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Bone Jun 2013Multiple lines of evidence support the idea that osteocytes act as mechanosensors in bone and that they control bone formation, in part, by expressing the Wnt antagonist... (Review)
Review
Multiple lines of evidence support the idea that osteocytes act as mechanosensors in bone and that they control bone formation, in part, by expressing the Wnt antagonist sclerostin. However, the role of osteocytes in the control of bone resorption has been less clear. Recent studies have demonstrated that osteocytes are the major source of the cytokine RANKL involved in osteoclast formation in cancellous bone. The goal of this review is to discuss these and other studies that reveal mechanisms whereby osteocytes control osteoclast formation and thus bone resorption.
Topics: Animals; Cell Differentiation; Humans; Osteoclasts; Osteocytes; Osteogenesis; RANK Ligand; Signal Transduction
PubMed: 22939943
DOI: 10.1016/j.bone.2012.08.121 -
Materials Science & Engineering. C,... Oct 2016A new era of osteomyelitis treatment has been taking strides towards efficient, local administration of antibiotics at the site of infection. By having them localized to... (Review)
Review
A new era of osteomyelitis treatment has been taking strides towards efficient, local administration of antibiotics at the site of infection. By having them localized to the site of infection, this toxicity is no longer an issue and actually has shown to be a more productive treatment for osteomyelitis. Researchers have focused the production of non-biodegradable, antibiotic, infused bone cements specifically designed for proficient osteocyte binding, useful antibiotic release over a desirable period of time, and promotion of bone regeneration. These cements are then surgically placed on the infected site following debridement and irrigation. The problem, however, is that the use of ineffective cements and the overuse of antibiotics has led to the development of resistant bacteria. Due to this, further research is being done in the field of antibiotic discovery and delivery. Specifically, the development of biodegradable materials capable of efficiently delivering antibiotics and also eliminating the need for follow-up surgery to remove the delivery material is being done, thus reducing exposure risk. Nanoparticles have been developed in the forms of scaffolds and injections to deliver a higher degree and longer lasting duration of antibiotic release, while promoting bone regeneration.
Topics: Animals; Anti-Bacterial Agents; Bone Cements; Delayed-Action Preparations; Humans; Nanostructures; Osteocytes; Osteomyelitis
PubMed: 27287180
DOI: 10.1016/j.msec.2016.04.062 -
Kidney International Jun 2017In an important new cross-sectional analysis in this issue, Graciolli and colleagues present bone data from 148 adult patients across the spectrum of chronic kidney...
In an important new cross-sectional analysis in this issue, Graciolli and colleagues present bone data from 148 adult patients across the spectrum of chronic kidney disease that confirm that disrupted osteocyte function and abnormal bone histology characterize all stages of chronic kidney disease and suggest that osteocytic Wnt signaling and osteocyte maturation may play a role in the pathogenesis of renal osteodystrophy. These concepts may alter how the skeletal, cardiovascular, and infectious complications of chronic kidney disease are managed.
Topics: Calcium; Chronic Kidney Disease-Mineral and Bone Disorder; Cross-Sectional Studies; Humans; Kidney Failure, Chronic; Osteocytes; Phosphorus
PubMed: 28501301
DOI: 10.1016/j.kint.2017.02.026 -
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 Oral Science Jun 2009With additional functions of osteocytes being identified, the concept that osteocytes are just "static lacunar-dwelling cells" is no longer accepted. We reviewed most of... (Review)
Review
With additional functions of osteocytes being identified, the concept that osteocytes are just "static lacunar-dwelling cells" is no longer accepted. We reviewed most of the relevant literature on osteocyte's function in the direct remodeling of the perilucunar matrix, discussing the advantages and disadvantages. Special attention was paid to how the negative researchers argue about the "osteocytic osteolysis" principle, and how the positive side addressed the arguments. We also discussed the newly found data of osteocytic remodeling function from our group. With more biotechnology in hand, there is increased excitement in the prospect of now being able to answer the two important questions: do osteocytes have the capability to remove mineral from the perilacunar matrix and if so what are the molecular and cellular mechanisms? do osteocytes have the capability to deposit new mineral on the perilacunar matrix and if so what are the cellular and molecular mechanisms?
Topics: Animals; Bone Matrix; Bone Remodeling; Humans; Osteocytes; Osteogenesis; Osteolysis
PubMed: 20687297
DOI: 10.4248/ijos.09019 -
Nutrients Sep 2023The pathophysiology of chronic kidney disease-mineral and bone disorder (CKD-MBD) is not well understood. Specific factors secreted by osteocytes are elevated in the...
