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Journal of Orthopaedic Research :... Feb 2018Mechanical loading preserves bone mass and stimulates bone formation, whereas skeletal unloading leads to bone loss. In addition to osteocytes, which are considered the... (Review)
Review
Mechanical loading preserves bone mass and stimulates bone formation, whereas skeletal unloading leads to bone loss. In addition to osteocytes, which are considered the primary sensor of mechanical load, osteoblasts, and bone specific mesenchymal stem cells also are involved. The skeletal response to mechanical signals is a complex process regulated by multiple signaling pathways including that of insulin-like growth factor-1 (IGF-1). Conditional osteocyte deletion of IGF-1 ablates the osteogenic response to mechanical loading. Similarly, osteocyte IGF-1 receptor (IGF-1R) expression is necessary for reloading-induced periosteal bone formation. Transgenic overexpression of IGF-1 in osteoblasts results in enhanced responsiveness to in vivo mechanical loading in mice, a response which is eliminated by osteoblastic conditional disruption of IGF-1 in vivo. Bone marrow derived stem cells (BMSC) from unloaded bone fail to respond to IGF-1 in vitro. IGF-1R is required for the transduction of a mechanical stimulus to downstream effectors, transduction which is lost when the IGF-1R is deleted. Although the molecular mechanisms are not yet fully elucidated, the IGF signaling pathway and its interactions with potentially interlinked signaling cascades involving integrins, the estrogen receptor, and wnt/β-catenin play an important role in regulating adaptive response of cancer bone cells to mechanical stimuli. In this review, we discuss recent advances investigating how IGF-1 and other interlinked molecules and signaling pathways regulate skeletal mechano-transduction involving different bone cells, providing an overview of the IGF-1 signaling mediated cell-specific response to mechanical stimuli. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:576-583, 2018.
Topics: Animals; Bone and Bones; Insulin-Like Growth Factor I; Mechanotransduction, Cellular; Mesenchymal Stem Cells; Osteocytes; Signal Transduction
PubMed: 28980721
DOI: 10.1002/jor.23767 -
Calcified Tissue International Jul 2023Bone is a highly dynamic tissue, and the constant actions of bone-forming and bone-resorbing cells are responsible for attaining peak bone mass, maintaining bone mass in... (Review)
Review
Bone is a highly dynamic tissue, and the constant actions of bone-forming and bone-resorbing cells are responsible for attaining peak bone mass, maintaining bone mass in the adults, and the subsequent bone loss with aging and menopause, as well as skeletal complications of diseases and drug side-effects. It is now accepted that the generation and activity of bone-forming osteoblasts and bone-resorbing osteoclasts is modulated by osteocytes, osteoblast-derived cells embedded in the bone matrix. The interaction among bone cells occurs through direct contact and via secreted molecules. In addition to the regulation of bone cell function, molecules released by these cells are also able to reach the circulation and have effects in other tissues and organs in healthy individuals. Moreover, bone cell products have also been associated with the establishment or progression of diseases, including cancer and muscle weakness. In this review, we will discuss the role of bone as an endocrine organ, and the effect of selected, osteoblast-, osteocyte-, and osteoclast-secreted molecules on other tissues.
Topics: Humans; Osteocytes; Osteoblasts; Bone and Bones; Osteoclasts; Minerals; Cell Differentiation
PubMed: 37171619
DOI: 10.1007/s00223-023-01091-2 -
Current Osteoporosis Reports Jun 2012Osteocytes, the cells residing within the bone matrix and comprising 90% to 95% of the all bone cells, have long been considered quiescent bystander cells compared to... (Review)
Review
Osteocytes, the cells residing within the bone matrix and comprising 90% to 95% of the all bone cells, have long been considered quiescent bystander cells compared to the osteoblasts and osteoclasts whose activities cause bone gain and loss, and whose dysfunction lead to growth defects and osteoporosis. However, recent studies show that osteocytes play a crucial, central role in regulating the dynamic nature of bone in all its diverse functions. Osteocytes are now known to be the principal sensors for mechanical loading of bone. They produce the soluble factors that regulate the onset of both bone formation and resorption. Osteocytes regulate local mineral deposition and chemistry at the bone matrix level, and they also function as endocrine cells producing factors that target distant organs such as the kidney to regulate phosphate transport. Osteocytes appear to be the major local orchestrator of many of bone's functions.
