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Advances in Protein Chemistry and... 2019The achievement of proper bone mass and architecture, and their maintenance throughout life requires the concerted actions of osteoblasts, the bone forming cells, and... (Review)
Review
The achievement of proper bone mass and architecture, and their maintenance throughout life requires the concerted actions of osteoblasts, the bone forming cells, and osteoclasts, the bone resorbing cells. The differentiation and activity of osteoblasts and osteoclasts are regulated by molecules produced by matrix-embedded osteocytes, as well as by cross talk between osteoblasts and osteoclasts through secreted factors. In addition, it is likely that direct contact between osteoblast and osteoclast precursors, and the contact of these cells with osteocytes and cells in the bone marrow, also modulates bone cell differentiation and function. With the advancement of molecular and genetic tools, our comprehension of the intracellular signals activated in bone cells has evolved significantly, from early suggestions that osteoblasts and osteoclasts have common precursors and that osteocytes are inert cells in the bone matrix, to the very sophisticated understanding of a network of receptors, ligands, intracellular kinases/phosphatases, transcription factors, and cell-specific genes that are known today. These advances have allowed the design and FDA-approval of new therapies to preserve and increase bone mass and strength in a wide variety of pathological conditions, improving bone health from early childhood to the elderly. We have summarized here the current knowledge on selected intracellular signal pathways activated in osteoblasts, osteocytes, and osteoclasts.
Topics: Animals; Apoptosis; Bone Morphogenetic Proteins; Cell Communication; Cell Differentiation; Humans; Osteoblasts; Osteoclasts; Osteocytes; Osteogenesis; Signal Transduction
PubMed: 31036293
DOI: 10.1016/bs.apcsb.2019.01.002 -
International Journal of Biological... 2019The skeleton is one of the largest organs in the human body. In addition to its conventional functions such as support, movement and protection, the skeleton also... (Review)
Review
The skeleton is one of the largest organs in the human body. In addition to its conventional functions such as support, movement and protection, the skeleton also contributes to whole body homeostasis and maintenance of multiple important non-bone organs/systems (extraskeletal functions). Both conventional and extraskeletal functions of the skeleton are defined as . Bone-derived factors (BDFs) are key players regulating bone function. In some pathophysiological situations, including diseases affecting bone and/or other organs/systems, the disorders of bone itself and the subsequently impaired functions of extraskeletal organs/systems caused by abnormal bone (impaired extraskeletal functions of bone) are defined as . In critical illness, which is a health status characterized by the dysfunction or severe damage of one or multiple important organs or systems, the skeleton shows rapid bone loss resulting from bone hyper-resorption and impaired osteoblast function. In addition, the dysfunctions of the skeleton itself are also closely related to the severity and prognosis of critical illness. Therefore, we propose that there is bone dysfunction in critical illness. Some methods to inhibit osteoclast activity or promote osteoblast function by the treatment of bisphosphonates or PTH1-34 benefit the outcome of critical illness, which indicates that enhancing bone function may be a potential novel strategy to improve prognosis of diseases including critical illness.
Topics: Animals; Bone Resorption; Critical Illness; Diphosphonates; Humans; Osteoblasts; Osteoclasts
PubMed: 30906209
DOI: 10.7150/ijbs.27063 -
International Journal of Food Sciences... Sep 2022Short-chain fatty acids, including acetate, propionate, and butyrate are metabolites of dietary fibre produced by microbiota in the large intestine, have been proposed...
Short-chain fatty acids, including acetate, propionate, and butyrate are metabolites of dietary fibre produced by microbiota in the large intestine, have been proposed to contribute to effects on bone homeostasis. However, it is unclear whether they are used in osteoblasts and directly affect bone formation. We investigated whether short-chain fatty acids are absorbed in osteoblast cells and influence early osteoblastic differentiation using MC3T3-E1 cells. Acetate and propionate upregulated alkaline phosphatase activity, which is an osteoblast differentiation marker, and acetate upregulated alkaline phosphatase mRNA expression after treatment for 9 days, whereas butyrate did not in MC3T3-E1 cells. Butyrate was absorbed more rapidly and to a greater extent than acetate and propionate. These results indicate that short-chain fatty acids were used in osteoblastic cells, and particularly acetate and propionate directly upregulated differentiation in primary osteoblasts. Therefore, acetate and propionate might be useful for maintaining a positive balance of bone turnover.
