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International Journal of Molecular... Oct 2023Osteoporosis is a widespread systemic disease characterized by a decrease in bone mass and an imbalance of the microarchitecture of bone tissue. Experimental and... (Review)
Review
Osteoporosis is a widespread systemic disease characterized by a decrease in bone mass and an imbalance of the microarchitecture of bone tissue. Experimental and clinical studies devoted to investigating the main pathogenetic mechanisms of osteoporosis revealed the important role of estrogen deficiency, inflammation, oxidative stress, cellular senescence, and epigenetic factors in the development of bone resorption due to osteoclastogenesis, and decreased mineralization of bone tissue and bone formation due to reduced function of osteoblasts caused by apoptosis and age-depended differentiation of osteoblast precursors into adipocytes. The current review was conducted to describe the basic mechanisms of the development of osteoporosis at molecular and cellular levels and to elucidate the most promising therapeutic strategies of pathogenetic therapy of osteoporosis based on articles cited in PubMed up to September 2023.
Topics: Humans; Osteogenesis; Osteoblasts; Osteoporosis; Bone and Bones; Osteoclasts; Cell Differentiation
PubMed: 37958752
DOI: 10.3390/ijms242115772 -
Advanced Materials (Deerfield Beach,... Oct 2023Neural-vascular networks are densely distributed through periosteum, cortical bone, and cancellous bone, which is of great significance for bone regeneration and...
Neural-vascular networks are densely distributed through periosteum, cortical bone, and cancellous bone, which is of great significance for bone regeneration and remodeling. Although significant progress has been made in bone tissue engineering, ineffective bone regeneration, and delayed osteointegration still remains an issue due to the ignorance of intrabony nerves and blood vessels. Herein, inspired by space-filling polyhedra with open architectures, polyhedron-like scaffolds with spatial topologies are prepared via 3D-printing technology to mimic the meshwork structure of cancellous bone. Benefiting from its spatial topologies, polyhedron-like scaffolds greatly promoted the osteogenic differentiation of bone mesenchymal stem cells (BMSCs) via activating PI3K-Akt signals, and exhibiting satisfactory performance on angiogenesis and neurogenesis. Computational fluid dynamic (CFD) simulation elucidates that polyhedron-like scaffolds have a relatively lower area-weighted average static pressure, which is beneficial to osteogenesis. Furthermore, in vivo experiments further demonstrate that polyhedron-like scaffolds obviously promote bone formation and osteointegration, as well as inducing vascularization and ingrowth of nerves, leading to innervated and vascularized bone regeneration. Taken together, this work offers a promising approach for fabricating multifunctional scaffolds without additional exogenous seeding cells and growth factors, which holds great potential for functional tissue regeneration and further clinical translation.
Topics: Biocompatible Materials; Osteogenesis; Tissue Scaffolds; Phosphatidylinositol 3-Kinases; Bone Regeneration; Tissue Engineering; Cell Differentiation; Printing, Three-Dimensional
PubMed: 37434296
DOI: 10.1002/adma.202302716 -
ACS Nano Sep 2023An essential challenge in diabetic periodontal regeneration is achieving the transition from a hyperglycemic inflammatory microenvironment to a regenerative one. Here,...
An essential challenge in diabetic periodontal regeneration is achieving the transition from a hyperglycemic inflammatory microenvironment to a regenerative one. Here, we describe a polydopamine (PDA)-mediated ultralong silk microfiber (PDA-mSF) and metformin (Met)-loaded zeolitic imidazolate framework (ZIF) incorporated into a silk fibroin/gelatin (SG) patch to promote periodontal soft and hard tissue regeneration by regulating the immunomodulatory microenvironment. The PDA-mSF endows the patch with a reactive oxygen species (ROS)-scavenging ability and anti-inflammatory activity, reducing the inflammatory response by suppressing M1 macrophage polarization. Moreover, PDA improves periodontal ligament reconstruction via its cell affinity. Sustained release of Met from the Met-ZIF system confers the patch with antiaging and immunomodulatory abilities by activating M2 macrophage polarization to secrete osteogenesis-related cytokines, while release of Zn also promotes bone regeneration. Consequently, the Met-ZIF system creates a favorable microenvironment for periodontal tissue regeneration. These features synergistically accelerate diabetic periodontal bone and ligament regeneration. Thus, our findings offer a potential therapeutic strategy for hard and soft tissue regeneration in diabetic periodontitis.
