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Advanced Science (Weinheim,... Jun 2023Bone undergoes constant remodeling by osteoclast bone resorption coupled with osteoblast bone formation at the bone surface. A third major cell type in the bone is...
Bone undergoes constant remodeling by osteoclast bone resorption coupled with osteoblast bone formation at the bone surface. A third major cell type in the bone is osteocytes, which are embedded in the matrix, are well-connected to the lacunar network, and are believed to act as mechanical sensors. Here, it is reported that sympathetic innervation directly regulates lacunar osteocyte-mediated bone resorption inside cortical bone. It is found that sympathetic activity is elevated in different mouse models of bone loss, including lactation, ovariectomy, and glucocorticoid treatment. Further, during lactation elevated sympathetic outflow induces netrin-1 expression by osteocytes to further promote sympathetic nerve sprouting in the cortical bone endosteum in a feed-forward loop. Depletion of tyrosine hydroxylase-positive (TH ) sympathetic nerves ameliorated osteocyte-mediated perilacunar bone resorption in lactating mice. Moreover, norepinephrine activates β-adrenergic receptor 2 (Adrb2) signaling to promote secretion of extracellular vesicles (EVs) containing bone-degrading enzymes for perilacunar bone resorption and inhibit osteoblast differentiation. Importantly, osteocyte-specific deletion of Adrb2 or treatment with a β-blocker results in lower bone resorption in lactating mice. Together, these findings show that the sympathetic nervous system promotes osteocyte-driven bone loss during lactation, likely as an adaptive response to the increased energy and mineral demands of the nursing mother.
Topics: Female; Animals; Mice; Osteocytes; Lactation; Bone and Bones; Cortical Bone; Bone Resorption; Bone Diseases, Metabolic
PubMed: 37186379
DOI: 10.1002/advs.202207602 -
Current Osteoporosis Reports Aug 2021In this review, we provide a recent update on bioenergetic pathways in osteocytes and identify potential future areas of research interest. Studies have identified a... (Review)
Review
PURPOSE OF REVIEW
In this review, we provide a recent update on bioenergetic pathways in osteocytes and identify potential future areas of research interest. Studies have identified a role for regulation of bone formation and bone resorption through osteocyte mechanosensing and osteocyte secreted factors. Nevertheless, there is a paucity of studies on the bioenergetics and energy metabolism of osteocytes, which are required for the regulation of bone remodeling.
RECENT FINDINGS
Osteocytes are cells of the osteoblast lineage embedded in bone. The osteocyte lacunocanalicular network within the skeletal matrix is exposed to a unique hypoxic environment. Therefore, the bioenergetic requirements of these cells could differ from other bone cells due to its location in the ossified matrix and its role in bone regulation transduced by mechanical signals. Recent findings highlighted in this review provide some evidence that metabolism of these cells is dependent on their location due to the substrates present in the microenvironment and metabolic cues from stress pathways. Both glycolysis (glucose metabolism) and oxidative phosphorylation (mitochondrial dynamics, ROS generation) affect osteocyte function and viability. In this review, we provide evidence that is currently available about information regarding bioenergetics pathways in osteocytes. We discuss published studies showing a role for hypoxia-driven glucose metabolism in regulating osteocyte bioenergetics. We also provide information on various substrates that osteocytes could utilize to fuel energetic needs, namely pyruvate, amino acids, and fatty acids. This is based on some preliminary experimental evidence that is available in literature. The role of parathyroid hormone PTH and parathryoid hormone-related peptide PTHrP in bone anabolism and resorption, along with regulation of metabolic pathways in the cells of the skeletal niche, needs to be explored further. Mitochondrial metabolism has a role in osteocyte bioenergetics through substrate utilization, location of the osteocyte in the bone cortex, and mitochondrial biogenesis. While there are limitations in studying metabolic flux in traditional cell lines, there are now novel cell lines and sophisticated tools available to study osteocyte bioenergetics to help harness its potential in vivo in the future.
Topics: Animals; Energy Metabolism; Humans; Mechanotransduction, Cellular; Osteocytes
PubMed: 34117625
DOI: 10.1007/s11914-021-00688-6 -
Current Osteoporosis Reports Dec 2021Osteocytes are considered to be the cells responsible for mastering the remodeling process that follows the exposure to unloading conditions. Given the invasiveness of... (Review)
Review
PURPOSE OF REVIEW
Osteocytes are considered to be the cells responsible for mastering the remodeling process that follows the exposure to unloading conditions. Given the invasiveness of bone biopsies in humans, both rodents and in vitro culture systems are largely adopted as models for studies in space missions or in simulated microgravity conditions models on Earth.
