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Frontiers in Bioscience : a Journal and... May 2007The major event that triggers osteogenesis is the transition of mesenchymal stem cells into bone forming, differentiating osteoblast cells. Osteoblast differentiation is... (Review)
Review
The major event that triggers osteogenesis is the transition of mesenchymal stem cells into bone forming, differentiating osteoblast cells. Osteoblast differentiation is the primary component of bone formation, exemplified by the synthesis, deposition and mineralization of extracellular matrix. Although not well understood, osteoblast differentiation from mesenchymal stem cells is a well-orchestrated process. Recent advances in molecular and genetic studies using gene targeting in mouse enable a better understanding of the multiple factors and signaling networks that control the differentiation process at a molecular level. Osteoblast commitment and differentiation are controlled by complex activities involving signal transduction and transcriptional regulation of gene expression. We review Wnt signaling pathway and Runx2 regulation network, which are critical for osteoblast differentiation. Many other factors and signaling pathways have been implicated in regulation of osteoblast differentiation in a network manner, such as the factors Osterix, ATF4, and SATB2 and the TGF-beta, Hedgehog, FGF, ephrin, and sympathetic signaling pathways. This review summarizes the recent advances in the studies of signaling transduction pathways and transcriptional regulation of osteoblast cell lineage commitment and differentiation. The knowledge of osteoblast commitment and differentiation should be applied towards the development of new diagnostic and therapeutic alternatives for human bone diseases.
Topics: Animals; Cell Differentiation; Cell Lineage; Gene Expression Regulation; Humans; Osteoblasts; Signal Transduction; Transcription Factors; Transcription, Genetic
PubMed: 17485283
DOI: 10.2741/2296 -
International Journal of Molecular... Jul 2021A review of the available literature was performed in order to summarize the existing evidence between osteoblast dysfunction and clinical features in non-hereditary... (Review)
Review
A review of the available literature was performed in order to summarize the existing evidence between osteoblast dysfunction and clinical features in non-hereditary sclerosing bone diseases. It has been known that proliferation and migration of osteoblasts are concerted by soluble factors such as fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), transforming growth factor (TGF), bone morphogenetic protein (BMP) but also by signal transduction cascades such as Wnt signaling pathway. Protein kinases play also a leading role in triggering the activation of osteoblasts in this group of diseases. Post-zygotic changes in mitogen-activated protein kinase (MAPK) have been shown to be associated with sporadic cases of Melorheostosis. Serum levels of FGF and PDGF have been shown to be increased in myelofibrosis, although studies focusing on Sphingosine-1-phosphate receptor was shown to be strongly expressed in Paget disease of the bone, which may partially explain the osteoblastic hyperactivity during this condition. Pathophysiological mechanisms of osteoblasts in osteoblastic metastases have been studied much more thoroughly than in rare sclerosing syndromes: striking cellular mechanisms such as osteomimicry or complex intercellular signaling alterations have been described. Further research is needed to describe pathological mechanisms by which rare sclerosing non hereditary diseases lead to osteoblast dysfunction.
Topics: Animals; Bone Morphogenetic Proteins; Fibroblast Growth Factors; Humans; MAP Kinase Signaling System; Melorheostosis; Osteoblasts; Platelet-Derived Growth Factor; Sphingosine-1-Phosphate Receptors
PubMed: 34360745
DOI: 10.3390/ijms22157980 -
Frontiers in Endocrinology 2020The skeleton is a dynamic and metabolically active organ with the capacity to influence whole body metabolism. This newly recognized function has propagated interest in... (Review)
Review
The skeleton is a dynamic and metabolically active organ with the capacity to influence whole body metabolism. This newly recognized function has propagated interest in the connection between bone health and metabolic dysfunction. Osteoblasts, the specialized mesenchymal cells responsible for the production of bone matrix and mineralization, rely on multiple fuel sources. The utilization of glucose by osteoblasts has long been a focus of research, however, lipids and their derivatives, are increasingly recognized as a vital energy source. Osteoblasts possess the necessary receptors and catabolic enzymes for internalization and utilization of circulating lipids. Disruption of these processes can impair osteoblast function, resulting in skeletal deficits while simultaneously altering whole body lipid homeostasis. This article provides an overview of the metabolism of postprandial and stored lipids and the osteoblast's ability to acquire and utilize these molecules. We focus on the requirement for fatty acid oxidation and the pathways regulating this function as well as the negative impact of dyslipidemia on the osteoblast and skeletal health. These findings provide key insights into the nuances of lipid metabolism in influencing skeletal homeostasis which are critical to appreciate the extent of the osteoblast's role in metabolic homeostasis.