The pathophysiology of chronic kidney disease-mineral and bone disorder (CKD-MBD) is not well understood. Specific factors secreted by osteocytes are elevated in the serum of adults and pediatric patients with CKD-MBD, including FGF-23 and sclerostin, a known inhibitor of the Wnt signaling pathway. The molecular mechanisms that promote bone disease during the progression of CKD are incompletely understood. In this study, we performed a cross-sectional analysis of 87 pediatric patients with pre-dialysis CKD and post-dialysis (CKD 5D). We assessed the associations between serum and bone sclerostin levels and biomarkers of bone turnover and bone histomorphometry. We report that serum sclerostin levels were elevated in both early and late CKD. Higher circulating and bone sclerostin levels were associated with histomorphometric parameters of bone turnover and mineralization. Immunofluorescence analyses of bone biopsies evaluated osteocyte staining of antibodies towards the canonical Wnt target, β-catenin, in the phosphorylated (inhibited) or unphosphorylated (active) forms. Bone sclerostin was found to be colocalized with phosphorylated β-catenin, which suggests that Wnt signaling was inhibited. In patients with low serum sclerostin levels, increased unphosphorylated "active" β-catenin staining was observed in osteocytes. These data provide new mechanistic insight into the pathogenesis of CKD-MBD and suggest that sclerostin may offer a potential biomarker or therapeutic target in pediatric renal osteodystrophy.
Topics: Adult; Humans; Child; Chronic Kidney Disease-Mineral and Bone Disorder; Osteocytes; Wnt Signaling Pathway; beta Catenin; Cross-Sectional Studies; Biomarkers; Renal Insufficiency, Chronic
PubMed: 37836411
DOI: 10.3390/nu15194127 -
Current Osteoporosis Reports Oct 2020Bone regeneration plays an important role in contemporary clinical treatment. Bone tissue engineering should result in successful bone regeneration to restore congenital... (Review)
Review
PURPOSE OF REVIEW
Bone regeneration plays an important role in contemporary clinical treatment. Bone tissue engineering should result in successful bone regeneration to restore congenital or acquired bone defects in the human skeleton. Osteocytes are thought to have a governing role in bone remodeling by regulating osteoclast and osteoblast activity, and thus bone loss and formation. In this review, we address the so far largely unknown role osteocytes may play in bone tissue regeneration.
RECENT FINDINGS
Osteocytes release biochemical signaling molecules involved in bone remodeling such as prostaglandins, nitric oxide, Wnts, and insulin-like growth factor-1 (IGF-1). Treatment of mesenchymal stem cells in bone tissue engineering with prostaglandins (e.g., PGE, PGI, PGF), nitric oxide, IGF-1, or Wnts (e.g., Wnt3a) improves osteogenesis. This review provides an overview of the functions of osteocytes in bone tissue, their interaction with other bone cells, and their role in bone remodeling. We postulate that osteocytes may have a pivotal role in bone regeneration as well, and consequently that the bone regeneration process may be improved effectively and rapidly if osteocytes are optimally used and stimulated.
Topics: Bone Regeneration; Bone Remodeling; Bone Resorption; Guided Tissue Regeneration; Humans; Insulin-Like Growth Factor I; Nitric Oxide; Osteoblasts; Osteoclasts; Osteocytes; Osteogenesis; Prostaglandins; Signal Transduction; Tissue Engineering; Wnt Proteins
PubMed: 32676786
DOI: 10.1007/s11914-020-00610-6 -
Nutrients Jul 2016Oats contain unique bioactive compounds known as avenanthramides (AVAs) with antioxidant properties. AVAs might enhance the endogenous antioxidant cellular response by... (Comparative Study)
Comparative Study
Oats contain unique bioactive compounds known as avenanthramides (AVAs) with antioxidant properties. AVAs might enhance the endogenous antioxidant cellular response by activation of the transcription factor Nrf2. Accumulation of reactive oxygen species plays a critical role in many chronic and degenerative diseases, including osteoporosis. In this disease, there is an imbalance between bone formation by osteoblasts and bone resorption by osteoclasts, which is accompanied by increased osteoblast/osteocyte apoptosis and decreased osteoclast apoptosis. We investigated the ability of the synthethic AVAs 2c, 2f and 2p, to 1-regulate gene expression in bone cells, 2-affect the viability of osteoblasts, osteocytes and osteoclasts, and the generation of osteoclasts from their precursors, and 3-examine the potential involvement of the transcription factor Nrf2 in these actions. All doses of AVA 2c and 1 and 5 µM dose of 2p up-regulated collagen 1A expression. Lower doses of AVAs up-regulated OPG (osteoprotegerin) in OB-6 osteoblastic cells, whereas 100 μM dose of 2f and all concentrations of 2c down-regulated RANKL gene expression in MLO-Y4 osteocytic cells. AVAs did not affect apoptosis of OB-6 osteoblastic cells or MLO-Y4 osteocytic cells; however, they prevented apoptosis induced by the DNA topoisomerase inhibitor etoposide, the glucocorticoid dexamethasone, and hydrogen peroxide. AVAs prevented apoptosis of both wild type (WT) and Nrf2 Knockout (KO) osteoblasts, demonstrating that AVAs-induced survival does not require Nrf2 expression. Further, KO osteoclast precursors produced more mature osteoclasts than WT; and KO cultures exhibited less apoptotic osteoclasts than WT cultures. Although AVAs did not affect WT osteoclasts, AVA 2p reversed the low apoptosis of KO osteoclasts. These in vitro results demonstrate that AVAs regulate, in part, the function of osteoblasts and osteocytes and prevent osteoblast/osteocyte apoptosis and increase osteoclast apoptosis; further, these regulatory actions are independent of Nrf2.
