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Frontiers in Endocrinology 2021Flavonoids are polyphenolic compounds spotted in various fruits, vegetables, barks, tea plants, and stems and many more natural commodities. They have a multitude of... (Review)
Review
Flavonoids are polyphenolic compounds spotted in various fruits, vegetables, barks, tea plants, and stems and many more natural commodities. They have a multitude of applications through their anti-inflammatory, anti-oxidative, anti-carcinogenic properties, along with the ability to assist in the stimulation of bone formation. Bone, a rigid connective body tissue made up of cells embedded in a mineralised matrix is maintained by an assemblage of pathways assisting osteoblastogenesis and osteoclastogenesis. These have a significant impact on a plethora of bone diseases. The homeostasis between osteoblast and osteoclast formation decides the integrity and structure of the bone. The flavonoids discussed here are quercetin, kaempferol, icariin, myricetin, naringin, daidzein, luteolin, genistein, hesperidin, apigenin and several other flavonoids. The effects these flavonoids have on the mitogen activated protein kinase (MAPK), nuclear factor kappa β (NF-kβ), Wnt/β-catenin and bone morphogenetic protein 2/SMAD (BMP2/SMAD) signalling pathways, and apoptotic pathways lead to impacts on bone remodelling. In addition, these polyphenols regulate angiogenesis, decrease the levels of inflammatory cytokines and play a crucial role in scavenging reactive oxygen species (ROS). Considering these important effects of flavonoids, they may be regarded as a promising agent in treating bone-related ailments in the future.
Topics: Animals; Anti-Inflammatory Agents; Bone Diseases; Bone Remodeling; Flavonoids; Humans; Osteoblasts; Osteoclasts; Osteogenesis; Signal Transduction
PubMed: 34887836
DOI: 10.3389/fendo.2021.779638 -
ELife Oct 2022The skeletal system contains a series of sophisticated cellular lineages arising from the mesenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs) that...
The skeletal system contains a series of sophisticated cellular lineages arising from the mesenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs) that determine the homeostasis of bone and bone marrow. Here, we reasoned that osteocyte may exert a function in regulation of these lineage cell specifications and tissue homeostasis. Using a mouse model of conditional deletion of osteocytes by the expression of diphtheria toxin subunit α in dentin matrix protein 1 (DMP1)-positive osteocytes, we demonstrated that partial ablation of DMP1-positive osteocytes caused severe sarcopenia, osteoporosis, and degenerative kyphosis, leading to shorter lifespan in these animals. Osteocytes reduction altered mesenchymal lineage commitment, resulting in impairment of osteogenesis and induction of osteoclastogensis. Single-cell RNA sequencing further revealed that hematopoietic lineage was mobilized toward myeloid lineage differentiation with expanded myeloid progenitors, neutrophils, and monocytes, while the lymphopoiesis was impaired with reduced B cells in the osteocyte ablation mice. The acquisition of a senescence-associated secretory phenotype (SASP) in both osteogenic and myeloid lineage cells was the underlying cause. Together, we showed that osteocytes play critical roles in regulation of lineage cell specifications in bone and bone marrow through mediation of senescence.
Topics: Animals; Osteocytes; Osteoblasts; Bone Marrow; Bone and Bones; Osteogenesis
PubMed: 36305580
DOI: 10.7554/eLife.81480 -
Stem Cell Research & Therapy Jan 2020As important players in cell-to-cell communication, exosomes (exo) are believed to play a similar role in promoting fracture healing. This study investigated whether...
BACKGROUND
As important players in cell-to-cell communication, exosomes (exo) are believed to play a similar role in promoting fracture healing. This study investigated whether exosomes derived from bone marrow mesenchymal stem cells (BMMSC-Exos) could improve fracture healing of nonunion.
METHODS
BMMSC-Exos were isolated and transplanted into the fracture site in a rat model of femoral nonunion (Exo group) every week. Moreover, equal volumes of phosphate-buffered saline (PBS) and exosome-depleted conditioned medium (CM-Exo) were injected into the femoral fracture sites of the rats in the control and CM-Exo groups. Bone healing processes were recorded and evaluated by radiographic methods on weeks 8, 14 and 20 after surgery. Osteogenesis and angiogenesis at the fracture sites were evaluated by radiographic and histological methods on postoperative week 20. The expression levels of osteogenesis- or angiogenesis-related genes were evaluated in vitro by western blotting and immunohistochemistry. The ability to internalize exosomes was assessed using the PKH26 assay. Altered proliferation and migration of human umbilical vein endothelial cells (HUVECs) and mouse embryo osteoblast precursor cells (MC3TE-E1s) treated with BMMSC-Exos were determined by utilizing EdU incorporation, immunofluorescence staining, and scratch wound assay. The angiogenesis ability of HUVECs was evaluated through tube formation assays. Finally, to explore the effect of exosomes in osteogenesis via the BMP-2/Smad1/RUNX2 signalling pathway, the BMP-2 inhibitors noggin and LDN193189 were utilized, and their subsequent effects were observed.
