was also carried out. In addition, functional enrichment analysis and immune correlation analysis were performed and the miRNAs targeted for the abnormally methylated DEmRNAs were predicted. Finally, expression validation was performed using real-time PCR.
RESULTS
Compared with low-grade IDD, seven abnormal methylation-modified DEmRNAs (AOX1, IBSP, QDPR, ABLIM1, CRISPLD2, ACTC1 and EMILIN1) were identified in high-grade IDD, and the classification models of random forests (RF) and support vector machine (SVM) were constructed. Moreover, seven abnormal methylation-modified DEmRNAs and classification models have high diagnostic accuracy (area under the curve [AUC] > 0.8). We also found that AUC values of single abnormal methylation-modified DEmRNA were all lower than those of RF and SVM classification models. Pearson correlation analysis found that macrophages M2 and EMILIN1 had significant negative correlation, while macrophages M2 and IBSP had significant positive correlation. In addition, four targeted relationship pairs (hsa-miR-4728-5p-QDPR, hsa-miR-4533-ABLIM1, hsa-miR-4728-5p-ABLIM1 and hsa-miR-4534-CRISPLD2) and multiple signalling pathways (for example, PI3K-AKT signalling pathway, osteoclast differentiation and calcium signalling pathway) were also identified that may be involved in the progression of IDD.
CONCLUSION
The identification of abnormal methylation-modified DEmRNAs and the construction of classification models in this study were helpful for the diagnosis and management of IDD progression.
Topics: Humans; Intervertebral Disc Degeneration; DNA Methylation; RNA, Messenger; MicroRNAs; Gene Expression Profiling; ROC Curve
PubMed: 38819022
DOI: 10.1080/07853890.2024.2357742 -
International Journal of Molecular... Jul 2024Osteoporosis is a common bone metabolic disease that causes a heavy social burden and seriously threatens life. Improving osteogenic capacity is necessary to correct... (Review)
Review
Osteoporosis is a common bone metabolic disease that causes a heavy social burden and seriously threatens life. Improving osteogenic capacity is necessary to correct bone mass loss in the treatment of osteoporosis. Osteoblasts are derived from the differentiation of bone marrow mesenchymal stem cells, a process that opposes adipogenic differentiation. The peroxisome proliferator‑activated receptor γ and Wnt/β‑catenin signaling pathways mediate the mutual regulation of osteogenesis and adipogenesis. Lipid substances play an important role in the occurrence and development of osteoporosis. The content and proportion of lipids modulate the activity of immunocytes, mainly macrophages, and the secretion of inflammatory factors, such as IL‑1, IL‑6 and TNF‑α. These inflammatory effectors increase the activity and promote the differentiation of osteoclasts, which leads to bone imbalance and stronger bone resorption. Obesity also decreases the activity of antioxidases and leads to oxidative stress, thereby inhibiting osteogenesis. The present review starts by examining the bidirectional differentiation of BM‑MSCs, describes in detail the mechanism by which lipids affect bone metabolism, and discusses the regulatory role of inflammation and oxidative stress in this process. The review concludes that a reasonable adjustment of the content and proportion of lipids, and the alleviation of inflammatory storms and oxidative damage induced by lipid imbalances, will improve bone mass and treat osteoporosis.
Topics: Humans; Osteoporosis; Lipid Metabolism; Obesity; Animals; Osteogenesis; Oxidative Stress; Mesenchymal Stem Cells; Cell Differentiation
PubMed: 38818830
DOI: 10.3892/ijmm.2024.5385