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Nature Communications Mar 2022Adipocyte differentiation of bone marrow mesenchymal stem/stromal cells (BMSCs) instead of osteoblast formation contributes to age- and menopause-related marrow...
Adipocyte differentiation of bone marrow mesenchymal stem/stromal cells (BMSCs) instead of osteoblast formation contributes to age- and menopause-related marrow adiposity and osteoporosis. Vascular calcification often occurs with osteoporosis, a contradictory association called "calcification paradox". Here we show that extracellular vesicles derived from aged bone matrix (AB-EVs) during bone resorption favor BMSC adipogenesis rather than osteogenesis and augment calcification of vascular smooth muscle cells. Intravenous or intramedullary injection of AB-EVs promotes bone-fat imbalance and exacerbates Vitamin D3 (VD3)-induced vascular calcification in young or old mice. Alendronate (ALE), a bone resorption inhibitor, down-regulates AB-EVs release and attenuates aging- and ovariectomy-induced bone-fat imbalance. In the VD3-treated aged mice, ALE suppresses the ovariectomy-induced aggravation of vascular calcification. MiR-483-5p and miR-2861 are enriched in AB-EVs and essential for the AB-EVs-induced bone-fat imbalance and exacerbation of vascular calcification. Our study uncovers the role of AB-EVs as a messenger for calcification paradox by transferring miR-483-5p and miR-2861.
Topics: Animals; Bone Matrix; Cell Differentiation; Extracellular Vesicles; Female; Mesenchymal Stem Cells; Mice; MicroRNAs; Osteogenesis
PubMed: 35304471
DOI: 10.1038/s41467-022-29191-x -
International Journal of Molecular... May 2022Runt-related transcription factor 2 (Runx2) is a fundamental transcription factor for bone development. In endochondral ossification, Runx2 induces chondrocyte... (Review)
Review
Runt-related transcription factor 2 (Runx2) is a fundamental transcription factor for bone development. In endochondral ossification, Runx2 induces chondrocyte maturation, enhances chondrocyte proliferation through Indian hedgehog (Ihh) induction, and induces the expression of vascular endothelial growth factor A (Vegfa), secreted phosphoprotein 1 (Spp1), integrin-binding sialoprotein (Ibsp), and matrix metallopeptidase 13 (Mmp13) in the terminal hypertrophic chondrocytes. Runx2 inhibits the apoptosis of the terminal hypertrophic chondrocytes and induces their transdifferentiation into osteoblasts and osteoblast progenitors. The transdifferentiation is required for trabecular bone formation during embryonic and newborn stages but is dispensable for acquiring normal bone mass in young and adult mice. Runx2 enhances the proliferation of osteoblast progenitors and induces their commitment to osteoblast lineage cells through the direct regulation of the expressions of a hedgehog, fibroblast growth factor (Fgf), Wnt, and parathyroid hormone-like hormone (Pthlh) signaling pathway genes and distal-less homeobox 5 (Dlx5), which all regulate Runx2 expression and/or protein activity. Runx2, Sp7, and Wnt signaling further induce osteoblast differentiation. In immature osteoblasts, Runx2 regulates the expression of bone matrix protein genes, including Col1a1, Col1a2, Spp1, Ibsp, and bone gamma carboxyglutamate protein (Bglap)/Bglap2, and induces osteoblast maturation. Osteocalcin (Bglap/Bglap2) is required for the alignment of apatite crystals parallel to the collagen fibers; however, it does not physiologically work as a hormone that regulates glucose metabolism, testosterone synthesis, or muscle mass. Thus, Runx2 exerts multiple functions essential for skeletal development.
Topics: Animals; Core Binding Factor Alpha 1 Subunit; Hedgehog Proteins; Hormones; Integrin-Binding Sialoprotein; Mice; Osteogenesis; Transcription Factors; Vascular Endothelial Growth Factor A
PubMed: 35628587
DOI: 10.3390/ijms23105776 -
Nature Communications Jun 2022Bone growth requires a specialised, highly angiogenic blood vessel subtype, so-called type H vessels, which pave the way for osteoblasts surrounding these vessels. At...