RECENT FINDINGS
After a brief recall of the main changes in bone mass and osteoclastic and osteoblastic activities in space-related models, this review focuses on the potential role of osteocytes in directing these changes. The role of the best-known signalling molecules is questioned, in particular in relation to osteocyte apoptosis. The mechanotransduction actors identified in spatial conditions and the problems related to fluid flow and shear stress changes, probably enhanced by the alteration in fluid flow and lack of convection during spaceflight, are recalled and discussed.
Topics: Aging; Animals; Apoptosis; Humans; Mechanotransduction, Cellular; Mice; Osteocytes; Space Flight; Weightlessness
PubMed: 34767119
DOI: 10.1007/s11914-021-00713-8 -
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 -
International Journal of Molecular... Apr 2022Osteocytes connect with neighboring osteocytes and osteoblasts through their processes and form an osteocyte network. Shear stress on osteocytes, which is induced by... (Review)
Review
Osteocytes connect with neighboring osteocytes and osteoblasts through their processes and form an osteocyte network. Shear stress on osteocytes, which is induced by fluid flow in the lacunae and canaliculi, has been proposed as an important mechanism for mechanoresponses. The lacunocanalicular structure is differentially developed in the compression and tension sides of femoral cortical bone and the compression side is more organized and has denser and thinner canaliculi. Mice with an impaired lacunocanalicular structure may be useful for evaluation of the relationship between lacunocanalicular structure and mechanoresponses, although their bone component cells are not normal. We show three examples of mice with an impaired lacunocanalicular structure. Ablation of osteocytes by diphtheria toxin caused massive osteocyte apoptosis, necrosis or secondary necrosis that occurred after apoptosis. Osteoblast-specific Bcl2 transgenic mice were found to have a reduced number of osteocyte processes and canaliculi, which caused massive osteocyte apoptosis and a completely interrupted lacunocanalicular network. Osteoblast-specific Sp7 transgenic mice were also revealed to have a reduced number of osteocyte processes and canaliculi, as well as an impaired, but functionally connected, lacunocanalicular network. Here, we show the phenotypes of these mice in physiological and unloaded conditions and deduce the relationship between lacunocanalicular structure and mechanoresponses.
Topics: Animals; Bone and Bones; Mice; Mice, Transgenic; Necrosis; Osteoblasts; Osteocytes; Stress, Mechanical
PubMed: 35457191
DOI: 10.3390/ijms23084373 -
Bone May 2023Although osteoblasts and osteocytes are descended from the same lineage, they each have unique and essential roles in bone. Targeting gene deletion to osteoblasts and... (Review)
Review
Although osteoblasts and osteocytes are descended from the same lineage, they each have unique and essential roles in bone. Targeting gene deletion to osteoblasts and osteocytes using the Cre/loxP system has greatly increased our current understanding of how these cells function. Additionally, the use of the Cre/loxP system in conjunction with cell-specific reporters has enabled lineage tracing of these bone cells both in vivo and ex vivo. However, concerns have been raised regarding the specificity of the promoters used and the resulting off-target effects on cells within and outside of the bone. In this review, we have summarized the main mouse models that have been used to determine the functions of specific genes in osteoblasts and osteocytes. We discuss the expression patterns and specificity of the different promoter fragments during osteoblast to osteocyte differentiation in vivo. We also highlight how their expression in non-skeletal tissues may complicate the interpretation of study results. A thorough understanding of when and where these promoters are activated will enable improved study design and greater confidence in data interpretation.
Topics: Animals; Mice; Osteocytes; Osteoblasts; Bone and Bones; Cell Differentiation
PubMed: 36868508
DOI: 10.1016/j.bone.2023.116724 -
Current Osteoporosis Reports Dec 2023Orthodontic tooth movement is characterized by periodontal tissue responses to mechanical loading, leading to clinically relevant functional adaptation of jaw bone.... (Review)
Review
PURPOSE OF REVIEW
Orthodontic tooth movement is characterized by periodontal tissue responses to mechanical loading, leading to clinically relevant functional adaptation of jaw bone. Since osteocytes are significant in mechanotransduction and orchestrate osteoclast and osteoblast activity, they likely play a central role in orthodontic tooth movement. In this review, we attempt to shed light on the impact and role of osteocyte mechanotransduction during orthodontic tooth movement.
RECENT FINDINGS
Mechanically loaded osteocytes produce signaling molecules, e.g., bone morphogenetic proteins, Wnts, prostaglandins, osteopontin, nitric oxide, sclerostin, and RANKL, which modulate the recruitment, differentiation, and activity of osteoblasts and osteoclasts. The major signaling pathways activated by mechanical loading in osteocytes are the wingless-related integration site (Wnt)/β-catenin and RANKL pathways, which are key regulators of bone metabolism. Moreover, osteocytes are capable of orchestrating bone adaptation during orthodontic tooth movement. A better understanding of the role of osteocyte mechanotransduction is crucial to advance orthodontic treatment. The optimal force level on the periodontal tissues for orthodontic tooth movement producing an adequate biological response, is debated. This review emphasizes that both mechanoresponses and inflammation are essential for achieving tooth movement clinically. To fully comprehend the role of osteocyte mechanotransduction in orthodontic tooth movement, more knowledge is needed of the biological pathways involved. This will contribute to optimization of orthodontic treatment and enhance patient outcomes.