RESULTS
BMMSC-Exos were observed to be spherical with a diameter of approximately 122 nm. CD9, CD63 and CD81 were expressed. Transplantation of BMMSC-Exos obviously enhanced osteogenesis, angiogenesis and bone healing processes in a rat model of femoral nonunion. BMMSC-Exos were taken up by HUVECs and MC3T3-E1 in vitro, and their proliferation and migration were also improved. Finally, experiments with BMP2 inhibitors confirmed that the BMP-2/Smad1/RUNX2 signalling pathway played an important role in the pro-osteogenesis induced by BMMSC-Exos and enhanced fracture healing of nonunion.
CONCLUSIONS
Our findings suggest that transplantation of BMMSC-Exos exerts a critical effect on the treatment of nonunion by promoting osteogenesis and angiogenesis. This promoting effect might be ascribed to the activation of the BMP-2/Smad1/RUNX2 and the HIF-1α/VEGF signalling pathways.
Topics: Animals; Disease Models, Animal; Exosomes; Fracture Healing; Humans; Male; Mesenchymal Stem Cells; Osteogenesis; Rats
PubMed: 31992369
DOI: 10.1186/s13287-020-1562-9 -
Nature Communications Jan 2020Recent interest in the control of bone metabolism has focused on a specialized subset of CD31endomucin vessels, which are reported to couple angiogenesis with...
Recent interest in the control of bone metabolism has focused on a specialized subset of CD31endomucin vessels, which are reported to couple angiogenesis with osteogenesis. However, the underlying mechanisms that link these processes together remain largely undefined. Here we show that the zinc-finger transcription factor ZEB1 is predominantly expressed in CD31endomucin endothelium in human and mouse bone. Endothelial cell-specific deletion of ZEB1 in mice impairs CD31endomucin vessel formation in the bone, resulting in reduced osteogenesis. Mechanistically, ZEB1 deletion reduces histone acetylation on Dll4 and Notch1 promoters, thereby epigenetically suppressing Notch signaling, a critical pathway that controls bone angiogenesis and osteogenesis. ZEB1 expression in skeletal endothelium declines in osteoporotic mice and humans. Administration of Zeb1-packaged liposomes in osteoporotic mice restores impaired Notch activity in skeletal endothelium, thereby promoting angiogenesis-dependent osteogenesis and ameliorating bone loss. Pharmacological reversal of the low ZEB1/Notch signaling may exert therapeutic benefit in osteoporotic patients by promoting angiogenesis-dependent bone formation.
Topics: Adaptor Proteins, Signal Transducing; Aged; Animals; Calcium-Binding Proteins; Endothelial Cells; Epigenesis, Genetic; Female; Humans; Mice, Knockout; Mice, Transgenic; Middle Aged; Neovascularization, Physiologic; Osteogenesis; Osteoporosis; Ovariectomy; Platelet Endothelial Cell Adhesion Molecule-1; Receptor, Notch1; Zinc Finger E-box-Binding Homeobox 1
PubMed: 31974363
DOI: 10.1038/s41467-019-14076-3 -
International Journal of Biological... 2021Both osteoblasts and preosteoclasts contribute to the coupling of osteogenesis and angiogenesis, regulating bone regeneration. Astragaloside IV (AS-IV), a glycoside of...
Both osteoblasts and preosteoclasts contribute to the coupling of osteogenesis and angiogenesis, regulating bone regeneration. Astragaloside IV (AS-IV), a glycoside of cycloartane-type triterpene derived from the Chinese herb , exhibits various biological activities, including stimulating angiogenesis and attenuating ischemic-hypoxic injury. However, the effects and underlying mechanisms of AS-IV in osteogenesis, osteoclastogenesis, and bone regeneration remain poorly understood. In the present study, we found that AS-IV treatment inhibited osteoclastogenesis, preserved preosteoclasts, and enhanced platelet-derived growth factor-BB (PDGF-BB)-induced angiogenesis. Additionally, AS-IV promoted cell viability, osteogenic differentiation, and angiogenic gene expression in bone marrow mesenchymal stem cells (BMSCs). The activation of AKT/GSK-3β/β-catenin signaling was found to contribute to the effects of AS-IV on osteoclastogenesis and osteogenesis. Furthermore, AS-IV accelerated bone regeneration during distraction osteogenesis (DO), as evidenced from the improved radiological and histological manifestations and biomechanical parameters, accompanied by enhanced angiogenesis within the distraction zone. In summary, AS-IV accelerates bone regeneration during DO, by enhancing osteogenesis and preosteoclast-induced angiogenesis simultaneously, partially through AKT/GSK-3β/β-catenin signaling. These findings reveal that AS-IV may serve as a potential bioactive molecule for promoting the coupling of osteogenesis and angiogenesis, and imply that AKT/GSK-3β/β-catenin signaling may be a promising therapeutic target for patients during DO treatment.