Topics: Zeolites; Metformin; Cell Differentiation; Periodontium; Osteogenesis; Diabetes Mellitus
PubMed: 37578444
DOI: 10.1021/acsnano.3c02407 -
Nature Communications Sep 2023Treatment of osteoporosis commonly diminishes osteoclast number which suppresses bone formation thus compromising fracture prevention. Bone formation is not suppressed,...
Treatment of osteoporosis commonly diminishes osteoclast number which suppresses bone formation thus compromising fracture prevention. Bone formation is not suppressed, however, when bone degradation is reduced by retarding osteoclast functional resorptive capacity, rather than differentiation. We find deletion of deubiquitinase, BRCA1-associated protein 1 (Bap1), in myeloid cells (Bap1), arrests osteoclast function but not formation. Bap1 osteoclasts fail to organize their cytoskeleton which is essential for bone degradation consequently increasing bone mass in both male and female mice. The deubiquitinase activity of BAP1 modifies osteoclast function by metabolic reprogramming. Bap1 deficient osteoclast upregulate the cystine transporter, Slc7a11, by enhanced H2Aub occupancy of its promoter. SLC7A11 controls cellular reactive oxygen species levels and redirects the mitochondrial metabolites away from the tricarboxylic acid cycle, both being necessary for osteoclast function. Thus, in osteoclasts BAP1 appears to regulate the epigenetic-metabolic axis and is a potential target to reduce bone degradation while maintaining osteogenesis in osteoporotic patients.
Topics: Animals; Female; Humans; Male; Mice; Bone Density; Citric Acid Cycle; Deubiquitinating Enzymes; Osteoclasts; Osteogenesis; Tumor Suppressor Proteins; Ubiquitin Thiolesterase
PubMed: 37740028
DOI: 10.1038/s41467-023-41629-4 -
Advanced Materials (Deerfield Beach,... Jan 2024Elimination of bacterial infections and simultaneously promoting osteogenic differentiation are highly required for infectious bone diseases. Massive reactive oxygen...
Elimination of bacterial infections and simultaneously promoting osteogenic differentiation are highly required for infectious bone diseases. Massive reactive oxygen species (ROS) can damage cells, while low ROS concentrations as a molecular signal can regulate cellular fate. In this study, a Janus-ROS healing system is developed for infectious bone regeneration. An alendronate (ALN)-mediated defective metal-organic framework (MOF) sonosensitizer is prepared, which can effectively clear Methicillin-resistant Staphylococcus aureus (MRSA) infections and promote osteogenic differentiation under differential ultrasonic irradiation. In the presence of zirconium-phosphate coordination, the ALN-mediated porphyrin-based MOF (HN25) with a proper defect has great sonodynamic antibacterial efficiency (98.97%, 15 min) and bone-targeting ability. Notably, under low-power ultrasound irradiation, HN25 can increase the chromatin accessibility of ossification-related genes and FOXO1 to promote bone repair through low ROS concentrations. Animal models of paravertebral infection, fracture with infection, and osteomyelitis demonstrate that HN25 successfully realizes the targeted and potent repair of various infectious bone tissues through rapid MRSA elimination, inhibiting osteoclast activity and promoting bone regeneration. The results show that high catalytic efficiency and bioactive MOF can be constructed using pharmaceutical-mediated defect engineering. The Janus-ROS treatment is also a promising therapeutic mode for infectious tissue regeneration.
Topics: Animals; Osteogenesis; Reactive Oxygen Species; Methicillin-Resistant Staphylococcus aureus; Bone Regeneration; Bone and Bones; Metal-Organic Frameworks
PubMed: 37855420
DOI: 10.1002/adma.202307846 -
Clinical and Translational Medicine Sep 2023The imbalance between osteoblasts and osteoclasts may lead to osteoporosis. Osteoblasts and osteoclasts have different energy requirements, with aerobic glycolysis being...
BACKGROUND
The imbalance between osteoblasts and osteoclasts may lead to osteoporosis. Osteoblasts and osteoclasts have different energy requirements, with aerobic glycolysis being the prominent metabolic feature of osteoblasts, while osteoclast differentiation and fusion are driven by oxidative phosphorylation.
