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Frontiers in Endocrinology 2024Osteoporosis (OP) is a chronic systemic bone metabolism disease characterized by decreased bone mass, microarchitectural deterioration, and fragility fractures. With the... (Review)
Review
Osteoporosis (OP) is a chronic systemic bone metabolism disease characterized by decreased bone mass, microarchitectural deterioration, and fragility fractures. With the demographic change caused by long lifespans and population aging, OP is a growing health problem. The role of miRNA in the pathogenesis of OP has also attracted widespread attention from scholars in recent years. Type H vessels are unique microvessels of the bone and have become a new focus in the pathogenesis of OP because they play an essential role in osteogenesis-angiogenesis coupling. Previous studies found some miRNAs regulate type H vessel formation through the regulatory factors, including platelet-derived growth factor-BB (PDGF-BB), hypoxia-inducible factor 1α (HIF-1α), vascular endothelial growth factor (VEGF), and so on. These findings help us gain a more in-depth understanding of the relationship among miRNAs, type H vessels, and OP to find a new perspective on treating OP. In the present mini-review, we will introduce the role of type H vessels in the pathogenesis of OP and the regulation of miRNAs on type H vessel formation by affecting regulatory factors to provide some valuable insights for future studies of OP treatment.
Topics: Humans; MicroRNAs; Osteoporosis; Animals; Osteogenesis; Neovascularization, Pathologic; Bone and Bones; Microvessels
PubMed: 38883597
DOI: 10.3389/fendo.2024.1394785 -
Drug Design, Development and Therapy 2024Autologous stem cell transplantation has emerged as a promising strategy for bone repair. However, the osteogenic potential of mesenchymal stem cells derived from...
Extracellular Vesicles Derived from HO-Stimulated Adipose-Derived Stem Cells Alleviate Senescence in Diabetic Bone Marrow Mesenchymal Stem Cells and Restore Their Osteogenic Capacity.
INTRODUCTION
Autologous stem cell transplantation has emerged as a promising strategy for bone repair. However, the osteogenic potential of mesenchymal stem cells derived from diabetic patients is compromised, possibly due to hyperglycemia-induced senescence. The objective of this study was to assess the preconditioning effects of extracellular vesicles derived from HO-stimulated adipose-derived stem cells (ADSCs) and non-modified ADSCs on the osteogenic potential of diabetic bone marrow mesenchymal stem cells (BMSCs).
METHODS
Sprague-Dawley (SD) rats were experimentally induced into a diabetic state through a high-fat diet followed by an injection of streptozotocin, and diabetic BMSCs were collected from the bone marrow of these rats. Extracellular vesicles (EVs) were isolated from the conditioned media of ADSCs, with or without hydrogen peroxide (HO) preconditioning, using density gradient centrifugation. The effects of HO preconditioning on the morphology, marker expression, and particle size of the EVs were analyzed. Furthermore, the impact of EV-pretreatment on the viability, survivability, migration ability, osteogenesis, cellular senescence, and oxidative stress of diabetic BMSCs was examined. Moreover, the expression of the Nrf2/HO-1 pathway was also assessed to explore the underlying mechanism. Additionally, we transplanted EV-pretreated BMSCs into calvarial defects in diabetic rats to assess their in vivo bone formation and anti-senescence capabilities.
RESULTS
Our study demonstrated that pretreatment with EVs from ADSCs significantly improved the viability, senescence, and osteogenic differentiation potential of diabetic BMSCs. Moreover, in-vitro experiments revealed that diabetic BMSCs treated with HO-activated EVs exhibited increased viability, reduced senescence, and enhanced osteogenic differentiation compared to those treated with non-modified EVs. Furthermore, when transplanted into rat bone defects, diabetic BMSCs treated with HO-activated EVs showed improved bone regeneration potential and enhanced anti-senescence function t compared to those treated with non-modified EVs. Both HO-activated EVs and non-modified EVs upregulated the expression of the Nrf2/HO-1 pathway in diabetic BMSCs, however, the promoting effect of HO-activated EVs was more pronounced than that of non-modified EVs.
CONCLUSION
Extracellular vesicles derived from HO-preconditioned ADSCs mitigated senescence in diabetic BMSCs and enhanced their bone regenerative functions via the activation of the Nrf2/HO-1 pathway.
Topics: Animals; Hydrogen Peroxide; Extracellular Vesicles; Rats, Sprague-Dawley; Mesenchymal Stem Cells; Rats; Osteogenesis; Diabetes Mellitus, Experimental; Cellular Senescence; Male; Cells, Cultured; Adipose Tissue; Oxidative Stress; Streptozocin
PubMed: 38882044
DOI: 10.2147/DDDT.S454509 -
Orthopaedic Journal of Sports Medicine Jun 2024Medial patellar facet lesions have been well-described in the setting of patellar instability. However, relatively little is known about risk factors for atraumatic...