Topics: Animals; Bone Marrow; Bone Regeneration; Cell Proliferation; Cells, Cultured; Drugs, Chinese Herbal; Male; Models, Animal; Neovascularization, Physiologic; Osteoblasts; Osteogenesis; Rats; Rats, Sprague-Dawley; Saponins; Triterpenes
PubMed: 33994865
DOI: 10.7150/ijbs.57681 -
International Journal of Molecular... Jun 2023The bone is an important organ that performs various functions, and the bone marrow inside the skeleton is composed of a complex intermix of hematopoietic, vascular, and... (Review)
Review
The bone is an important organ that performs various functions, and the bone marrow inside the skeleton is composed of a complex intermix of hematopoietic, vascular, and skeletal cells. Current single-cell RNA sequencing (scRNA-seq) technology has revealed heterogeneity and sketchy differential hierarchy of skeletal cells. Skeletal stem and progenitor cells (SSPCs) are located upstream of the hierarchy and differentiate into chondrocytes, osteoblasts, osteocytes, and bone marrow adipocytes. In the bone marrow, multiple types of bone marrow stromal cells (BMSCs), which have the potential of SSPCs, are spatiotemporally located in distinct areas, and SSPCs' potential shift of BMSCs may occur with the advancement of age. These BMSCs contribute to bone regeneration and bone diseases, such as osteoporosis. In vivo lineage-tracing technologies show that various types of skeletal lineage cells concomitantly gather and contribute to bone regeneration. In contrast, these cells differentiate into adipocytes with aging, leading to senile osteoporosis. scRNA-seq analysis has revealed that alteration in the cell-type composition is a major cause of tissue aging. In this review, we discuss the cellular dynamics of skeletal cell populations in bone homeostasis, regeneration, and osteoporosis.
Topics: Humans; Mesenchymal Stem Cells; Adipocytes; Stem Cells; Bone Marrow Cells; Osteoporosis; Osteoblasts; RNA; Cell Differentiation; Osteogenesis
PubMed: 37372962
DOI: 10.3390/ijms24129814 -
Proceedings of the National Academy of... Jan 2023Insulin-like growth factor I (IGF-1) is a key regulator of tissue growth and development in response to growth hormone stimulation. In the skeletal system, IGF-1 derived...
Insulin-like growth factor I (IGF-1) is a key regulator of tissue growth and development in response to growth hormone stimulation. In the skeletal system, IGF-1 derived from osteoblasts and chondrocytes are essential for normal bone development; however, whether bone marrow (BM)-resident cells provide distinct sources of IGF-1 in the adult skeleton remains elusive. Here, we show that BM stromal cells (BMSCs) and megakaryocytes/platelets (MKs/PLTs) express the highest levels of IGF-1 in adult long bones. Deletion of from BMSCs by Lepr-Cre leads to decreased bone formation, impaired bone regeneration, and increased BM adipogenesis. Importantly, reduction of BMSC-derived IGF-1 contributes to fasting-induced marrow fat accumulation. In contrast, deletion of from MKs/PLTs by Pf4-Cre leads to reduced bone formation and regeneration without affecting BM adipogenesis. To our surprise, MKs/PLTs are also an important source of systemic IGF-1. Platelet-rich plasma (PRP) from mice showed compromised osteogenic potential both in vivo and in vitro, suggesting that MK/PLT-derived IGF-1 underlies the therapeutic effects of PRP. Taken together, this study identifies BMSCs and MKs/PLTs as two important sources of IGF-1 that coordinate to maintain and regenerate the adult skeleton, highlighting reciprocal regulation between the hematopoietic and skeletal systems.