Topics: Animals; Homeostasis; Humans; Lipids; Osteoblasts
PubMed: 33071983
DOI: 10.3389/fendo.2020.578194 -
Bone Nov 2016Advancing our understanding of osteoblast biology and differentiation is critical to elucidate the pathological mechanisms responsible for skeletal diseases such as... (Review)
Review
Advancing our understanding of osteoblast biology and differentiation is critical to elucidate the pathological mechanisms responsible for skeletal diseases such as osteoporosis. Histology and histomorphometry, the classical methods to study osteoblast biology, identify osteoblasts based on their location and morphology and ability to mineralize matrix, but do not clearly define their stage of differentiation. Introduction of visual transgenes into the cells of osteoblast lineage has revolutionized the field and resulted in a paradigm shift that allowed for specific identification and isolation of subpopulations within the osteoblast lineage. Knowledge acquired from the studies based on GFP transgenes has allowed for more precise interpretation of studies analyzing targeted overexpression or deletion of genes in the osteoblast lineage. Here, we provide a condensed overview of the currently available promoter-fluorescent reporter transgenic mice that have been generated and evaluated to varying extents. We cover different stages of the lineage as transgenes have been utilized to identify osteoprogenitors, pre-osteoblasts, osteoblasts, or osteocytes. We show that each of these promoters present with advantages and disadvantages. The studies based on the use of these reporter mice have improved our understanding of bone biology. They constitute attractive models to target osteoblasts and help to understand their cell biology.
Topics: Animals; Cell Differentiation; Cell Lineage; Green Fluorescent Proteins; Humans; Luminescent Proteins; Osteoblasts; Osteocytes; Transgenes
PubMed: 27616604
DOI: 10.1016/j.bone.2016.09.004 -
International Journal of Molecular... Dec 2016Cell death in skeletal component cells, including chondrocytes, osteoblasts, and osteocytes, plays roles in skeletal development, maintenance, and repair as well as in... (Review)
Review
Cell death in skeletal component cells, including chondrocytes, osteoblasts, and osteocytes, plays roles in skeletal development, maintenance, and repair as well as in the pathogenesis of osteoarthritis and osteoporosis. Chondrocyte proliferation, differentiation, and apoptosis are important steps for endochondral ossification. Although the inactivation of and is involved in the pathogenesis of osteosarcomas, the deletion of and inactivation of Rb are insufficient to enhance chondrocyte proliferation, indicating the presence of multiple inhibitory mechanisms against sarcomagenesis in chondrocytes. The inflammatory processes induced by mechanical injury and chondrocyte death through the release of danger-associated molecular patterns (DAMPs) are involved in the pathogenesis of posttraumatic osteoarthritis. The overexpression of increases bone volume with a normal structure and maintains bone during aging by inhibiting osteoblast apoptosis. p53 inhibits osteoblast proliferation and enhances osteoblast apoptosis, thereby reducing bone formation, but also exerts positive effects on osteoblast differentiation through the Akt-FoxOs pathway. Apoptotic osteocytes release ATP, which induces the receptor activator of nuclear factor κ-B ligand (Rankl) expression and osteoclastogenesis, from pannexin 1 channels. Osteocyte death ultimately results in necrosis; DAMPs are released to the bone surface and promote the production of proinflammatory cytokines, which induce Rankl expression, and osteoclastogenesis is further enhanced.