METHODS
By polymerase chain reaction as well as Western blotting, we assayed coactivator-associated arginine methyltransferase 1 (CARM1) expression in bone tissue, the mouse precranial osteoblast cell line MC3T3-E1 and the mouse monocyte macrophage leukaemia cell line RAW264.7, and expression of related genes during osteogenic differentiation and osteoclast differentiation. Using gene overexpression (lentivirus) and loss-of-function approach (CRISPR/Cas9-mediated knockout) in vitro, we examined whether CARM1 regulates osteogenic differentiation and osteoblast differentiation by metabolic regulation. Transcriptomic assays and metabolomic assays were used to find the mechanism of action of CARM1. Furthermore, in vitro methylation assays were applied to clarify the arginine methylation site of PPP1CA by CARM1.
RESULTS
We discovered that CARM1 reprogrammed glucose metabolism in osteoblasts and osteoclasts from oxidative phosphorylation to aerobic glycolysis, thereby promoting osteogenic differentiation and inhibiting osteoclastic differentiation. In vivo experiments revealed that CARM1 significantly decreased bone loss in osteoporosis model mice. Mechanistically, CARM1 methylated R23 of PPP1CA, affected the dephosphorylation of AKT-T450 and AMPK-T172, and increased the activities of phosphofructokinase-1 and pructose-2,6-biphosphatase3, causing an up-regulation of glycolytic flux. At the same time, as a transcriptional coactivator, CARM1 regulated the expression of pyruvate dehydrogenase kinase 3, which resulted in the inhibition of pyruvate dehydrogenase activity and inhibition of the tricarboxylic acid cycle, leading to a subsequent decrease in the flux of oxidative phosphorylation.
CONCLUSIONS
These findings reveal for the first time the mechanism by which CARM1 affects both osteogenesis and osteoclast differentiation through metabolic regulation, which may represent a new feasible treatment strategy for osteoporosis.
Topics: Animals; Mice; Osteogenesis; Methylation; Cell Differentiation; Arginine; Glucose
PubMed: 37649137
DOI: 10.1002/ctm2.1369 -
Journal of Dental Research Jan 2024The regeneration of periodontal, periapical, and pulpal tissues is a complex process requiring the direct involvement of cells derived from pluripotent stem cells in the...
The regeneration of periodontal, periapical, and pulpal tissues is a complex process requiring the direct involvement of cells derived from pluripotent stem cells in the periodontal ligament and dental pulp. Dental pulp stem cells (DPSCs) and periodontal ligament stem cells (PDLSCs) are spatially distinct with the potential to differentiate into similar functional and phenotypic cells. We aimed to identify the cell heterogeneity of DPSCs and PDLSCs and explore the differentiation potentials of their specialized organ-specific functions using single-cell transcriptomic analysis. Our results revealed 7 distinct clusters, with cluster 3 showing the highest potential for differentiation. Clusters 0 to 2 displayed features similar to fibroblasts. The trajectory route of the cell state transition from cluster 3 to clusters 0, 1, and 2 indicated the distinct nature of cell differentiation. PDLSCs had a higher proportion of cells (78.6%) at the G1 phase, while DPSCs had a higher proportion of cells at the S and G2/M phases (36.1%), mirroring the lower cell proliferation capacity of PDLSCs than DPSCs. Our study suggested the heterogeneity of stemness across PDLSCs and DPSCs, the similarities of these 2 stem cell compartments to be potentially integrated for regenerative strategies, and the distinct features between them potentially particularized for organ-specific functions of the dental pulp and periodontal ligament for a targeted regenerative dental tissue repair and other regeneration therapies.
