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Swiss Medical Weekly Jan 2020Although the impact of osteoblast-osteoclast crosstalk in bone remodelling has been intensively studied, the importance of osteocytes, descendants of osteoblasts, in... (Review)
Review
Although the impact of osteoblast-osteoclast crosstalk in bone remodelling has been intensively studied, the importance of osteocytes, descendants of osteoblasts, in this process has for a long time been neglected. During their embedding phase, osteocytes undergo considerable phenotypic transformation, from a cuboidal, highly metabolically active osteoblast secreting extracellular matrix to a small, stellate, quiescent osteocyte with numerous long dendrites. Osteocytes are encysted in cavities (lacunae) and their dendritic extensions are located in tunnels (canaliculi) forming a remarkable, highly branched, lacunar-canalicular signalling network that spans the entire bone matrix. Osteocytes and their dendrites can communicate directly with each other and through the release of effector proteins such as sclerostin and nuclear factor κB ligand (RANKL), influence osteoblast and osteoclast formation. This allows osteocytes embedded within the bone matrix to communicate and coordinate activity of cells on the bone surface to adapt to mechanical needs and hormonal changes. Besides their importance in sustaining physiological bone homeostasis, accumulating evidence suggests that dysregulated osteocyte function and alterations in the osteocyte lacunar-canalicular network structure are characteristics of skeletal diseases. This review highlights some aspects of osteocyte communication with osteoclasts and mesenchymal stromal cells, the importance of blood vessel-osteocyte interaction and describes central functions of these cells in rheumatoid arthritis, osteoarthritis, osteomyelitis and osteoporosis. Within the last decade new technologies and tools have facilitated the study of osteocyte biology and the search for therapeutic targets to address bone fragility in the near future.
Topics: Bone Diseases; Bone and Bones; Humans; Osteoclasts; Osteocytes
PubMed: 32031236
DOI: 10.4414/smw.2020.20187 -
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 -
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 -
Current Osteoporosis Reports Mar 2014Studies from the 1950s and 1960s already recognize the fact that osteocytes, although long living cells, die, as evidenced by accumulation of osteocytic lacunae devoid... (Review)
Review
Studies from the 1950s and 1960s already recognize the fact that osteocytes, although long living cells, die, as evidenced by accumulation of osteocytic lacunae devoid of cells. More recently, it was demonstrated that these cells die by apoptosis. The rate of osteocyte apoptosis is regulated by the age of the bone, as well as by systemic hormones, local growth factors, cytokines, pharmacological agents, and mechanical forces. Apoptotic osteocytes, in turn, recruit osteoclasts to initiate targeted bone resorption. This results in the removal of "dead" bone and may improve the mechanical properties of the skeleton. However, the molecular regulators of osteocyte survival and targeted bone remodeling are not completely known. In this review, the current knowledge on the molecular mechanism that lead to osteocyte death or survival, and the signals that mediate targeted bone resorption is discussed.
Topics: Apoptosis; Bone Remodeling; Bone Resorption; Humans; Osteocytes; Signal Transduction
PubMed: 24470254
DOI: 10.1007/s11914-014-0194-3 -
Trends in Endocrinology and Metabolism:... Jun 2010The adverse effects of aging of other organs (ovaries at menopause) on the skeleton are well known, but ironically little is known of skeletal aging itself. Evidence... (Review)
Review
The adverse effects of aging of other organs (ovaries at menopause) on the skeleton are well known, but ironically little is known of skeletal aging itself. Evidence indicates that age-related changes, such as oxidative stress, are fundamental mechanisms of the decline of bone mass and strength. Unlike the short-lived osteoclasts and osteoblasts, osteocytes--former osteoblasts entombed in the mineralized matrix--live as long as 50 years, and their death is dependent on skeletal age. Osteocyte death is a major contributor to the decline of bone strength with age, and the likely mechanisms are oxidative stress, autophagy failure and nuclear pore "leakiness". Unraveling these mechanisms should improve understanding of the age-related increase in fractures and suggest novel targets for its prevention.