Topics: Humans; Osteocytes; Mechanotransduction, Cellular; Tooth Movement Techniques; Osteoclasts; Osteoblasts; Bone Remodeling
PubMed: 37792246
DOI: 10.1007/s11914-023-00826-2 -
Current Osteoporosis Reports Oct 2017The bone is able to adapt its structure to mechanical signals via the bone remodeling process governed by mechanosensitive osteocytes. With aging, an imbalance in bone... (Review)
Review
PURPOSE OF REVIEW
The bone is able to adapt its structure to mechanical signals via the bone remodeling process governed by mechanosensitive osteocytes. With aging, an imbalance in bone remodeling results in osteoporosis. In this review, we hypothesized that changes in lacunar morphology underlie the decreased bone mechanoresponsiveness to mechanical loading with aging.
RECENT FINDINGS
Several studies have reported considerable variations in the shape of osteocytes and their lacunae with aging. Since osteocytes can sense matrix strain directly via their cell bodies, the variations in osteocyte morphology may cause changes in osteocyte mechanosensitivity. As a consequence, the load-adaptive response of osteocytes may change with aging, even when mechanical loading would remain unchanged. Though extensive quantitative data is lacking, evidence exists that the osteocyte lacunae are becoming smaller and more spherical with aging. Future dedicated studies might reveal whether these changes would affect osteocyte mechanosensation and the subsequent biological response, and whether this is (one of) the pathways involved in age-related bone loss.
Topics: Aging; Bone Remodeling; Humans; Mechanotransduction, Cellular; Osteocytes; Osteoporosis; Stress, Mechanical
PubMed: 28891009
DOI: 10.1007/s11914-017-0402-z -
Bone Feb 2019This past decade has witnessed a renewed interest in the function and biology of matrix-embedded osteocytes and these cells have emerged as master regulators of bone... (Review)
Review
This past decade has witnessed a renewed interest in the function and biology of matrix-embedded osteocytes and these cells have emerged as master regulators of bone homeostasis. They secrete two very powerful proteins, sclerostin, a Wnt-inhibitor, that suppresses bone formation, and receptor-activator of NF-kB ligand (RANKL), a cytokine required for osteoclastogenesis. Neutralizing antibodies against these proteins are currently used for the treatment of osteoporosis. Recent studies however, ascribed yet another function to osteocytes: the control of hematopoiesis and the HSPC niche, directly and through secreted factors. In the absence of osteocytes there is an increase in HSC mobilization and abnormal lymphopoiesis whereas in the absence of Gα signaling in these cells there is an increase of myeloid cells. How exactly osteocytes control hematopoiesis or the HSPC niche is still not completely understood. In this review we summarize the actions of osteocytes in bone and then analyze the effects of these cells on hematopoiesis. Future directions and gaps in current knowledge are further discussed.
Topics: Animals; Blood; Bone and Bones; Hematopoiesis; Humans; Models, Biological; Osteocytes; Stem Cell Niche
PubMed: 29458123
DOI: 10.1016/j.bone.2018.02.012 -
Current Osteoporosis Reports Dec 2022The purpose of this review is to discuss the molecular mechanisms involved in osteocyte dendrite formation, summarize the similarities between osteocytic and neuronal... (Review)
Review
PURPOSE OF REVIEW
The purpose of this review is to discuss the molecular mechanisms involved in osteocyte dendrite formation, summarize the similarities between osteocytic and neuronal projections, and highlight the importance of osteocyte dendrite maintenance in human skeletal disease.
RECENT FINDINGS
It is suggested that there is a causal relationship between the loss of osteocyte dendrites and the increased osteocyte apoptosis during conditions including aging, microdamage, and skeletal disease. A few mechanisms are proposed to control dendrite formation and outgrowth, such as via the regulation of actin polymerization dynamics. This review addresses the impact of osteocyte dendrites in bone health and disease. Recent advances in multi-omics, in vivo and in vitro models, and microscopy-based imaging have provided novel approaches to reveal the underlying mechanisms that regulate dendrite development. Future therapeutic approaches are needed to target the process of osteocyte dendrite formation.
Topics: Humans; Osteocytes; Bone and Bones; Aging; Dendrites
PubMed: 36087214
DOI: 10.1007/s11914-022-00753-8