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Current Osteoporosis Reports Dec 2023The purpose of this review is to provide a background on osteocytes and the primary cilium, discussing the role it plays in osteocyte mechanosensing. (Review)
Review
PURPOSE OF REVIEW
The purpose of this review is to provide a background on osteocytes and the primary cilium, discussing the role it plays in osteocyte mechanosensing.
RECENT FINDINGS
Osteocytes are thought to be the primary mechanosensing cells in bone tissue, regulating bone adaptation in response to exercise, with the primary cilium suggested to be a key mechanosensing mechanism in bone. More recent work has suggested that, rather than being direct mechanosensors themselves, primary cilia in bone may instead form a key chemo-signalling nexus for processing mechanoregulated signalling pathways. Recent evidence suggests that pharmacologically induced lengthening of the primary cilium in osteocytes may potentiate greater mechanotransduction, rather than greater mechanosensing. While more research is required to delineate the specific osteocyte mechanobiological molecular mechanisms governed by the primary cilium, it is clear from the literature that the primary cilium has significant potential as a therapeutic target to treat mechanoregulated bone diseases, such as osteoporosis.
Topics: Humans; Osteocytes; Mechanotransduction, Cellular; Cilia; Signal Transduction; Bone and Bones
PubMed: 37682373
DOI: 10.1007/s11914-023-00819-1 -
Proceedings of the National Academy of... Jun 2021Skeletal fragility in the elderly does not simply result from a loss of bone mass. However, the mechanisms underlying the concurrent decline in bone mass, quality, and...
Skeletal fragility in the elderly does not simply result from a loss of bone mass. However, the mechanisms underlying the concurrent decline in bone mass, quality, and mechanosensitivity with age remain unclear. The important role of osteocytes in these processes and the age-related degeneration of the intricate lacunocanalicular network (LCN) in which osteocytes reside point to a primary role for osteocytes in bone aging. Since LCN complexity severely limits experimental dissection of these mechanisms in vivo, we used two in silico approaches to test the hypothesis that LCN degeneration, due to aging or an osteocyte-intrinsic defect in transforming growth factor beta (TGF-β) signaling (TβRII), is sufficient to compromise essential osteocyte responsibilities of mass transport and exposure to mechanical stimuli. Using reconstructed confocal images of bone with fluorescently labeled osteocytes, we found that osteocytes from aged and TβRII mice had 33 to 45% fewer, and more tortuous, canaliculi. Connectomic network analysis revealed that diminished canalicular density is sufficient to impair diffusion even with intact osteocyte numbers and overall LCN architecture. Computational fluid dynamics predicts that the corresponding drop in shear stress experienced by aged or TβRII osteocytes is highly sensitive to canalicular surface area but not tortuosity. Simulated expansion of the osteocyte pericellular space to mimic osteocyte perilacunar/canalicular remodeling restored predicted shear stress for aged osteocytes to young levels. Overall, these models show how loss of LCN volume through LCN pruning may lead to impaired fluid dynamics and osteocyte exposure to mechanostimulation. Furthermore, osteocytes emerge as targets of age-related therapeutic efforts to restore bone health and function.
Topics: Aging; Animals; Bone and Bones; Finite Element Analysis; Hydrodynamics; Male; Mice, Inbred C57BL; Models, Biological; Osteocytes; Protein Transport; Receptors, Transforming Growth Factor beta; Signal Transduction; Stress, Mechanical; Transforming Growth Factor beta; Mice
PubMed: 34161267
DOI: 10.1073/pnas.2023999118 -
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 -
Frontiers in Endocrinology 2022Osteocytes are dendritic cells in the mineralized bone matrix that descend from osteoblasts. They play critical roles in controlling bone mass through the production of... (Review)
Review
Osteocytes are dendritic cells in the mineralized bone matrix that descend from osteoblasts. They play critical roles in controlling bone mass through the production of sclerostin, an inhibitor of bone formation, and receptor activator of nuclear factor κ B ligand, an inducer of osteoblastic bone resorption. Osteocytes also govern phosphate homeostasis through the production of fibroblast growth factor 23 (FGF23), which lowers serum phosphate levels by increasing renal phosphate excretion and reducing the synthesis of 1,25-dihydroxyvitamin D (1,25(OH)D), an active metabolite of vitamin D. The production of FGF23 in osteocytes is regulated by various local and systemic factors. (), (), and function as local negative regulators of FGF23 production in osteocytes, and their inactivation causes the overproduction of FGF23 and hypophosphatemia. Sclerostin has been suggested to regulate the production of FGF23, which may link the two functions of osteocytes, namely, the control of bone mass and regulation of phosphate homeostasis. Systemic regulators of FGF23 production include 1,25(OH)D, phosphate, parathyroid hormone, insulin, iron, and inflammation. Therefore, the regulation of FGF23 in osteocytes is complex and multifactorial. Recent mouse studies have suggested that decreases in serum phosphate levels from youth to adulthood are caused by growth-related increases in FGF23 production by osteocytes, which are associated with the down-regulation of and .