Topics: Aging; Animals; Bone Diseases; Bone and Bones; Cell Death; Humans; Menopause; Osteocytes
PubMed: 20223679
DOI: 10.1016/j.tem.2010.01.010 -
Calcified Tissue International Jan 2014Osteocytes comprise the overwhelming majority of cells in bone and are its only true "permanent" resident cell population. In recent years, conceptual and technological... (Review)
Review
Osteocytes comprise the overwhelming majority of cells in bone and are its only true "permanent" resident cell population. In recent years, conceptual and technological advances on many fronts have helped to clarify the role osteocytes play in skeletal metabolism and the mechanisms they use to perform them. The osteocyte is now recognized as a major orchestrator of skeletal activity, capable of sensing and integrating mechanical and chemical signals from their environment to regulate both bone formation and resorption. Recent studies have established that the mechanisms osteocytes use to sense stimuli and regulate effector cells (e.g., osteoblasts and osteoclasts) are directly coupled to the environment they inhabit-entombed within the mineralized matrix of bone and connected to each other in multicellular networks. Communication within these networks is both direct (via cell-cell contacts at gap junctions) and indirect (via paracrine signaling by secreted signals). Moreover, the movement of paracrine signals is dependent on the movement of both solutes and fluid through the space immediately surrounding the osteocytes (i.e., the lacunar-canalicular system). Finally, recent studies have also shown that the regulatory capabilities of osteocytes extend beyond bone to include a role in the endocrine control of systemic phosphate metabolism. This review will discuss how a highly productive combination of experimental and theoretical approaches has managed to unearth these unique features of osteocytes and bring to light novel insights into the regulatory mechanisms operating in bone.
Topics: Animals; Bone and Bones; Cell Communication; Humans; Osteoclasts; Osteocytes; Osteogenesis; Stress, Mechanical
PubMed: 24042263
DOI: 10.1007/s00223-013-9790-y -
Frontiers in Endocrinology 2020Osteocytes are the most abundant (~95%) cells in bone with the longest half-life (~25 years) in humans. In the past osteocytes have been regarded as vestigial cells in... (Review)
Review
Osteocytes are the most abundant (~95%) cells in bone with the longest half-life (~25 years) in humans. In the past osteocytes have been regarded as vestigial cells in bone, since they are buried inside the tough bone matrix. However, during the last 30 years it has become clear that osteocytes are as important as bone forming osteoblasts and bone resorbing osteoclasts in maintaining bone homeostasis. The osteocyte cell body and dendritic processes reside in bone in a complex lacuno-canalicular system, which allows the direct networking of osteocytes to their neighboring osteocytes, osteoblasts, osteoclasts, bone marrow, blood vessels, and nerves. Mechanosensing of osteocytes translates the applied mechanical force on bone to cellular signaling and regulation of bone adaptation. The osteocyte lacuno-canalicular system is highly efficient in transferring external mechanical force on bone to the osteocyte cell body and dendritic processes via displacement of fluid in the lacuno-canalicular space. Osteocyte mechanotransduction regulates the formation and function of the osteoblasts and osteoclasts to maintain bone homeostasis. Osteocytes produce a variety of proteins and signaling molecules such as sclerostin, cathepsin K, Wnts, DKK1, DMP1, IGF1, and RANKL/OPG to regulate osteoblast and osteoclast activity. Various genetic abnormality-associated rare bone diseases are related to disrupted osteocyte functions, including sclerosteosis, van Buchem disease, hypophosphatemic rickets, and WNT1 and plastin3 mutation-related disorders. Meticulous studies during the last 15 years on disrupted osteocyte function in rare bone diseases guided for the development of various novel therapeutic agents to treat bone diseases. Studies on genetic, molecular, and cellular mechanisms of sclerosteosis and van Buchem disease revealed a role for sclerostin in bone homeostasis, which led to the development of the sclerostin antibody to treat osteoporosis and other bone degenerative diseases. The mechanism of many other rare bone diseases and the role of the osteocyte in the development of such conditions still needs to be investigated. In this review, we mainly discuss the knowledge obtained during the last 30 years on the role of the osteocyte in rare bone diseases. We speculate about future research directions to develop novel therapeutic drugs targeting osteocyte functions to treat both common and rare bone diseases.
