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Nature Reviews. Molecular Cell Biology Nov 2020Bone development occurs through a series of synchronous events that result in the formation of the body scaffold. The repair potential of bone and its surrounding... (Review)
Review
Bone development occurs through a series of synchronous events that result in the formation of the body scaffold. The repair potential of bone and its surrounding microenvironment - including inflammatory, endothelial and Schwann cells - persists throughout adulthood, enabling restoration of tissue to its homeostatic functional state. The isolation of a single skeletal stem cell population through cell surface markers and the development of single-cell technologies are enabling precise elucidation of cellular activity and fate during bone repair by providing key insights into the mechanisms that maintain and regenerate bone during homeostasis and repair. Increased understanding of bone development, as well as normal and aberrant bone repair, has important therapeutic implications for the treatment of bone disease and ageing-related degeneration.
Topics: Animals; Bone Development; Bone Diseases; Bone and Bones; Humans; Regeneration
PubMed: 32901139
DOI: 10.1038/s41580-020-00279-w -
Nature Reviews. Rheumatology Oct 2021Blood vessels form a versatile transport network that is best known for its critical roles in processes such as tissue oxygenation, metabolism and immune surveillance.... (Review)
Review
Blood vessels form a versatile transport network that is best known for its critical roles in processes such as tissue oxygenation, metabolism and immune surveillance. The vasculature also provides local, often organ-specific, molecular signals that control the behaviour of other cell types in their vicinity during development, homeostasis and regeneration, and also in disease processes. In the skeletal system, the local vasculature is actively involved in both bone formation and resorption. In addition, blood vessels participate in inflammatory processes and contribute to the pathogenesis of diseases that affect the joints, such as rheumatoid arthritis and osteoarthritis. This Review summarizes the current understanding of the architecture, angiogenic growth and functional properties of the bone vasculature. The effects of ageing and pathological conditions, including arthritis and osteoporosis, are also discussed.
Topics: Aging; Animals; Arthritis; Bone Development; Bone Diseases; Bone Regeneration; Bone and Bones; Chondrocytes; Endothelium, Vascular; Fractures, Bone; Homeostasis; Humans; Joint Diseases; Macrophages; Mice; Neovascularization, Pathologic; Neovascularization, Physiologic; Osteoblasts; Osteogenesis; Osteoporosis; Receptor Cross-Talk; Synoviocytes
PubMed: 34480164
DOI: 10.1038/s41584-021-00682-3 -
Theranostics 2022Single-cell RNA sequencing (scRNA-seq) enables specific profiling of cell populations at single-cell resolution. The osteoimmunology microenvironment in the occurrence...
Single-cell RNA sequencing (scRNA-seq) enables specific profiling of cell populations at single-cell resolution. The osteoimmunology microenvironment in the occurrence and development of periodontitis remains poorly understood at the single-cell level. In this study, we used single-cell transcriptomics to comprehensively reveal the complexities of the molecular components and differences with counterparts residing in periodontal tissues. We performed scRNA-seq to identify 51248 single cells from healthy controls (n=4), patients with severe chronic periodontitis (n=5), and patients with severe chronic periodontitis after initial periodontal therapy within 1 month (n=3). Uniform manifold approximation and projection (UMAP) were further conducted to explore the cellular composition of periodontal tissues. Pseudotime cell trajectory and RNA velocity analysis, combined with gene enrichment analysis were used to reveal the molecular pathways underlying cell fate decisions. CellPhoneDB were performed to identify ligand-receptor pairs among the major cell types in the osteoimmunology microenvironment of periodontal tissues. A cell atlas of the osteoimmunology microenvironment in periodontal tissues was characterized and included ten major cell types, such as fibroblasts, monocytic cells, endothelial cells, and T and B cells. The enrichment of fibroblasts with high expression of , and was detected in patients with periodontitis compared to healthy individuals. The fractions of mesenchymal stem cells (MSCs), pre-osteoblasts (pre-OBs), and osteoblasts decreased significantly in response to initial periodontal therapy. In addition, MSC-like pericytes could convert their identity into a pre-OB state during inflammatory responses even after initial periodontal therapy confirmed by single-cell trajectory. Moreover, we portrayed the distinct subtypes of monocytic cells and abundant endothelial cells significantly involved in the immune response. The heterogeneity of T and B cells in periodontal tissues was characterized. Finally, we mapped osteoblast/osteoclast differentiation mediators to their source cell populations by identifying ligand-receptor pairs and highlighted the effects of Ephrin-Eph signaling on bone regeneration after initial periodontal therapy. Our analyses uncovered striking spatiotemporal dynamics in gene expression, population composition, and cell-cell interactions during periodontitis progression. These findings provide insights into the cellular and molecular underpinning of periodontal bone regeneration.