Topics: Animals; Bone Density; Fibroblast Growth Factors; Humans; Mice; Osteocytes; Parathyroid Hormone; Phosphates
PubMed: 35909535
DOI: 10.3389/fendo.2022.967774 -
Journal of Bone and Mineral Research :... Oct 2023Mouse ligature-induced periodontitis (LIP) has been used to study bone loss in periodontitis. However, the role of osteocytes in LIP remains unclear. Furthermore, there...
Mouse ligature-induced periodontitis (LIP) has been used to study bone loss in periodontitis. However, the role of osteocytes in LIP remains unclear. Furthermore, there is no consensus on the choice of alveolar bone parameters and time points to evaluate LIP. Here, we investigated the dynamics of changes in osteoclastogenesis and bone volume (BV) loss in LIP over 14 days. Time-course analysis revealed that osteoclast induction peaked on days 3 and 5, followed by the peak of BV loss on day 7. Notably, BV was restored by day 14. The bone formation phase after the bone resorption phase was suggested to be responsible for the recovery of bone loss. Electron microscopy identified bacteria in the osteocyte lacunar space beyond the periodontal ligament (PDL) tissue. We investigated how osteocytes affect bone resorption of LIP and found that mice lacking receptor activator of NF-κB ligand (RANKL), predominantly in osteocytes, protected against bone loss in LIP, whereas recombination activating 1 (RAG1)-deficient mice failed to resist it. These results indicate that T/B cells are dispensable for osteoclast induction in LIP and that RANKL from osteocytes and mature osteoblasts regulates bone resorption by LIP. Remarkably, mice lacking the myeloid differentiation primary response gene 88 (MYD88) did not show protection against LIP-induced bone loss. Instead, osteocytic cells expressed nucleotide-binding oligomerization domain containing 1 (NOD1), and primary osteocytes induced significantly higher Rankl than primary osteoblasts when stimulated with a NOD1 agonist. Taken together, LIP induced both bone resorption and bone formation in a stage-dependent manner, suggesting that the selection of time points is critical for quantifying bone loss in mouse LIP. Pathogenetically, the current study suggests that bacterial activation of osteocytes via NOD1 is involved in the mechanism of osteoclastogenesis in LIP. The NOD1-RANKL axis in osteocytes may be a therapeutic target for bone resorption in periodontitis. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
Topics: Animals; Osteocytes; Periodontitis; RANK Ligand; Bone Resorption; Mice; Osteoclasts; Mice, Inbred C57BL; Ligation; Osteogenesis; Male
PubMed: 37551879
DOI: 10.1002/jbmr.4897 -
Frontiers in Endocrinology 2020Osteocytes make up 90-95% of the cellular content of bone and form a rich dendritic network with a vastly greater surface area than either osteoblasts or osteoclasts.... (Review)
Review
Osteocytes make up 90-95% of the cellular content of bone and form a rich dendritic network with a vastly greater surface area than either osteoblasts or osteoclasts. Osteocytes are well positioned to play a role in bone homeostasis by interacting directly with the matrix; however, the ability for these cells to modify bone matrix remains incompletely understood. With techniques for examining the nano- and microstructure of bone matrix components including hydroxyapatite and type I collagen becoming more widespread, there is great potential to uncover novel roles for the osteocyte in maintaining bone quality. In this review, we begin with an overview of osteocyte biology and the lacunar-canalicular system. Next, we describe recent findings from models of osteocytes, focusing on the transitions in cellular phenotype as they mature. Finally, we describe historical and current research on matrix alteration by osteocytes , focusing on the exciting potential for osteocytes to directly form, degrade, and modify the mineral and collagen in their surrounding matrix.