Topics: Alarmins; Animals; Apoptosis; Chondrocytes; Humans; Osteoblasts; Osteocytes
PubMed: 27929439
DOI: 10.3390/ijms17122045 -
European Cells & Materials Jul 2012The process of bone formation, remodelling and healing involves a coordinated action of various cell types. Advances in understanding the biology of osteoblast cells... (Review)
Review
The process of bone formation, remodelling and healing involves a coordinated action of various cell types. Advances in understanding the biology of osteoblast cells during these processes have been enabled through the use of various in vitro culture models from different origins. In an era of intensive bone tissue engineering research, these cell models are more and more often applied due to limited availability of primary human osteoblast cells. While they are a helpful tool in developing novel therapies or biomaterials; concerns arise regarding their phenotypic state and differences in relation to primary human osteoblast cells. In this review we discuss the osteoblastic development of some of the available cell models; such as primary human, rat, mouse, bovine, ovine and rabbit osteoblast cells; as well as MC3T3-E1, MG-63 and SaOs-2 cell lines, together with their advantages and disadvantages. Through this, we provide suggestions on the selection of the appropriate and most relevant osteoblast model for in vitro studies, with specific emphasis on cell-material based studies.
Topics: Animals; Bone and Bones; Cattle; Cell Differentiation; Cell Line; Humans; Mice; Models, Biological; Osteoblasts; Primary Cell Culture; Rabbits; Rats; Sheep; Species Specificity; Tissue Engineering
PubMed: 22777949
DOI: 10.22203/ecm.v024a01 -
Hormones (Athens, Greece) Apr 2017Parathyroid hormone receptors are present in bone cells and play a crucial role in the maintenance of skeletal integrity, bone homeostasis and regulation of calcium and... (Review)
Review
Parathyroid hormone receptors are present in bone cells and play a crucial role in the maintenance of skeletal integrity, bone homeostasis and regulation of calcium and phosphate metabolism. Although the function of these receptors has long being recognized in the cells of the osteoblastic lineage regulating directly osteoblast differentiation and function and indirectly osteoclastogenesis, recent findings demonstrate their functional presence in osteocytes participating in the co-ordination of bone remodelling. In this review we focus on the key roles of these receptors in osteoblasts and osteocytes, combining what is known and what is new regarding these interesting pleiotropic hormone receptors.
Topics: Animals; Humans; Osteoblasts; Osteocytes; Parathyroid Hormone; Receptor, Parathyroid Hormone, Type 1
PubMed: 28742503
DOI: 10.14310/horm.2002.1730 -
Archives of Biochemistry and Biophysics May 2008Skeletal development (bone modeling) and its maintenance in post-natal life in response to local and systemic stimuli (bone remodeling) require coordinated activity... (Review)
Review
Skeletal development (bone modeling) and its maintenance in post-natal life in response to local and systemic stimuli (bone remodeling) require coordinated activity among osteoblasts (bone forming cells), osteocytes (cells embedded in bone) and osteoclasts (bone resorbing cells), in order to meet the needs of structural integrity, mechanical competence and maintenance of mineral homeostasis. One mechanism of cell-cell interaction is via direct cell-cell communication via gap junctions. These are transmembrane channels that allow continuity of cytoplasms between communicating cells. The biologic importance of connexin43 (Cx43), the most abundant gap junction protein in the skeleton is demonstrated by the skeletal malformations present in oculodentodigital dysplasia (ODDD), a disease linked to Cx43 gene (GJA1) mutations, and by the low bone mass and osteoblast dysfunction in Gja1 ablated mice. The presence of Cx43 is required for osteoblast differentiation and function, and by forming either gap junctions or "hemichannels" Cx43 allows participation of cell networks to responses to extracellular stimuli, via propagation of specific signals converging upon connexin sensitive transcriptional units. Hence, Cx43 is involved in skeletal responsiveness to anabolic signals, as those provided by parathyroid hormone and physical load, the latter function probably involving osteocyte-osteoblast communication.