BACKGROUND
Medial patellar facet lesions have been well-described in the setting of patellar instability. However, relatively little is known about risk factors for atraumatic medial patellar facet lesions.
PURPOSE/HYPOTHESIS
To identify clinical and radiographic risk factors for medial patellar facet lesions in patients without a history of trauma or patellar instability. It was hypothesized that a posterior tibial tubercle relative to the trochlear groove would be a risk factor for atraumatic medial patellar facet lesions.
STUDY DESIGN
Case-control study; Level of evidence, 3.
METHODS
A total of 37 patients with atraumatic medial patellar facet lesions were matched by age, sex, and body mass index with 37 control patients without a history of patellofemoral dysplasia. Demographic and imaging characteristics were compared between groups. Plain radiography was used to evaluate Wiberg type, and magnetic resonance imaging was used to calculate Caton-Deschamps index, tibial tubercle-trochlear groove distance, trochlear facet asymmetry ratio, patellotrochlear index, sulcus depth, patellar bisect ratio, and tibial tubercle height. Statistically significant variables from univariate analysis were used as inputs to the multivariate regression model to assess independent risk factors.
RESULTS
There were no differences between groups with respect to Wiberg type, Caton-Deschamps index, tibial tubercle-trochlear groove distance, sulcus depth, or patellotrochlear index ( > .05 for all). The medial facet lesion group had a larger medial trochlear facet (trochlear facet asymmetry ratio, 0.72 ± 0.11 vs 0.60 ± 0.09; < .001), a more medial-lying patella in the trochlear groove (patellar bisect ratio, 0.57 ± 0.06 vs 0.55 ± 0.07; = .035), and a more posterior tibial tubercle relative to the trochlear groove (tibial tubercle height, -3.13 ± 5.21 vs -0.23 ± 5.93 mm; = .030) compared with the control group. Multivariate regression analysis identified trochlear facet asymmetry and tibial tubercle height as independent risk factors for medial patellar facet lesions (relative risk = 97.3 [95% CI, 14.9-635.1], < .001 and relative risk = 0.95 [95% CI, 0.92-0.98], = .004, respectively).
CONCLUSION
A relatively larger medial trochlear facet and a more posterior tibial tubercle relative to the trochlear groove were found to be risk factors for medial patellar facet lesions in patients without a history of trauma or patellar instability.
PubMed: 38881850
DOI: 10.1177/23259671241255681 -
Nature Communications Jun 2024Coordination of neuronal differentiation with expansion of the neuroepithelial/neural progenitor cell (NEPC/NPC) pool is essential in early brain development. Our in...
Coordination of neuronal differentiation with expansion of the neuroepithelial/neural progenitor cell (NEPC/NPC) pool is essential in early brain development. Our in vitro and in vivo studies identify independent and opposing roles for two neural-specific and differentially expressed non-coding RNAs derived from the same locus: the evolutionarily conserved lncRNA Rncr3 and the embedded microRNA miR124a-1. Rncr3 regulates NEPC/NPC proliferation and controls the biogenesis of miR124a, which determines neuronal differentiation. Rncr3 conserved exons 2/3 are cytosine methylated and bound by methyl-CpG binding protein MeCP2, which restricts expression of miR124a embedded in exon 4 to prevent premature neuronal differentiation, and to orchestrate proper brain growth. MeCP2 directly binds cytosine-methylated Rncr3 through previously unrecognized lysine residues and suppresses miR124a processing by recruiting PTBP1 to block access of DROSHA-DGCR8. Thus, miRNA processing is controlled by lncRNA mC methylation along with the defined mC epitranscriptomic RNA reader protein MeCP2 to coordinate brain development.
Topics: MicroRNAs; Methyl-CpG-Binding Protein 2; Neurogenesis; Animals; Mice; RNA, Long Noncoding; Neural Stem Cells; Brain; Humans; Cell Differentiation; DNA Methylation; Polypyrimidine Tract-Binding Protein; Cell Proliferation; Mice, Inbred C57BL; 5-Methylcytosine; Male; Exons; Neurons; Ribonuclease III
PubMed: 38879605
DOI: 10.1038/s41467-024-49368-w -
Cell Communication and Signaling : CCS Jun 2024Sex-specific gonadal differentiation is directed by complex signalling promoting development in either male or female direction, while simultaneously inhibiting the...