Topics: Animals; Bone Matrix; Bone Remodeling; Homeostasis; Humans; Minerals; Osteocytes; Osteogenesis
PubMed: 33537002
DOI: 10.3389/fendo.2020.578477 -
Journal of Musculoskeletal & Neuronal... Sep 2018Osteocytes, the most abundant bone cell in the adult skeleton, can function as mechanosensors directing osteoblast and osteoclast function in order to maintain optimal... (Review)
Review
Osteocytes, the most abundant bone cell in the adult skeleton, can function as mechanosensors directing osteoblast and osteoclast function in order to maintain optimal load bearing bone in addition to functioning as endocrine cells regulating phosphate metabolism. A controversial function, previously overlooked or denied, has been osteocytes as regulators of calcium metabolism. Early histologists upon observing enlarged osteocyte lacunae in bone sections proposed that mature osteocytes could remove their perilacunar matrix, a term called "osteocytic osteolysis". New insights into this process have occurred during the last decade using novel technology thereby providing a means to identify molecular mechanisms responsible for osteocytic osteolysis. As release of calcium from a mineralized matrix requires a more acidic pH and specialized enzymes, it was proposed that osteocytes may utilize similar molecular mechanisms as osteoclasts to remove mineral. The idea that a cell descended from mesenchymal progenitors (the osteocyte) could function similarly to a cell descended from hematopoietic progenitors (the osteoclast) was challenged as being improbable. Here we review the molecular mechanisms behind this osteocyte function, the role of osteocytic osteolysis in health and disease, and the capacity of the osteocyte to reverse the osteolytic process by replacing the removed matrix, a revived osteoblast function.
Topics: Animals; Bone Remodeling; Calcium; Humans; Osteocytes; Osteolysis; Parathyroid Hormone
PubMed: 30179206
DOI: No ID Found -
Bone Dec 2021Osteocytes are dynamic, bone matrix-remodeling cells that form an intricate network of interconnected projections through the bone matrix, called the lacunar-canalicular... (Review)
Review
Osteocytes are dynamic, bone matrix-remodeling cells that form an intricate network of interconnected projections through the bone matrix, called the lacunar-canalicular system. Osteocytes are the dominant mechanosensory cells in bone and their mechanosensory and mechanotransductive functions follow their morphological form. During osteocytogenesis and development of the osteocyte lacunar-canalicular network, osteocytes must dramatically remodel both their cytoskeleton and their extracellular matrix. In this review, we summarize our current understanding of the mechanisms that govern osteocyte differentiation, cytoskeletal morphogenesis, mechanotransduction, and matrix remodeling. We postulate that the physiologic activation of matrix remodeling in adult osteocytes, known as perilacunar/canalicular remodeling (PLR) represents a re-activation of the developmental program by which the osteocyte network is first established. While much of osteocyte biology remains unclear, new tools and approaches make the present moment a particularly fruitful and exciting time to study the development of these remarkable cells.
Topics: Bone Matrix; Bone Remodeling; Mechanotransduction, Cellular; Morphogenesis; Osteocytes
PubMed: 34245936
DOI: 10.1016/j.bone.2021.116104 -
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 -
Journal of Bone and Mineral Research :... Oct 2007Since the initial demonstration of the phenomenon in murine and human bone sections approximately 10 yr ago, appreciation of the biologic significance of osteoblast... (Review)
Review
Since the initial demonstration of the phenomenon in murine and human bone sections approximately 10 yr ago, appreciation of the biologic significance of osteoblast apoptosis has contributed greatly not only to understanding the regulation of osteoblast number during physiologic bone remodeling, but also the pathogenesis of metabolic bone diseases and the pharmacology of some of the drugs used for their treatment. It is now appreciated that all major regulators of bone metabolism including bone morphogenetic proteins (BMPs), Wnts, other growth factors and cytokines, integrins, estrogens, androgens, glucocorticoids, PTH and PTH-related protein (PTHrP), immobilization, and the oxidative stress associated with aging contribute to the regulation of osteoblast and osteocyte life span by modulating apoptosis. Moreover, osteocyte apoptosis has emerged as an important regulator of remodeling on the bone surface and a critical determinant of bone strength, independently of bone mass. The detection of apoptotic osteoblasts in bone sections remains challenging because apoptosis represents only a tiny fraction of the life span of osteoblasts, not unlike a 6-mo-long terminal illness in the life of a 75-yr-old human. Importantly, the phenomenon is 50 times less common in human bone biopsies because human osteoblasts live longer and are fewer in number. Be that as it may, well-controlled assays of apoptosis can yield accurate and reproducible estimates of the prevalence of the event, particularly in rodents where there is an abundance of osteoblasts for inspection. In this perspective, we focus on the biological significance of the phenomenon for understanding basic bone biology and the pathogenesis and treatment of metabolic bone diseases and discuss limitations of existing techniques for quantifying osteoblast apoptosis in human biopsies and their methodologic pitfalls.
Topics: Aging; Animals; Apoptosis; Hormones; Humans; Osteoblasts; Osteocytes; Oxidative Stress
PubMed: 17542686
DOI: 10.1359/jbmr.070518