Topics: Animals; Bone Density; Bone Resorption; Bone and Bones; Humans; Models, Animal; Osteocytes; Osteogenesis; Signal Transduction
PubMed: 22552701
DOI: 10.1007/s11914-012-0105-4 -
Bone May 2019Osteoporosis is an aging-related disease of reduced bone mass that is particularly prevalent in post-menopausal women, but also affects the aged male population and is... (Review)
Review
Osteoporosis is an aging-related disease of reduced bone mass that is particularly prevalent in post-menopausal women, but also affects the aged male population and is associated with increased fracture risk. Osteoporosis is the result of an imbalance whereby bone formation by osteoblasts no longer keeps pace with resorption of bone by osteoclasts. Osteocytes are the most abundant cells in bone and, although previously thought to be quiescent, they are now known to be active, multifunctional cells that play a key role in the maintenance of bone mass by regulating both osteoblast and osteoclast activity. They are also thought to regulate bone mass through their role as mechanoresponsive cells in bone that coordinate adaptive responses to mechanical loading. Osteocytes form an extensive interconnected network throughout the mineralized bone matrix and receive their nutrients as well as hormones and signaling factors through the lacunocanalicular system. Several studies have shown that the extent and connectivity of the lacunocanalicular system and osteocyte networks degenerates in aged humans as well as in animal models of aging. It is also known that the bone anabolic response to loading is decreased with aging. This review summarizes recent research on the degenerative changes that occur in osteocytes and their lacunocanalicular system as a result of aging and discusses the implications for skeletal health and homeostasis as well as potential mechanisms that may underlie these degenerative changes. Since osteocytes are such key regulators of skeletal homeostasis, maintaining the health of the osteocyte network would seem critical for maintenance of bone health. Therefore, a more complete understanding of the structure and function of the osteocyte network, its lacunocanalicular system, and the degenerative changes that occur with aging should lead to advances in our understanding of age related bone loss and potentially lead to improved therapies.
Topics: Aging; Animals; Bone and Bones; Humans; Nerve Degeneration; Osteocytes
PubMed: 30743014
DOI: 10.1016/j.bone.2019.01.025 -
Cell and Tissue Research May 2013Osteocytes establish an extensive intracellular and extracellular communication system via gap-junction-coupled cell processes and canaliculi throughout bone and the... (Review)
Review
Osteocytes establish an extensive intracellular and extracellular communication system via gap-junction-coupled cell processes and canaliculi throughout bone and the communication system is extended to osteoblasts on the bone surface. The osteocyte network is an ideal mechanosensory system and suitable for mechanotransduction. However, the overall function of the osteocyte network remains to be clarified, since bone resorption is enhanced by osteocyte apoptosis, which is followed by a process of secondary necrosis attributable to the lack of scavengers. The enhanced bone resorption is caused by the release of intracellular content, including immunostimulatory molecules that activate osteoclastogenesis through the canaliculi. Therefore, a mouse model is required in which the osteocyte network is disrupted but in which no bone resorption is induced, in order to evaluate the overall functions of the osteocyte network. One such model is the BCL2 transgenic mouse, in which the osteocyte network, including both intracellular and extracellular networks, is disrupted. Another model is the osteocyte-specific Gja1 knockout mouse, in which intercellular communication through gap junctions is impaired but the canalicular system is intact. Combining the findings from these mouse models with previous histological observations showing the inverse linkage between osteocyte density and bone formation, we conclude that the osteocyte network enhances bone resorption and inhibits bone formation under physiological conditions. Further, studies with BCL2 transgenic mice show that these osteocyte functions are augmented in the unloaded condition. In this condition, Rankl upregulation in osteoblasts and Sost upregulation in osteocytes are, at least in part, responsible for enhanced bone resorption and suppressed bone formation, respectively.