Sex-specific gonadal differentiation is directed by complex signalling promoting development in either male or female direction, while simultaneously inhibiting the opposite pathway. In mice, the WNT/β-catenin pathway promotes ovarian development and the importance of actively inhibiting this pathway to ensure normal testis development has been recognised. However, the implications of alterations in the tightly regulated WNT/β-catenin signalling during human fetal gonad development has not yet been examined in detail. Thus, the aim of this study was to examine the consequences of dysregulating the WNT/β-catenin signalling pathway in the supporting cell lineage during sex-specific human fetal gonad development using an established and extensively validated ex vivo culture model. Inhibition of WNT/β-catenin signalling in human fetal ovary cultures resulted in only minor effects, including reduced secretion of RSPO1 and reduced cell proliferation although this was not consistently found in all treatment groups. In contrast, promotion of WNT/β-catenin signalling in testes severely affected development and function. This included disrupted seminiferous cord structures, reduced cell proliferation, reduced expression of SOX9/AMH, reduced secretion of Inhibin B and AMH as well as loss of the germ cell population. Additionally, Leydig cell function was markedly impaired with reduced secretion of testosterone, androstenedione and INSL3. Together, this study suggests that dysregulated WNT/β-catenin signalling during human fetal gonad development severely impairs testicular development and function. Importantly, our study highlights the notion that sufficient inhibition of the opposite pathway during sex-specific gonadal differentiation is essential to ensure normal development and function also applies to human fetal gonads.
Topics: Humans; Male; Wnt Signaling Pathway; Testis; Female; Sex Differentiation; Fetus; Cell Differentiation; Cell Proliferation; beta Catenin; Leydig Cells; Ovary
PubMed: 38879537
DOI: 10.1186/s12964-024-01704-9 -
Scientific Reports Jun 2024Chemobrionic systems have attracted great attention in material science for development of novel biomimetic materials. This study aims to design a new bioactive material...
Chemobrionic systems have attracted great attention in material science for development of novel biomimetic materials. This study aims to design a new bioactive material by integrating biosilica into chemobrionic structure, which will be called biochemobrionic, and to comparatively investigate the use of both chemobrionic and biochemobrionic materials as bone scaffolds. Biosilica, isolated from Amphora sp. diatom, was integrated into chemobrionic structure, and a comprehensive set of analysis was conducted to evaluate their morphological, chemical, mechanical, thermal, and biodegradation properties. Then, the effects of both scaffolds on cell biocompatibility and osteogenic differentiation capacity were assessed. Cells attached to the scaffolds, spread out, and covered the entire surface, indicating the absence of cytotoxicity. Biochemobrionic scaffold exhibited a higher level of mineralization and bone formation than the chemobrionic structure due to the osteogenic activity of biosilica. These results present a comprehensive and pioneering understanding of the potential of (bio)chemobrionics for bone regeneration.
Topics: Tissue Engineering; Tissue Scaffolds; Osteogenesis; Cell Differentiation; Bone Regeneration; Bone and Bones; Biocompatible Materials; Diatoms; Humans; Animals
PubMed: 38877025
DOI: 10.1038/s41598-024-63171-z -
PLoS Genetics Jun 2024Gene regulatory networks that act upstream of skeletal muscle fate determinants are distinct in different anatomical locations. Despite recent efforts, a clear...
Gene regulatory networks that act upstream of skeletal muscle fate determinants are distinct in different anatomical locations. Despite recent efforts, a clear understanding of the cascade of events underlying the emergence and maintenance of the stem cell pool in specific muscle groups remains unresolved and debated. Here, we invalidated Pitx2 with multiple Cre-driver mice prenatally, postnatally, and during lineage progression. We showed that this gene becomes progressively dispensable for specification and maintenance of the muscle stem (MuSC) cell pool in extraocular muscles (EOMs) despite being, together with Myf5, a major upstream regulator during early development. Moreover, constitutive inactivation of Pax7 postnatally led to a greater loss of MuSCs in the EOMs compared to the limb. Thus, we propose a relay between Pitx2, Myf5 and Pax7 for EOM stem cell maintenance. We demonstrate also that MuSCs in the EOMs adopt a quiescent state earlier that those in limb muscles and do not spontaneously proliferate in the adult, yet EOMs have a significantly higher content of Pax7+ MuSCs per area pre- and post-natally. Finally, while limb MuSCs proliferate in the mdx mouse model for Duchenne muscular dystrophy, significantly less MuSCs were present in the EOMs of the mdx mouse model compared to controls, and they were not proliferative. Overall, our study provides a comprehensive in vivo characterisation of MuSC heterogeneity along the body axis and brings further insights into the unusual sparing of EOMs during muscular dystrophy.