Topics: Periodontal Ligament; Dental Pulp; Cells, Cultured; Stem Cells; Cell Differentiation; Cell Proliferation; Gene Expression Profiling; Osteogenesis
PubMed: 37982164
DOI: 10.1177/00220345231205283 -
Biomedicine & Pharmacotherapy =... Dec 2023Osteoporosis (OP) is characterized by reduced bone mass, decreased strength, and enhanced bone fragility fracture risk. Activating transcription factor 4 (ATF4) plays a... (Review)
Review
Osteoporosis (OP) is characterized by reduced bone mass, decreased strength, and enhanced bone fragility fracture risk. Activating transcription factor 4 (ATF4) plays a role in cell differentiation, proliferation, apoptosis, redox balance, amino acid uptake, and glycolipid metabolism. ATF4 induces the differentiation of bone marrow mesenchymal stem cells (BM-MSCs) into osteoblasts, increases osteoblast activity, and inhibits osteoclast formation, promoting bone formation and remodeling. In addition, ATF4 mediates the energy metabolism in osteoblasts and promotes angiogenesis. ATF4 is also involved in the mediation of adipogenesis. ATF4 can selectively accumulate in osteoblasts. ATF4 can directly interact with RUNT-related transcription factor 2 (RUNX2) and up-regulate the expression of osteocalcin (OCN) and osterix (Osx). Several upstream factors, such as Wnt/β-catenin and BMP2/Smad signaling pathways, have been involved in ATF4-mediated osteoblast differentiation. ATF4 promotes osteoclastogenesis by mediating the receptor activator of nuclear factor κ-B (NF-κB) ligand (RANKL) signaling. Several agents, such as parathyroid (PTH), melatonin, and natural compounds, have been reported to regulate ATF4 expression and mediate bone metabolism. In this review, we comprehensively discuss the biological activities of ATF4 in maintaining bone homeostasis and inhibiting OP development. ATF4 has become a therapeutic target for OP treatment.
Topics: Humans; Activating Transcription Factor 4; Osteoclasts; Cell Differentiation; Signal Transduction; Osteoblasts; Osteogenesis; Osteoporosis
PubMed: 37948991
DOI: 10.1016/j.biopha.2023.115864 -
Orphanet Journal of Rare Diseases Aug 2023Osteogenesis imperfecta (OI) is a connective tissue disorder affecting the skeleton and other organs, which has multiple genetic patterns, numerous causative genes, and... (Review)
Review
Osteogenesis imperfecta (OI) is a connective tissue disorder affecting the skeleton and other organs, which has multiple genetic patterns, numerous causative genes, and complex pathogenic mechanisms. The previous classifications lack structure and scientific basis and have poor applicability. In this paper, we summarize and sort out the pathogenic mechanisms of OI, and analyze the molecular pathogenic mechanisms of OI from the perspectives of type I collagen defects(synthesis defects, processing defects, post-translational modification defects, folding and cross-linking defects), bone mineralization disorders, osteoblast differentiation and functional defects respectively, and also generalize several new untyped OI-causing genes and their pathogenic mechanisms, intending to provide the evidence of classification and a scientific basis for the precise diagnosis and treatment of OI.
Topics: Humans; Osteogenesis Imperfecta; Collagen Type I; Osteogenesis; Calcification, Physiologic; Bone Diseases; Mutation
PubMed: 37559063
DOI: 10.1186/s13023-023-02849-5 -
Periodontology 2000 Feb 2024The recognition and importance of immune cells during bone regeneration, including around bone biomaterials, has led to the development of an entire field termed... (Review)
Review
The recognition and importance of immune cells during bone regeneration, including around bone biomaterials, has led to the development of an entire field termed "osteoimmunology," which focuses on the connection and interplay between the skeletal system and immune cells. Most studies have focused on the "osteogenic" capacity of various types of bone biomaterials, and much less focus has been placed on immune cells despite being the first cell type in contact with implantable devices. Thus, the amount of literature generated to date on this topic makes it challenging to extract needed information. This review article serves as a guide highlighting advancements made in the field of osteoimmunology emphasizing the role of the osteoimmunomodulatory properties of biomaterials and their impact on osteoinduction. First, the various immune cell types involved in bone biomaterial integration are discussed, including the prominent role of osteal macrophages (OsteoMacs) during bone regeneration. Thereafter, key biomaterial properties, including topography, wettability, surface charge, and adsorption of cytokines, growth factors, ions, and other bioactive molecules, are discussed in terms of their impact on immune responses. These findings highlight and recognize the importance of the immune system and osteoimmunology, leading to a shift in the traditional models used to understand and evaluate biomaterials for bone regeneration.
Topics: Humans; Biocompatible Materials; Bone Regeneration; Osteogenesis; Macrophages; Bone and Bones; Cytokines; Osseointegration; Bone Substitutes; Animals
PubMed: 37658591
DOI: 10.1111/prd.12519