Topics: Acetates; Alkaline Phosphatase; Butyrates; Cell Differentiation; Fatty Acids, Volatile; Osteoblasts; Propionates
PubMed: 35616294
DOI: 10.1080/09637486.2022.2078285 -
Prostaglandins, Leukotrienes, and... Feb 2024Linoleic acid (LNA), an essential polyunsaturated fatty acid (PUFA), plays a crucial role in cellular functions. However, excessive intake of LNA, characteristic of...
BACKGROUND
Linoleic acid (LNA), an essential polyunsaturated fatty acid (PUFA), plays a crucial role in cellular functions. However, excessive intake of LNA, characteristic of Western diets, can have detrimental effects on cells and organs. Human observational studies have shown an inverse relationship between plasma LNA concentrations and bone mineral density. The mechanism by which LNA impairs the skeleton is unclear, and there is a paucity of research on the effects of LNA on bone-forming osteoblasts.
METHODS
The effect of LNA on osteoblast differentiation, cellular bioenergetics, and production of oxidized PUFA metabolites in vitro, was studied using primary mouse bone marrow stromal cells (BMSC) and MC3T3-E1 osteoblast precursors.
RESULTS
LNA treatment decreased alkaline phosphatase activity, an early marker of osteoblast differentiation, but had no effect on committed osteoblasts or on mineralization by differentiated osteoblasts. LNA suppressed osteoblast commitment by blunting the expression of Runx2 and Osterix, key transcription factors involved in osteoblast differentiation, and other key osteoblast-related factors involved in bone formation. LNA treatment was associated with increased production of oxidized LNA- and arachidonic acid-derived metabolites and blunted oxidative phosphorylation, resulting in decreased ATP production.
CONCLUSION
Our results show that LNA inhibited early differentiation of osteoblasts and this inhibitory effect was associated with increased production of oxidized PUFA metabolites that likely impaired energy production via oxidative phosphorylation.
Topics: Animals; Osteoblasts; Cell Differentiation; Mice; Oxidative Phosphorylation; Linoleic Acid; Alkaline Phosphatase; Core Binding Factor Alpha 1 Subunit; Mesenchymal Stem Cells; Cells, Cultured
PubMed: 38788347
DOI: 10.1016/j.plefa.2024.102617 -
BMB Reports Jul 2019Kruppel-like factor 2 (KLF2) has been implicated in the regulation of cell proliferation, differentiation, and survival in a variety of cells. Recently, it has been...
Kruppel-like factor 2 (KLF2) has been implicated in the regulation of cell proliferation, differentiation, and survival in a variety of cells. Recently, it has been reported that KLF2 regulates the p65-mediated transactivation of NF-κB. Although the NF-κB pathway plays an important role in the differentiation of osteoclasts and osteoblasts, the role of KLF2 in these bone cells has not yet been fully elucidated. In this study, we demonstrated that KLF2 regulates osteoclast and osteoblast differentiation. The overexpression of KLF2 in osteoclast precursor cells inhibited osteoclast differentiation by downregulating c-Fos, NFATc1, and TRAP expression, while KLF2 overexpression in osteoblasts enhanced osteoblast differentiation and function by upregulating Runx2, ALP, and BSP expression. Conversely, the downregulation of KLF2 with KLF2-specific siRNA increased osteoclast differentiation and inhibited osteoblast differentiation. Moreover, the overexpression of interferon regulatory protein 2-binding protein 2 (IRF2BP2), a regulator of KLF2, suppressed osteoclast differentiation and enhanced osteoblast differentiation and function. These effects were reversed by downregulating KLF2. Collectively, our data provide new insights and evidence to suggest that the IRF2BP2/KLF2 axis mediates osteoclast and osteoblast differentiation, thereby affecting bone homeostasis. [BMB Reports 2019; 52(7): 469-474].