Topics: Animals; PAX7 Transcription Factor; Homeobox Protein PITX2; Mice; Homeodomain Proteins; Transcription Factors; Oculomotor Muscles; Myogenic Regulatory Factor 5; Cell Differentiation; Stem Cells; Gene Expression Regulation, Developmental; Muscle Development; Mice, Inbred mdx; Muscular Dystrophy, Duchenne; Muscle, Skeletal; Humans; Cell Proliferation; Cell Lineage
PubMed: 38875306
DOI: 10.1371/journal.pgen.1010935 -
Mathematical Biosciences and... Mar 2024The objective of the present study was to improve our understanding of the complex biological process of bone mineralization by performing mathematical modeling with the...
The objective of the present study was to improve our understanding of the complex biological process of bone mineralization by performing mathematical modeling with the Caputo-Fabrizio fractional operator. To obtain a better understanding of Komarova's bone mineralization process, we have thoroughly examined the boundedness, existence, and uniqueness of solutions and stability analysis within this framework. To determine how model parameters affect the behavior of the system, sensitivity analysis was carried out. Furthermore, the fractional Adams-Bashforth method has been used to carry out numerical and graphical simulations. Our work is significant owing to its comparison of fractional- and integer-order models, which provides novel insight into the effectiveness of fractional operators in representing the complex dynamics of bone mineralization.
Topics: Calcification, Physiologic; Computer Simulation; Models, Biological; Nonlinear Dynamics; Humans; Algorithms; Bone and Bones; Animals; Computer Graphics
PubMed: 38872530
DOI: 10.3934/mbe.2024227 -
Scientific Reports Jun 2024Notum is a direct target of Wnt/β-catenin signaling and plays a crucial role as a Wnt inhibitor within a negative feedback loop. In the tooth, Notum is known to be...
Notum is a direct target of Wnt/β-catenin signaling and plays a crucial role as a Wnt inhibitor within a negative feedback loop. In the tooth, Notum is known to be expressed in odontoblasts, and severe dentin defects and irregular tooth roots have been reported in Notum-deficient mice. However, the precise expression pattern of Notum in early tooth development, and the role of Notum in crown and root patterns remain elusive. In the present study, we identified a novel Notum expression in primary enamel knot (EK), secondary EKs, and dental papilla during tooth development. Notum-deficient mice exhibited enlarged secondary EKs, resulting in broader cusp tips, altered cusp patterns, and reduced concavity in crown outline. These alterations in crown outline led to a reduction in cervical tongue length, thereby inducing root fusion in Notum-deficient mice. Overall, these results suggest that the secondary EK size, regulated by the Wnt/Notum negative feedback loop, has a significant impact on the patterns of crown and root during tooth morphogenesis.
Topics: Animals; Molar; Tooth Root; Mice; Tooth Crown; Odontogenesis; Wnt Signaling Pathway; Mice, Knockout; Gene Expression Regulation, Developmental; Receptors, G-Protein-Coupled
PubMed: 38871845
DOI: 10.1038/s41598-024-64340-w -
Nature Communications Jun 2024Generating 3D bone cell networks in vitro that mimic the dynamic process during early bone formation remains challenging. Here, we report a synthetic biodegradable...
Generating 3D bone cell networks in vitro that mimic the dynamic process during early bone formation remains challenging. Here, we report a synthetic biodegradable microporous hydrogel for efficient formation of 3D networks from human primary cells, analysis of cell-secreted extracellular matrix (ECM) and microfluidic integration. Using polymerization-induced phase separation, we demonstrate dynamic in situ formation of microporosity (5-20 µm) within matrix metalloproteinase-degradable polyethylene glycol hydrogels in the presence of living cells. Pore formation is triggered by thiol-Michael-addition crosslinking of a viscous precursor solution supplemented with hyaluronic acid and dextran. The resulting microporous architecture can be fine-tuned by adjusting the concentration and molecular weight of dextran. After encapsulation in microporous hydrogels, human mesenchymal stromal cells and osteoblasts spread rapidly and form 3D networks within 24 hours. We demonstrate that matrix degradability controls cell-matrix remodeling, osteogenic differentiation, and deposition of ECM proteins such as collagen. Finally, we report microfluidic integration and proof-of-concept osteogenic differentiation of 3D cell networks under perfusion on chip. Altogether, this work introduces a synthetic microporous hydrogel to efficiently differentiate 3D human bone cell networks, facilitating future in vitro studies on early bone development.
Topics: Humans; Hydrogels; Mesenchymal Stem Cells; Osteogenesis; Cell Differentiation; Osteoblasts; Extracellular Matrix; Porosity; Cell Culture Techniques, Three Dimensional; Polyethylene Glycols; Tissue Engineering; Hyaluronic Acid; Cells, Cultured; Tissue Scaffolds; Dextrans
PubMed: 38871693
DOI: 10.1038/s41467-024-49280-3