Topics: Mice; Animals; Insulin-Like Growth Factor I; Bone Marrow; Cell Differentiation; Blood Platelets; Osteogenesis; Bone Marrow Cells; Skeleton
PubMed: 36577075
DOI: 10.1073/pnas.2203779120 -
American Journal of Physiology. Cell... Mar 2022In recent years, technological advances have revealed a large potential number of long noncoding RNAs (lncRNAs). Findings recognize lncRNAs as orchestrating molecules in... (Review)
Review
In recent years, technological advances have revealed a large potential number of long noncoding RNAs (lncRNAs). Findings recognize lncRNAs as orchestrating molecules in a wide range of processes, at the transcriptional and posttranscriptional levels, although fewer studies address function. For differentiation, which consists of rearrangements in the gene expression profile and activation of stage- and cell type-dependent signaling mechanisms, the relevance of lncRNAs becomes crucial. The relationship between lncRNAs and key molecular factors in differentiation is strengthening; therefore the present review aims to comprehensively explain the role of lncRNAs in the signaling network involved in the main types of mesenchymal differentiation: adipogenesis, chondrogenesis, myogenesis, and osteogenesis. Notably, a step toward the integration of lncRNAs in the field of cell differentiation promises an exceptional impact.
Topics: Adipogenesis; Cell Differentiation; Mesenchymal Stem Cells; Osteogenesis; RNA, Long Noncoding
PubMed: 35080923
DOI: 10.1152/ajpcell.00364.2021 -
Cell Proliferation Aug 2020High glucose (HG)-mediated bone marrow mesenchymal stem cell (BMSC) dysfunction plays a key role in impaired bone formation induced by type 1 diabetes mellitus (T1DM)....
OBJECTIVES
High glucose (HG)-mediated bone marrow mesenchymal stem cell (BMSC) dysfunction plays a key role in impaired bone formation induced by type 1 diabetes mellitus (T1DM). Morroniside is an iridoid glycoside derived from the Chinese herb Cornus officinalis, and it has abundant biological activities associated with cell metabolism and tissue regeneration. However, the effects and underlying mechanisms of morroniside on HG-induced BMSC dysfunction remain poorly understood.
MATERIALS AND METHODS
Alkaline phosphatase (ALP) staining, ALP activity and Alizarin Red staining were performed to assess the osteogenesis of BMSCs. Quantitative real-time PCR and Western blot (WB) were used to investigate the osteo-specific markers, receptor for advanced glycation end product (RAGE) signalling and glyoxalase-1 (Glo1). Additionally, a T1DM rat model was used to assess the protective effect of morroniside in vivo.
RESULTS
Morroniside treatment reverses the HG-impaired osteogenic differentiation of BMSCs in vitro. Morroniside suppressed advanced glycation end product (AGEs) formation and RAGE expression by triggering Glo1. Moreover, the enhanced osteogenesis due to morroniside treatment was partially blocked by the Glo1 inhibitor, BBGCP2. Furthermore, in vivo, morroniside attenuated bone loss and improved bone microarchitecture accompanied by Glo1 upregulation and RAGE downregulation.
CONCLUSIONS
These findings suggest that morroniside attenuates HG-mediated BMSC dysfunction partly through the inhibition of AGE-RAGE signalling and activation of Glo1 and may be a potential treatment for diabetic osteoporosis.
Topics: Animals; Cell Differentiation; Glycation End Products, Advanced; Glycosides; Mesenchymal Stem Cells; Osteogenesis; Osteoporosis; Rats, Sprague-Dawley; Receptor for Advanced Glycation End Products; Wound Healing
PubMed: 32643284
DOI: 10.1111/cpr.12866 -
Experimental & Molecular Medicine Apr 2022Mesenchymal stem cells (MSCs) are a common kind of multipotent cell in vivo, but their heterogeneity limits their further applications. To identify MSC subpopulations...
Mesenchymal stem cells (MSCs) are a common kind of multipotent cell in vivo, but their heterogeneity limits their further applications. To identify MSC subpopulations and clarify their relationships, we performed cell mapping of bone-marrow-derived MSCs through single-cell RNA (scRNA) sequencing. In our study, three main subpopulations, namely, the stemness subpopulation, functional subpopulation, and proliferative subpopulation, were identified using marker genes and further bioinformatic analyses. Developmental trajectory analysis showed that the stemness subpopulation was the root and then became either the functional subpopulation or the proliferative subpopulation. The functional subpopulation showed stronger immunoregulatory and osteogenic differentiation abilities but lower proliferation and adipogenic differentiation. MSCs at different passages or isolated from different donors exhibited distinct cell mapping profiles, which accounted for their corresponding different functions. This study provides new insight into the biological features and clinical use of MSCs at the single-cell level, which may contribute to expanding their application in the clinic.
Topics: Bone Marrow; Bone Marrow Cells; Cell Differentiation; Cell Proliferation; Cells, Cultured; Humans; Mesenchymal Stem Cells; Osteogenesis; Sequence Analysis, RNA
PubMed: 35365767
DOI: 10.1038/s12276-022-00749-5