Topics: Animals; Bone Development; Bone Remodeling; Cell Communication; Cell Differentiation; Cell Lineage; Connexin 43; Gap Junctions; Humans; Osteoblasts; Osteocytes
PubMed: 18424255
DOI: 10.1016/j.abb.2008.04.005 -
Bone Jul 2011Bisphosphonates stop bone loss by inhibiting the activity of bone-resorbing osteoclasts. However, the effect of bisphosphonates on bone mass cannot completely explain... (Review)
Review
Bisphosphonates stop bone loss by inhibiting the activity of bone-resorbing osteoclasts. However, the effect of bisphosphonates on bone mass cannot completely explain the reduction in fracture incidence observed in patients treated with these agents. Recent research efforts provided an explanation to this dichotomy by demonstrating that part of the beneficial effect of bisphosphonates on the skeleton is due to prevention of osteoblast and osteocyte apoptosis. Work of our group, independently confirmed by other investigators, demonstrated that bisphosphonates are able to prevent osteoblast and osteocyte apoptosis in vitro and in vivo. This prosurvival effect is strictly dependent on the expression of connexin (Cx) 43, as demonstrated in vitro using cells lacking Cx43 or expressing dominant-negative mutants of the protein as well as in vivo using Cx43 osteoblast/osteocyte-specific conditional knock-out mice. Remarkably, this Cx43-dependent survival effect of bisphosphonates is independent of gap junctions and results from opening of Cx43 hemichannels. Hemichannel opening leads to activation of the kinases Src and extracellular signal-regulated kinases (ERKs), followed by phosphorylation of the ERK cytoplasmic target p90(RSK) kinase and its substrates BAD and C/EBPβ, resulting in inhibition of apoptosis. The antiapoptotic effect of bisphosphonates is separate from the effect of the drugs on osteoclasts, as analogs that lack antiresorptive activity are still able to inhibit osteoblast and osteocyte apoptosis in vitro. Furthermore, a bisphosphonate analog that does not inhibit osteoclast activity prevented osteoblast and osteocyte apoptosis and the loss of bone mass and strength induced by glucocorticoids in mice. Preservation of the bone-forming function of mature osteoblasts and maintenance of the osteocytic network, in combination with lack anticatabolic actions, open new therapeutic possibilities for bisphosphonates in the treatment of osteopenic conditions in which decreased bone resorption is not desired.
Topics: Animals; Bone and Bones; Cell Survival; Connexin 43; Diphosphonates; Humans; Osteoblasts; Osteocytes
PubMed: 20727997
DOI: 10.1016/j.bone.2010.08.008 -
Bone May 2023FBXO11 is the substrate-recognition component of a ubiquitin ligase complex called SKP1-cullin-F-boxes. The role of FBXO11 in bone development is unexplored. In this...
FBXO11 is the substrate-recognition component of a ubiquitin ligase complex called SKP1-cullin-F-boxes. The role of FBXO11 in bone development is unexplored. In this study, we reported a novel mechanism of how bone development is regulated by FBXO11. FBXO11 gene knockdown by lentiviral transduction in mouse pre-osteoblast MC3T3-E1 cells leads to reduced osteogenic differentiation, while overexpressing FBXO11 accelerates their osteogenic differentiation in vitro. Furthermore, we generated two osteoblastic-specific FBXO11 conditional knockout mouse models, Col1a1-ERT2-FBXO11KO and Bglap2-FBXO11KO mice. In both conditional FBXO11KO mouse models, we found FBXO11 deficiency inhibits normal bone growth, in which the osteogenic activity in FBXO11cKO mice is reduced, while osteoclastic activity is not significantly changed. Mechanistically, we found FBXO11 deficiency leads to Snail1 protein accumulation in osteoblasts, leading to suppression of osteogenic activity and inhibition of bone matrix mineralization. FBXO11 knockdown in MC3T3-E1 cells reduced Snail1 protein ubiquitination and increased Snail1 protein accumulation in the cells, which eventually inhibited osteogenic differentiation. In conclusion, FBXO11 deficiency in osteoblasts inhibits bone formation through Snail1 accumulation, inhibiting osteogenic activity and bone mineralization.
Topics: Animals; Mice; Osteogenesis; Cell Differentiation; Calcification, Physiologic; Osteoclasts; Osteoblasts
PubMed: 36863499
DOI: 10.1016/j.bone.2023.116709