Topics: Animals; Antioxidants; Apoptosis; Avena; Cell Differentiation; Cell Survival; Cells, Cultured; Dose-Response Relationship, Drug; Gene Expression Regulation; Mice, Inbred C57BL; Mice, Knockout; NF-E2-Related Factor 2; Osteoblasts; Osteoclasts; Osteocytes; Osteoprotegerin; RANK Ligand; Signal Transduction; ortho-Aminobenzoates
PubMed: 27409635
DOI: 10.3390/nu8070423 -
European Cells & Materials May 2016Extracellular matrix (ECM) stiffness and cell density can regulate osteoblast differentiation in two dimensional environments. However, it is not yet known how...
Extracellular matrix (ECM) stiffness and cell density can regulate osteoblast differentiation in two dimensional environments. However, it is not yet known how osteoblast-osteocyte differentiation is regulated within a 3D ECM environment, akin to that existing in vivo. In this study we test the hypothesis that osteocyte differentiation is regulated by a 3D cell environment, ECM stiffness and cell density. We encapsulated MC3T3-E1 pre-osteoblastic cells at varied cell densities (0.25, 1 and 2 × 106 cells/mL) within microbial transglutaminase (mtgase) gelatin hydrogels of low (0.58 kPa) and high (1.47 kPa) matrix stiffnesses. Cellular morphology was characterised from phalloidin-FITC and 4',6-diamidino-2-phenylindole (DAPI) dilactate staining. In particular, the expression of cell dendrites, which are phenotypic of osteocyte differentiation, were identified. Immunofluorescent staining for the osteocytes specific protein DMP-1 was conducted. Biochemical analyses were performed to determine cell number, alkaline phosphatase activity and mineralisation at 2.5 hours, 3, 21 and 56 days. We found that osteocyte differentiation and the formation of an interconnected network between dendritic cells was significantly increased within low stiffness 3D matrices, compared to cells within high stiffness matrices, at high cell densities. Moreover we saw that this network was interconnected, expressed DMP-1 and also connected with osteoblast-like cells at the matrix surface. This study shows for the first time the role of the 3D physical nature of the ECM and cell density for regulating osteocyte differentiation and the formation of the osteocyte network in vitro. Future studies could apply this method to develop 3D tissue engineered constructs with an osteocyte network in place.
Topics: Actins; Alkaline Phosphatase; Animals; Calcification, Physiologic; Calcium; Cell Count; Cell Differentiation; Cell Line; Cell Shape; Compressive Strength; DNA; Dendritic Cells; Extracellular Matrix Proteins; Fluorescent Antibody Technique; Hydrogel, Polyethylene Glycol Dimethacrylate; Materials Testing; Mice; Osteocytes; Phenotype
PubMed: 27215740
DOI: 10.22203/ecm.v031a21 -
Bone Jun 2013Osteocytes are ideally positioned to detect and respond to mechanical and hormonal stimuli and to coordinate the function of osteoblasts and osteoclasts. However,... (Review)
Review
Osteocytes are ideally positioned to detect and respond to mechanical and hormonal stimuli and to coordinate the function of osteoblasts and osteoclasts. However, evidence supporting the involvement of osteocytes in specific aspects of skeletal biology has been limited mainly due to the lack of suitable experimental approaches. Few crucial advances in the field in the past several years have markedly increased our understanding of the function of osteocytes. The development of osteocytic cell lines initiated a plethora of in vitro studies that have provided insights into the unique biology of osteocytes and continue to generate novel hypotheses. Genetic approaches using promoter fragments that direct gene expression to osteocytes allowed the generation of mice with gain or loss of function of particular genes revealing their role in osteocyte function. Furthermore, evidence that Sost/sclerostin is expressed primarily in osteocytes and inhibits bone formation by osteoblasts, fueled research attempting to identify regulators of this gene as well as other osteocyte products that impact the function of osteoblasts and osteoclasts. The discovery that parathyroid hormone (PTH), a central regulator of bone homeostasis, inhibits sclerostin expression generated a cascade of studies that revealed that osteocytes are crucial target cells of the actions of PTH. This review highlights these investigations and discusses their significance for advancing our understanding of the mechanisms by which osteocytes regulate bone homeostasis and for developing therapies for bone diseases targeting osteocytes.
Topics: Animals; Bone Remodeling; Homeostasis; Humans; Osteocytes; Osteogenesis; Parathyroid Hormone; Receptors, Parathyroid Hormone
PubMed: 23017659
DOI: 10.1016/j.bone.2012.09.016