Topics: Animals; Bone Density; Bone and Bones; Humans; Mice; Osteocytes
PubMed: 23329124
DOI: 10.1007/s00441-012-1546-x -
Molecular Medicine (Cambridge, Mass.) Sep 2022It is well-known that both macrophages and osteocytes are critical regulators of osteogenesis and osteoclastogenesis, yet there is limited understanding of the...
BACKGROUND
It is well-known that both macrophages and osteocytes are critical regulators of osteogenesis and osteoclastogenesis, yet there is limited understanding of the macrophage-osteocyte interaction, and how their crosstalk could affect bone homeostasis and mineralization. This research therefore aims to investigate the effects of macrophage polarization on osteocyte maturation and mineralization process.
METHODS
A macrophage-derived conditioned medium based osteocyte culture was set up to investigate the impact of macrophages on osteocyte maturation and terminal mineralization. Surgically induced osteoarthritis (OA) rat model was used to further investigate the macrophage-osteocyte interaction in inflammatory bone remodeling, as well as the involvement of the Notch signaling pathway in the mineralization process.
RESULTS
Our results identified that osteocytes were confined in an immature stage after the M1 macrophage stimulation, showing a more rounded morphology, higher expression of early osteocyte marker E11, and significantly lower expression of mature osteocyte marker DMP1. Immature osteocytes were also found in inflammatory bone remodeling areas, showing altered morphology and mineralized structures similar to those observed under the stimulation of M1 macrophages in vitro, suggesting that M1 macrophages negatively affect osteocyte maturation, leading to abnormal mineralization. The Notch signaling pathway was found to be down regulated in M1 macrophage-stimulated osteocytes as well as osteocytes in inflammatory bone. Overexpression of the Notch signaling pathway in osteocytes showed a significant circumvention on the negative effects from M1 macrophage.
CONCLUSION
Taken together, our findings provide valuable insights into the mechanisms involved in abnormal bone mineralization under inflammatory conditions.
Topics: Animals; Calcification, Physiologic; Calcinosis; Macrophages; Osteocytes; Osteogenesis; Rats; Signal Transduction
PubMed: 36058911
DOI: 10.1186/s10020-022-00530-4 -
Bone Apr 2019Osteocytes are the most prevalent cell in the skeleton and are the master regulator of bone remodeling. Despite the understanding that osteocytes have a multiyear... (Review)
Review
Osteocytes are the most prevalent cell in the skeleton and are the master regulator of bone remodeling. Despite the understanding that osteocytes have a multiyear lifespan, and some factors induce apoptosis in osteocytes, much less is understood about the induction and consequences of osteocyte senescence. Filling these gaps in knowledge will provide novel approaches to slowing age-related bone loss and preventing fragility fractures. The purpose of this review is to examine the roles of senescence and apoptosis in osteocytes in age-related bone loss. Based on evidence that exercise can prevent senescence in skeletal muscle, we provide a novel hypothesis by which exercise can prolong skeletal health.
Topics: Apoptosis; Cellular Senescence; Exercise; Humans; Mitochondria; Osteocytes; Osteoporosis
PubMed: 30735796
DOI: 10.1016/j.bone.2019.02.006 -
Advanced Science (Weinheim,... Mar 2024Ferroptosis is a necrotic form of iron-dependent regulatory cell death. Estrogen withdrawal can interfere with iron metabolism, which is responsible for the pathogenesis...
Ferroptosis is a necrotic form of iron-dependent regulatory cell death. Estrogen withdrawal can interfere with iron metabolism, which is responsible for the pathogenesis of postmenopausal osteoporosis (PMOP). Here, it is demonstrated that estrogen withdrawal induces iron accumulation in the skeleton and the ferroptosis of osteocytes, leading to reduced bone mineral density. Furthermore, the facilitatory effect of ferroptosis of osteocytes is verified in the occurrence and development of postmenopausal osteoporosis is associated with over activated osteoclastogenesis using a direct osteocyte/osteoclast coculture system and glutathione peroxidase 4 (GPX4) knockout ovariectomized mice. In addition, the nuclear factor erythroid derived 2-related factor-2 (Nrf2) signaling pathway is confirmed to be a crucial factor in the ferroptosis of osteocytic cells. Nrf2 regulates the expression of nuclear factor kappa-B ligand (RANKL) by regulating the DNA methylation level of the RANKL promoter mediated by DNA methyltransferase 3a (Dnmt3a), which is as an important mechanism in osteocytic ferroptosis-mediated osteoclastogenesis. Taken together, this data suggests that osteocytic ferroptosis is involved in PMOP and can be targeted to tune bone homeostasis.