Topics: Cell Differentiation; DNA-Binding Proteins; Homeostasis; Humans; Kruppel-Like Transcription Factors; Osteoblasts; Osteoclasts; Transcription Factors
PubMed: 31186082
DOI: 10.5483/BMBRep.2019.52.7.104 -
Cell Reports Sep 2020Osteoprotegerin (OPG) is a circulating decoy receptor for RANKL, a multifunctional cytokine essential for the differentiation of tissue-specific cells in bone and immune...
Osteoprotegerin (OPG) is a circulating decoy receptor for RANKL, a multifunctional cytokine essential for the differentiation of tissue-specific cells in bone and immune systems such as osteoclasts, medullary thymic epithelial cells (mTECs), and intestinal microfold cells (M cells). However, it is unknown whether OPG functions only at the production site or circulates to other tissues acting in an endocrine fashion. Here we explore the cellular source of OPG by generating OPG-floxed mice and show that locally produced OPG, rather than circulating OPG, is crucial for bone and immune homeostasis. Deletion of OPG in osteoblastic cells leads to severe osteopenia without affecting serum OPG. Deletion of locally produced OPG increases mTEC and M cell numbers while retaining the normal serum OPG level. This study shows that OPG limits its functions within the tissue where it was produced, illuminating the importance of local regulation of the RANKL system.
Topics: Animals; Mice; Osteoblasts; Osteoclasts; Osteoprotegerin
PubMed: 32905763
DOI: 10.1016/j.celrep.2020.108124 -
Seminars in Immunopathology Sep 2019Bone homeostasis depends on a balance between osteoclastic bone resorption and osteoblastic bone formation. Bone cells are regulated by a variety of biochemical factors,... (Review)
Review
Bone homeostasis depends on a balance between osteoclastic bone resorption and osteoblastic bone formation. Bone cells are regulated by a variety of biochemical factors, such as hormones and cytokines, as well as various types of physical stress. The immune system affects bone, since such factors are dysregulated under pathologic conditions, including infection. The bone marrow, one of the primary lymphoid organs, provides a special microenvironment that supports the function and differentiation of immune cells and hematopoietic stem cells (HSCs). Thus, bone cells contribute to immune regulation by modulating immune cell differentiation and/or function through the maintenance of the bone marrow microenvironment. Although osteoblasts were first reported as the population that supports HSCs, the role of osteoblast-lineage cells in hematopoiesis has been shown to be more limited than previously expected. Osteoblasts are specifically involved in the differentiation of lymphoid cells under physiological and pathological conditions. It is of critical importance how bone cells are modified during inflammation and/or infection and how such modification affects the immune system.
Topics: Animals; Bone and Bones; Cell Differentiation; Disease Susceptibility; Hematopoiesis; Hematopoietic Stem Cells; Humans; Immune System; Immunomodulation; Osteitis; Osteoblasts; Osteoclasts
PubMed: 31552472
DOI: 10.1007/s00281-019-00755-2 -
Cellular and Molecular Life Sciences :... Apr 2015Several metabolic, genetic and oncogenic bone diseases are characterized by defective or excessive bone formation. These abnormalities are caused by dysfunctions in the... (Review)
Review
Several metabolic, genetic and oncogenic bone diseases are characterized by defective or excessive bone formation. These abnormalities are caused by dysfunctions in the commitment, differentiation or survival of cells of the osteoblast lineage. During the recent years, significant advances have been made in our understanding of the cellular and molecular mechanisms underlying the osteoblast dysfunctions in osteoporosis, skeletal dysplasias and primary bone tumors. This led to suggest novel therapeutic approaches to correct these abnormalities such as the modulation of WNT signaling, the pharmacological modulation of proteasome-mediated protein degradation, the induction of osteoprogenitor cell differentiation, the repression of cancer cell proliferation and the manipulation of epigenetic mechanisms. This article reviews our current understanding of the major cellular and molecular mechanisms inducing osteoblastic cell abnormalities in age-related bone loss, genetic skeletal dysplasias and primary bone tumors, and discusses emerging therapeutic strategies to counteract the osteoblast abnormalities in these disorders of bone formation.