Topics: Chronic Periodontitis; Endothelial Cells; Humans; Ligands; Osteogenesis; RNA
PubMed: 35154475
DOI: 10.7150/thno.65694 -
Frontiers in Endocrinology 2020Excess adiposity in childhood may affect bone development, ultimately leading to bone frailty. Previous reports showing an increased rate of extremity fractures in... (Review)
Review
Excess adiposity in childhood may affect bone development, ultimately leading to bone frailty. Previous reports showing an increased rate of extremity fractures in children with obesity support this fear. On the other hand, there is also evidence suggesting that bone mineral content is higher in obese children than in normal weight peers. Both adipocytes and osteoblasts derive from multipotent mesenchymal stem cells (MSCs) and obesity drives the differentiation of MSCs toward adipocytes at the expense of osteoblast differentiation. Furthermore, adipocytes in bone marrow microenvironment release a number of pro-inflammatory and immunomodulatory molecules that up-regulate formation and activation of osteoclasts, thus favoring bone frailty. On the other hand, body adiposity represents a mechanical load, which is beneficial for bone accrual. In this frame, bone quality, and structure result from the balance of inflammatory and mechanical stimuli. Diet, physical activity and the hormonal milieu at puberty play a pivotal role on this balance. In this review, we will address the question whether the bone of obese children and adolescents is unhealthy in comparison with normal-weight peers and discuss mechanisms underlying the differences in bone quality and structure. We anticipate that many biases and confounders affect the clinical studies conducted so far and preclude us from achieving robust conclusions. Sample-size, lack of adequate controls, heterogeneity of study designs are the major drawbacks of the existing reports. Due to the increased body size of children with obesity, dual energy absorptiometry might overestimate bone mineral density in these individuals. Magnetic resonance imaging, peripheral quantitative CT (pQCT) scanning and high-resolution pQCT are promising techniques for the accurate estimate of bone mineral content in obese children. Moreover, no longitudinal study on the risk of incident osteoporosis in early adulthood of children and adolescents with obesity is available. Finally, we will address emerging dietary issues (i.e., the likely benefits for the bone health of polyunsaturated fatty acids and polyphenols) since an healthy diet (i.e., the Mediterranean diet) with balanced intake of certain nutrients associated with physical activity remain the cornerstones for achieving an adequate bone accrual in young individuals regardless of their adiposity degree.
Topics: Adolescent; Bone Density; Bone Development; Bone and Bones; Child; Exercise; Humans; Osteoporosis; Pediatric Obesity; Puberty
PubMed: 32390939
DOI: 10.3389/fendo.2020.00200 -
Biomaterials Apr 2022Embryogenic developmental processes involve a tightly controlled regulation between mechanical forces and biochemical cues such as growth factors, matrix proteins, and... (Review)
Review
Embryogenic developmental processes involve a tightly controlled regulation between mechanical forces and biochemical cues such as growth factors, matrix proteins, and cytokines. This interplay remains essential in the mature body, with aberrant pathway signaling leading to abnormalities such as atherosclerosis in the cardiovascular system, inflammation in tendon tissue, or osteoporosis in the bone. The aim of bone regenerative strategies is to develop tools and procedures that will harness the body's own self-repair ability in order to successfully regenerate even very large and complex bone defects and restore normal function. To achieve this, understanding pathways that govern processes of progenitor differentiation towards the osteogenic lineages, their phenotypical maintenance, and the construction of functional bone tissue is imperative to subsequently develop regenerative therapies that mimic these processes. While a body of literature exists that describes how biochemical stimuli guide cell behavior in the culture dish, due to the lack of an appropriate mechanical environment, these signals are often insufficient or inappropriate for achieving a desirable response in the body. Moreover, bone regenerative therapies rarely rely on a biochemical stimulus, such as a growth factor alone, and instead often comprise a carrier biomaterial that introduces a very different microenvironment from that of a cell culture dish. Therefore, in this review, we discuss which biomaterials elicit or influence pathways relevant for bone regeneration and describe mechanisms behind these effects, with the aim to inspire the development of novel, more effective bone regenerative therapies.