Topics: Mice; Humans; Animals; Female; Osteocytes; Osteoporosis, Postmenopausal; Ferroptosis; NF-E2-Related Factor 2; Estrogens; Iron
PubMed: 38233202
DOI: 10.1002/advs.202307388 -
Current Osteoporosis Reports Apr 2022Osteocytes are the conductors of bone adaptation and remodelling. Buried inside the calcified matrix, they sense mechanical cues and signal osteoclasts in case of low... (Review)
Review
PURPOSE OF REVIEW
Osteocytes are the conductors of bone adaptation and remodelling. Buried inside the calcified matrix, they sense mechanical cues and signal osteoclasts in case of low activity, and osteoblasts when stresses are high. How do osteocytes detect mechanical stress? What physical signal do they perceive? Finite element analysis is a useful tool to address these questions as it allows calculating stresses, strains and fluid flow where they cannot be measured. The purpose of this review is to evaluate the capabilities and challenges of finite element models of bone, in particular the osteocytes and load-induced activation mechanisms.
RECENT FINDINGS
High-resolution imaging and increased computational power allow ever more detailed modelling of osteocytes, either in isolation or embedded within the mineralised matrix. Over the years, homogeneous models of bone and osteocytes got replaced by heterogeneous and microstructural models, including, e.g. the lacuno-canalicular network and the cytoskeleton. The lacuno-canalicular network induces strain amplifications and the osteocyte protrusions seem to be stimulated much more than the cell body, both by strain and fluid flow. More realistic cell geometries, like minute constrictions of the canaliculi, increase this effect. Microstructural osteocyte models describe the transduction of external stimuli to the nucleus. Supracellular multiscale models (e.g. of a tunnelling osteon) allow to study differential loading of osteocytes and to distinguish between strain and fluid flow as the pivotal stimulatory cue. In the future, the finite element models may be enhanced by including chemical transport and intercellular communication between osteocytes, osteoclasts and osteoblasts.
Topics: Bone and Bones; Finite Element Analysis; Humans; Mechanotransduction, Cellular; Osteocytes; Stress, Mechanical
PubMed: 35298773
DOI: 10.1007/s11914-022-00728-9 -
Annals of the New York Academy of... Mar 2010Osteocytes are derived from osteoblasts and make up over 90% of the cells in bone. However, the mechanisms that control the differentiation of osteoblasts into... (Review)
Review
Osteocytes are derived from osteoblasts and make up over 90% of the cells in bone. However, the mechanisms that control the differentiation of osteoblasts into osteocytes embedded in bone matrix are not well understood. With the recent developments of transgenic models for manipulating gene expression in osteocytes and of transgenic mice carrying lineage reporters for osteoblasts and osteocytes, unprecedented new insights are becoming possible. In this article we review recent advances, such as comparative gene and protein expression studies, that are delineating the changes in gene and protein expression that accompany osteocyte differentiation. We also review recent studies in which time-lapse dynamic imaging approaches have been used to visualize osteoblast and osteocyte populations within bone. These approaches reveal the key role of cell motility in bone cell function and highlight the dynamic nature of mineralized tissues. Changes in motile properties of the cell may be key in the transition from osteoblast to osteocyte, as reflected in the altered expression of many molecules involved in cytoskeletal function.
Topics: Animals; Cell Differentiation; Cell Movement; Genes, Developmental; Humans; Kinetics; Mice; Models, Biological; Organ Specificity; Osteoblasts; Osteocytes; Osteogenesis
PubMed: 20392270
DOI: 10.1111/j.1749-6632.2009.05246.x