Topics: Apoptosis; Bone Diseases, Developmental; Bone Neoplasms; Cell Differentiation; Humans; Models, Biological; Osteoblasts; Osteoporosis; Signal Transduction
PubMed: 25487608
DOI: 10.1007/s00018-014-1801-2 -
Current Stem Cell Research & Therapy 2016Sharing the same precursor cell lineage located in the bone marrow, mesenchymal stroma/stem cells (MSCs), osteoblasts and adipocytes have a reciprocal relationship in... (Review)
Review
Sharing the same precursor cell lineage located in the bone marrow, mesenchymal stroma/stem cells (MSCs), osteoblasts and adipocytes have a reciprocal relationship in differentiation and function. The nuclear transcription factor peroxisome-proliferator- activated receptor-gamma (PPAR-γ) has been found expressed in both osteoblasts and adipocytes, as well as in MSCs, suggesting its crucial role in regulating adipocyte formation and osteoblast development. It has been observed in animal models that upregulated PPAR-γ activity results in bone loss where marrow adiposity is facilitated, while downregulated PPAR-γ activity leads to bone mass elevation. Evidence suggests that the dual function of PPAR-γ in either anti-osteoblastic or pro-adipocytic aspects is determined by its ligand. Furthermore, various cytokines and extracellular signaling pathways are involved in the transactivation of PPAR-γ, which can trigger the adipogenesis/osteoblastogenesis switch. PPAR-γ, therefore, shows tremendous potential in novel strategies for bone tissue engineering and clinical application. This review summarizes the regulatory function of PPAR-γ in MSC differentiation, as well as the cytokine and extracellular signaling pathways participating in the cross-talk between adipogenesis and osteoblastogenesis.
Topics: Adipocytes; Adipogenesis; Animals; Bone Marrow Cells; Bone Resorption; Cell Lineage; Humans; Mesenchymal Stem Cells; Osteoblasts; Osteogenesis; PPAR gamma
PubMed: 26027680
DOI: 10.2174/1574888x10666150531173309 -
PloS One 2018MicroRNAs (miRNAs) are important regulators of many cellular processes, including the differentiation and activity of osteoblasts, and therefore, of bone turnover....
MicroRNAs (miRNAs) are important regulators of many cellular processes, including the differentiation and activity of osteoblasts, and therefore, of bone turnover. MiR-320a is overexpressed in osteoporotic bone tissue but its role in osteoblast function is unknown. In the present study, functional assays were performed with the aim to elucidate the mechanism of miR-320a action in osteoblastic cells. MiR-320a was either overexpressed or inhibited in human primary osteoblasts (hOB) and gene expression changes were evaluated through microarray analysis. In addition, the effect of miR-320a on cell proliferation, viability, and oxidative stress in hOB was evaluated. Finally, matrix mineralization and alkaline phosphatase activity were assessed in order to evaluate osteoblast functionality. Microarray results showed miR-320a regulation of a number of key osteoblast genes and of genes involved in oxidative stress. Regulation of osteoblast differentiation and ossification appeared as the best significant biological processes (PANTHER P value = 3.74E-05; and P value = 3.06E-04, respectively). The other enriched pathway was that of the cellular response to cadmium and zinc ions, mostly by the overexpression of metallothioneins. In hOBs, overexpression of miR-320a increased cell proliferation and oxidative stress levels whereas mineralization capacity was reduced. In conclusion, overexpression of miR-320a increased stress oxidation levels and was associated with reduced osteoblast differentiation and functionality, which could trigger an osteoporotic phenotype.
Topics: Cell Differentiation; Cell Proliferation; Cells, Cultured; Gene Expression Regulation; Humans; MicroRNAs; Osteoblasts; Osteoporosis; Oxidative Stress; Up-Regulation
PubMed: 30485349
DOI: 10.1371/journal.pone.0208131