Topics: Biocompatible Materials; Bone Regeneration; Bone and Bones; Cell Differentiation; Osteogenesis; Tissue Engineering
PubMed: 35231787
DOI: 10.1016/j.biomaterials.2022.121431 -
Tissue Engineering and Regenerative... Jun 2021Autogenous odontogenic materials are a new, highly biocompatible option for jaw restoration. The inorganic component of autogenous teeth acts as a scaffold to maintain... (Review)
Review
Autogenous odontogenic materials are a new, highly biocompatible option for jaw restoration. The inorganic component of autogenous teeth acts as a scaffold to maintain the volume and enable donor cell attachment and proliferation; the organic component contains various growth factors that promote bone reconstruction and repair. The composition of dentin is similar to that of bone, which can be a rationale for promoting bone reconstruction. Recent advances have been made in the field of autogenous odontogenic materials, and studies have confirmed their safety and feasibility after successful clinical application. Autogenous odontogenic materials have unique characteristics compared with other bone-repair materials, such as the conventional autogenous, allogeneic, xenogeneic, and alloplastic bone substitutes. To encourage further research into odontogenic bone grafts, we compared the composition, osteogenesis, and development of autogenous odontogenic materials with those of other bone grafts. In conclusion, odontogenic bone grafts should be classified as a novel bone substitute.
Topics: Bone Substitutes; Bone Transplantation; Bone and Bones; Osteogenesis; Tooth
PubMed: 33929713
DOI: 10.1007/s13770-021-00333-4 -
Molecular and Cellular Endocrinology Jan 2021Growth hormone (GH) and its mediator, the insulin-like growth factor-1 (IGF-1) regulate somatic growth, metabolism and many aspects of aging. As such, actions of GH/IGF... (Review)
Review
Growth hormone (GH) and its mediator, the insulin-like growth factor-1 (IGF-1) regulate somatic growth, metabolism and many aspects of aging. As such, actions of GH/IGF have been studied in many tissues and organs over decades. GH and IGF-1 are part of the hypothalamic/pituitary somatotrophic axis that consists of many other regulatory hormones, receptors, binding proteins, and proteases. In humans, GH/IGF actions peak during pubertal growth and regulate skeletal acquisition through stimulation of extracellular matrix production and increases in bone mineral density. During aging the activity of these hormones declines, a state called somatopaguss, which associates with deleterious effects on the musculoskeletal system. In this review, we will focus on GH/IGF-1 action in bone and cartilage. We will cover many studies that have utilized congenital ablation or overexpression of members of this axis, as well as cell-specific gene-targeting approaches used to unravel the nature of the GH/IGF-1 actions in the skeleton in vivo.
Topics: Animals; Bone Development; Bone and Bones; Cartilage; Growth Hormone; Humans; Insulin-Like Growth Factor I; Osteoarthritis
PubMed: 33068640
DOI: 10.1016/j.mce.2020.111052 -
ELife Mar 2020Mechanical forces are fundamental regulators of cell behaviors. However, molecular regulation of mechanotransduction remain poorly understood. Here, we identified the...