Bone growth requires a specialised, highly angiogenic blood vessel subtype, so-called type H vessels, which pave the way for osteoblasts surrounding these vessels. At the end of adolescence, type H vessels differentiate into quiescent type L endothelium lacking the capacity to promote bone growth. Until now, the signals that switch off type H vessel identity and thus limit adolescent bone growth have remained ill defined. Here we show that mechanical forces, associated with increased body weight at the end of adolescence, trigger the mechanoreceptor PIEZO1 and thereby mediate enhanced production of the kinase FAM20C in osteoblasts. FAM20C, the major kinase of the secreted phosphoproteome, phosphorylates dentin matrix protein 1, previously identified as a key factor in bone mineralization. Thereupon, dentin matrix protein 1 is secreted from osteoblasts in a burst-like manner. Extracellular dentin matrix protein 1 inhibits vascular endothelial growth factor signalling by preventing phosphorylation of vascular endothelial growth factor receptor 2. Hence, secreted dentin matrix protein 1 transforms type H vessels into type L to limit bone growth activity and enhance bone mineralization. The discovered mechanism may suggest new options for the treatment of diseases characterised by aberrant activity of bone and vessels such as osteoarthritis, osteoporosis and osteosarcoma.
Topics: Adolescent; Bone Development; Bone Matrix; Calcification, Physiologic; Extracellular Matrix Proteins; Humans; Ion Channels; Morphogenesis; Neovascularization, Physiologic; Phosphoproteins; Stress, Mechanical; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2
PubMed: 35650194
DOI: 10.1038/s41467-022-30618-8 -
Bone Research Aug 2022The bone matrix plays an indispensable role in the human body, and its unique biomechanical and mechanobiological properties have received much attention. The bone... (Review)
Review
The bone matrix plays an indispensable role in the human body, and its unique biomechanical and mechanobiological properties have received much attention. The bone matrix has unique mechanical anisotropy and exhibits both strong toughness and high strength. These mechanical properties are closely associated with human life activities and correspond to the function of bone in the human body. None of the mechanical properties exhibited by the bone matrix is independent of its composition and structure. Studies on the biomechanics of the bone matrix can provide a reference for the preparation of more applicable bone substitute implants, bone biomimetic materials and scaffolds for bone tissue repair in humans, as well as for biomimetic applications in other fields. In providing mechanical support to the human body, bone is constantly exposed to mechanical stimuli. Through the study of the mechanobiology of the bone matrix, the response mechanism of the bone matrix to its surrounding mechanical environment can be elucidated and used for the health maintenance of bone tissue and defect regeneration. This paper summarizes the biomechanical properties of the bone matrix and their biological significance, discusses the compositional and structural basis by which the bone matrix is capable of exhibiting these mechanical properties, and studies the effects of mechanical stimuli, especially fluid shear stress, on the components of the bone matrix, cells and their interactions. The problems that occur with regard to the biomechanics and mechanobiology of the bone matrix and the corresponding challenges that may need to be faced in the future are also described.
PubMed: 36042209
DOI: 10.1038/s41413-022-00223-y -
Current Osteoporosis Reports Aug 2019In perilacunar/canalicular remodeling (PLR), osteocytes dynamically resorb, and then replace, the organic and mineral components of the pericellular extracellular... (Review)
Review
PURPOSE OF REVIEW
In perilacunar/canalicular remodeling (PLR), osteocytes dynamically resorb, and then replace, the organic and mineral components of the pericellular extracellular matrix. Given the enormous surface area of the osteocyte lacuna-canalicular network (LCN), PLR is important for maintaining homeostasis of the skeleton. The goal of this review is to examine the motivations and critical considerations for the analysis of PLR, in both in vitro and in vivo systems.