Topics: Adaptation, Physiological; Animals; Bone Diseases; Bone Remodeling; Humans; Mechanotransduction, Cellular; Osteocytes; Rare Diseases
PubMed: 32733380
DOI: 10.3389/fendo.2020.00405 -
International Journal of Oral Science Feb 2018Bone mass is important for dental implant success and is regulated by mechanoresponsive osteocytes. We aimed to investigate the relationship between the levels and...
Bone mass is important for dental implant success and is regulated by mechanoresponsive osteocytes. We aimed to investigate the relationship between the levels and orientation of tensile strain and morphology and orientation of osteocytes at different dental implant positions in the maxillary bone. Bone biopsies were retrieved from eight patients who underwent maxillary sinus-floor elevation with β-tricalcium phosphate prior to implant placement. Gap versus free-ending locations were compared using 1) a three-dimensional finite-element model of the maxilla to predict the tensile strain magnitude and direction and 2) histology and histomorphometric analyses. The finite-element model predicted larger, differently directed tensile strains in the gap versus free-ending locations. The mean percentage of mineralised residual native-tissue volume, osteocyte number (mean ± standard deviations: 97 ± 40/region-of-interest), and osteocyte shape (~90% elongated, ~10% round) were similar for both locations. However, the osteocyte surface area was 1.5-times larger in the gap than in the free-ending locations, and the elongated osteocytes in these locations were more cranially caudally oriented. In conclusion, significant differences in the osteocyte surface area and orientation seem to exist locally in the maxillary bone, which may be related to the tensile strain magnitude and orientation. This might reflect local differences in the osteocyte mechanosensitivity and bone quality, suggesting differences in dental implant success based on the location in the maxilla.
Topics: Biopsy; Bone-Implant Interface; Calcium Phosphates; Dental Implants; Finite Element Analysis; Humans; Maxilla; Osteocytes; Radiography, Panoramic; Sinus Floor Augmentation; Tensile Strength
PubMed: 29483534
DOI: 10.1038/s41368-017-0007-5 -
Bone Jun 2013It is widely hypothesized that osteocytes are the mechano-sensors residing in the bone's mineralized matrix which control load induced bone adaptation. Owing to their... (Review)
Review
It is widely hypothesized that osteocytes are the mechano-sensors residing in the bone's mineralized matrix which control load induced bone adaptation. Owing to their inaccessibility it has proved challenging to generate quantitative in vivo experimental data which supports this hypothesis. Recent advances in in situ imaging, both in non-living and living specimens, have provided new insights into the role of osteocytes in the skeleton. Combined with the retrieval of biochemical information from mechanically stimulated osteocytes using in vivo models, quantitative experimental data is now becoming available which is leading to a more accurate understanding of osteocyte function. With this in mind, here we review i) state of the art ex vivo imaging modalities which are able to precisely capture osteocyte structure in 3D, ii) live cell imaging techniques which are able to track structural morphology and cellular differentiation in both space and time, and iii) in vivo models which when combined with the latest biochemical assays and microfluidic imaging techniques can provide further insight on the biological function of osteocytes.
Topics: Animals; Cell Survival; Cellular Microenvironment; Gene Expression Regulation; Humans; Imaging, Three-Dimensional; Osteocytes
PubMed: 23318973
DOI: 10.1016/j.bone.2013.01.004 -
Annals of the New York Academy of... Mar 2010Bone is a dynamic tissue that adapts to its local loading environment. Mechanotransduction, the process by which cells convert mechanical forces into biochemical... (Review)
Review
Bone is a dynamic tissue that adapts to its local loading environment. Mechanotransduction, the process by which cells convert mechanical forces into biochemical signals, is important for maintaining bone health and homeostasis. It is less clear, however, what the cellular mechanosensor(s) are that sense and initiate these signaling cascades. Primary cilia are solitary rigid structures that extend from the cell body into the extracellular space and as a consequence are prime candidates for mechanosensing in bone. Primary cilia have been shown to be critical in development and have been implicated in mechanosensing in other tissue types, including liver and kidney. In this review we discuss the potential for primary cilia to play an important role in bone mechanotransduction and possible avenues for future study.
Topics: Animals; Bone Development; Bone Remodeling; Bone and Bones; Cilia; Homeostasis; Humans; Mechanotransduction, Cellular; Models, Biological; Osteocytes
PubMed: 20392268
DOI: 10.1111/j.1749-6632.2009.05243.x