Mechanical forces are fundamental regulators of cell behaviors. However, molecular regulation of mechanotransduction remain poorly understood. Here, we identified the mechanosensitive channels Piezo1 and Piezo2 as key force sensors required for bone development and osteoblast differentiation. Loss of Piezo1, or more severely Piezo1/2, in mesenchymal or osteoblast progenitor cells, led to multiple spontaneous bone fractures in newborn mice due to inhibition of osteoblast differentiation and increased bone resorption. In addition, loss of Piezo1/2 rendered resistant to further bone loss caused by unloading in both bone development and homeostasis. Mechanistically, Piezo1/2 relayed fluid shear stress and extracellular matrix stiffness signals to activate Ca influx to stimulate Calcineurin, which promotes concerted activation of NFATc1, YAP1 and ß-catenin transcription factors by inducing their dephosphorylation as well as NFAT/YAP1/ß-catenin complex formation. Yap1 and ß-catenin activities were reduced in the Piezo1 and Piezo1/2 mutant bones and such defects were partially rescued by enhanced ß-catenin activities.
Topics: Adaptor Proteins, Signal Transducing; Animals; Bone Development; Bone Marrow Cells; Cell Cycle Proteins; Extremities; Gene Expression Regulation, Developmental; Ion Channels; Mechanotransduction, Cellular; Mice; Mice, Knockout; NFATC Transcription Factors; Stromal Cells; Tissue Culture Techniques; YAP-Signaling Proteins; beta Catenin
PubMed: 32186512
DOI: 10.7554/eLife.52779 -
Best Practice & Research. Clinical... Jun 2020Diffuse idiopathic skeletal hyperostosis (DISH) is a systemic bone-forming condition characterized by the presence of at least three bony bridges at the anterolateral... (Review)
Review
Diffuse idiopathic skeletal hyperostosis (DISH) is a systemic bone-forming condition characterized by the presence of at least three bony bridges at the anterolateral spine. The aim of this review was to address the present state of pathophysiological knowledge, the clinical relevance, and diagnosis of DISH. The pathogenesis of DISH is currently unknown. The presence of DISH has been associated with older age, male sex, obesity, hypertension, atherosclerosis, and diabetes mellitus. Because the new bone forms mainly at entheseal sites, local fibroblasts, chondrocytes, collagen fibers, and calcified matrix are probably influenced by genetic, vascular, metabolic, and mechanical factors. Diagnosing the presence of DISH is of clinical importance, because the risk of a spinal fracture increases and associations with the metabolic syndrome, coronary and aortic disease, and respiratory effects are strong. Unravelling the pathogenesis of DISH can impact the field of regenerative medicine and bone tissue regeneration.
Topics: Aged; Bone Development; Humans; Hyperostosis, Diffuse Idiopathic Skeletal; Male; Spine
PubMed: 32456997
DOI: 10.1016/j.berh.2020.101527 -
Journal of Translational Medicine Sep 2023Osteoporosis is a systemic bone disease characterized by low bone mass, microarchitectural deterioration, increased bone fragility, and fracture susceptibility. It... (Review)
Review
Osteoporosis is a systemic bone disease characterized by low bone mass, microarchitectural deterioration, increased bone fragility, and fracture susceptibility. It commonly occurs in older people, especially postmenopausal women. As global ageing increases, osteoporosis has become a global burden. There are a number of medications available for the treatment of osteoporosis, categorized as anabolic and anti-resorptive. Unfortunately, there is no drugs which have dual influence on bone, while all drugs have limitations and adverse events. Some serious adverse events include jaw osteonecrosis and atypical femoral fracture. Recently, a novel medication has appeared that challenges this pattern. Romosozumab is a novel drug monoclonal antibody to sclerostin encoded by the SOST gene. It has been used in Japan since 2019 and has achieved promising results in treating osteoporosis. However, it is also accompanied by some controversy. While it promotes rapid bone growth, it may cause serious adverse events such as cardiovascular diseases. There has been scepticism about the drug since its inception. Therefore, the present review comprehensively covered romosozumab from its inception to its clinical application, from animal studies to human studies, and from safety to cost. We hope to provide a better understanding of romosozumab for its clinical application.
Topics: Animals; Female; Humans; Aged; Osteoporosis; Antibodies, Monoclonal; Aging; Bone Development
PubMed: 37759285
DOI: 10.1186/s12967-023-04563-z