RECENT FINDINGS
Morphological approaches alone are insufficient to elucidate the complex mechanisms regulating PLR in the healthy skeleton and in disease. Understanding the role and regulation of PLR will require the incorporation of standardized PLR outcomes as a routine part of skeletal phenotyping, as well as the development of improved molecular and cellular outcomes. Current PLR outcomes assess PLR enzyme expression, the LCN, and bone matrix composition and organization, among others. Here, we discuss current PLR outcomes and how they have been applied to study PLR induction and suppression in vitro and in vivo. Given the role of PLR in skeletal health and disease, integrated analysis of PLR has potential to elucidate new mechanisms by which osteocytes participate in skeletal health and disease.
Topics: Bone Matrix; Bone Remodeling; Carbonic Anhydrases; Cathepsin K; Cell Line; Homeostasis; Humans; Hydrogen-Ion Concentration; Imaging, Three-Dimensional; Matrix Metalloproteinases; Microscopy, Confocal; Microscopy, Electron, Scanning; Osteocytes; Proton-Translocating ATPases; X-Ray Microtomography
PubMed: 31227998
DOI: 10.1007/s11914-019-00514-0 -
Frontiers in Endocrinology 2020Osteocytes make up 90-95% of the cellular content of bone and form a rich dendritic network with a vastly greater surface area than either osteoblasts or osteoclasts.... (Review)
Review
Osteocytes make up 90-95% of the cellular content of bone and form a rich dendritic network with a vastly greater surface area than either osteoblasts or osteoclasts. Osteocytes are well positioned to play a role in bone homeostasis by interacting directly with the matrix; however, the ability for these cells to modify bone matrix remains incompletely understood. With techniques for examining the nano- and microstructure of bone matrix components including hydroxyapatite and type I collagen becoming more widespread, there is great potential to uncover novel roles for the osteocyte in maintaining bone quality. In this review, we begin with an overview of osteocyte biology and the lacunar-canalicular system. Next, we describe recent findings from models of osteocytes, focusing on the transitions in cellular phenotype as they mature. Finally, we describe historical and current research on matrix alteration by osteocytes , focusing on the exciting potential for osteocytes to directly form, degrade, and modify the mineral and collagen in their surrounding matrix.
Topics: Animals; Bone Matrix; Bone Remodeling; Homeostasis; Humans; Minerals; Osteocytes; Osteogenesis
PubMed: 33537002
DOI: 10.3389/fendo.2020.578477 -
Stem Cells International 2021The bone extracellular matrix (ECM) contains organic and mineral constituents. The establishment and degradation processes of ECM connect with spatial and temporal... (Review)
Review
The bone extracellular matrix (ECM) contains organic and mineral constituents. The establishment and degradation processes of ECM connect with spatial and temporal patterns, especially circadian rhythms in ECM. These patterns are responsible for the physical and biological characteristics of bone. The disturbances of the patterns disrupt bone matrix remodeling and cause diverse bone diseases, such as osteogenesis imperfecta (OI) and bone fracture. In addition, the main regulatory factors and inflammatory factors also follow circadian rhythms. Studies show that the circadian oscillations of these factors in bone ECM potentially influence the interactions between immune responses and bone formation. More importantly, mesenchymal stem cells (MSCs) within the specific microenvironments provide the regenerative potential for tissue remodeling. In this review, we summarize the advanced ECM spatial characteristics and the periodic patterns of bone ECM. Importantly, we focus on the intrinsic connections between the immunoinflammatory system and bone formation according to circadian rhythms of regulatory factors in bone ECM. And our research group emphasizes the multipotency of MSCs with their microenvironments. The advanced understandings of bone ECM formation patterns and MSCs contribute to providing optimal prevention and treatment strategies.
PubMed: 34777503
DOI: 10.1155/2021/4307961