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Inflammation and functional iron deficiency regulate fibroblast growth factor 23 production. Kidney Int. Mol Cell Endocrinol. Chronic skin inflammation leads to bone loss by ILmediated inhibition of Wnt signaling in osteoblasts. Sci Transl Med. Aging, osteocytes, and mechanotransduction. Curr Osteopor Rep. Changes in the osteocyte lacunocanalicular network with aging.
Identification of senescent cells in the bone microenvironment. Targeting cellular senescence prevents age-related bone loss in mice. Senescent and apoptotic osteocytes and aging: Exercise to the rescue? Denosumab treatment effects on structural damage, bone mineral density, and bone turnover in rheumatoid arthritis.
Robinson MK. A short treatment with an antibody to sclerostin can inhibit bone loss in an ongoing model of colitis. Zoledronic acid protects against local and systemic bone loss in tumor necrosis factor-mediated arthritis.
Ailmentary Pharmcol Ther. Immunogenicity and autoimmunity during anti-TNF therapy. Autoimmunity Rev. Ding T, Deighton C.
Complications of Anti-TNF therapies. Future Med. Osteocytes reflect a pro-inflammatory state following spinal cord injury in a rodent model. Resolvin E1 promotes bone preservation under inflammatory conditions.
Front Immunol. Low-dose TNF augments fracture healing in normal and osteoporotic bone by up-regulating the innate immune response. Keywords: osteocyte, cytokines, inflammation, tumor necorosis factor TNF , sclerostin. The use, distribution or reproduction in other forums is permitted, provided the original author s and the copyright owner s are credited and that the original publication in this journal is cited, in accordance with accepted academic practice.
No use, distribution or reproduction is permitted which does not comply with these terms. Metzger, metzgercorinne gmail. Anand Narayanan 2. Interactions of the Immune System and Bone The immune system interacting with bone physiology is being elucidated in the burgeoning field of osteoimmunology. The Role of osteocytes in Adaptations to Mechanical Strains In the past few decades, the central role of osteocytes in response to mechanical strains has been explored and identified.
Osteocytes and Cytokines Burgeoning research has shown cytokines directly impact osteocyte apoptosis and cause the release of cytokines that influence bone turnover. Mechanosensing and Inflammatory Signals Crucial to osteocyte function is sensing and responding to bone interstitial fluid shear stress and mechanical strains.
Future Directions With the accumulating knowledge of the role of osteocytes in inflammatory bone loss, future areas of interest may include therapeutically targeting osteocytes in inflammatory bone loss conditions. Conclusions Osteocytes play a central role in orchestrating changes in bone turnover. Conflict of Interest Statement The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Unlike the results of in vitro detection, in vivo recordings of the primary cilium showed a morphological change of the cell membrane in which the mother centriole contacts the plasma membrane and a very short axoneme forms a cilium-like protrusion. In addition to in vitro culture conditions, direct observation of the osteocyte primary cilium in bone samples has been achieved in vivo. In this study, Uzbekov et al. Rather than a clear and distinct primary cilium structure, Uzbekov et al.
The presence of this CMP structure indicates morphological changes of the cell membrane where the mother centriole contacts the plasma membrane, and a very short axoneme was associated with a cilium-like protrusion. Discrepancies in primary cilium length and frequency between in vitro and in vivo samples could result from different extracellular environments 2D culture vs LCS , cellular status immortalized cells vs primary cells , and even sample preparation procedures.
Primary cilia have been demonstrated to participate in osteocyte mechanotransduction both in vitro and in vivo. Under culture conditions, primary cilia were reflected in the direction of steady flow of 0.
Moreover, AC6 is a calcium ion-inhibited isoform of adenylyl cyclase. Depletion of stored intracellular calcium through thapsigargin treatment had no effect on the flow-mediated decrease in cAMP in MLO-Y4 cells. In addition to in vitro studies, several groups have investigated the function of primary cilium proteins in transgenic animals Table 4.
Moreover, another important cilia-related protein, Sperm flagellar protein 2 Spef2 , is also involved in the bone-formation process. Further examination showed that osteoblast differentiation was impaired in Spef2-KO mice, with decreased expression levels of Alp, Runx2, Col1 , and Oc Fig. Together, these data demonstrate the importance of the primary cilium in bone development.
To investigate the specific function of the primary cilium in skeletal cells, transgenic mice expressing tissue-specific Cre recombinase were used.
Temiyasathit et al. Similar to this study, Qiu et al. Interestingly, these differences in bone density between cKO and control mice decreased as the animals grew older, as reported in both studies. Aside from its roles in bone development, the primary cilium of osteocytes is also tightly associated with mechanotransduction. Similarly, mice with global AC6 KO exhibited a normal bone morphology and similar bone formation in response to an osteogenic agent PTH but impaired responses to mechanical loading.
Moreover, primary bone cells isolated from AC6-null mice showed an attenuated flow-induced increase in Cox-2 mRNA expression. Together, these in vivo data suggest that an intact primary cilium in osteocytes is required for proper responses to mechanical stimuli. Over the past decade, more than a dozen disorders in the human population have been reported to be associated with defective ciliary machinery.
These primary cilium-related diseases are named ciliopathies. Primary osteoblasts isolated from IS patients showed significantly elongated primary cilia.
Together, observation of the cilium structure in osteocytes from transgenic mice with bone defects and the severe phenotype of bone-related ciliopathies indicate the significance of the primary cilium in development and mechanical-related bone homeostasis. However, more direct and convincing evidence for morphological changes of the osteocyte primary cilium under both physiological and pathological conditions is urgently needed.
Cells sense neighboring microenvironments and nanoenvironments through the FA complex, an Integrin-based adhesion complex. The complexity and modular nature of different adhesion proteins allow cells to respond differently based on extracellular environment changes.
In a study combining IHC with structural illumination by super-resolution microscopy, Cabahug-Zuckerman et al. Instead, a specialized mechanotransduction complex was observed on the osteocyte processes.
Although these defects persisted into adulthood, they became milder with age. Taken together, both in vitro and in vivo data suggest the essential functions of Integrins in bone development and mechanical stimulation-associated bone homeostasis.
In addition to cell-ECM connections through the FA complex, cells communicate with neighboring cells and the environment through GJs and hemichannels. Both GJs and hemichannels are composed of a protein known as connexin. A hexameric array of six connexin subunits gives rise to a connexon. Connexons can be composed of the same type of connexins homomeric or different types of connexins heteromeric.
GJs are composed of two juxtaposed connexons on the surfaces of adjacent cells, and unopposed connexons called hemichannels at the cell membrane act as direct conduits between the cytosol and extracellular environment. In the skeleton, GJs are present in all cell types and particularly abundant in osteoblasts and osteocytes. Cx43 also participates in the regulation of osteoclast formation and resorption ability.
In osteocytes, Cxdependent GJIC and hemichannels contribute to the coordination of bone remodeling in response to anabolic factors and mechanical loading Fig.
Osteocyte gap junctions and hemichannels in mechanobiology. A hexameric array of six connexin subunits gives rise to a connexon, and two juxtaposed connexons on the surfaces of adjacent cells form a GJ. Unopposed connexons called hemichannels at the cell membrane act as direct conduits between the cytosol and extracellular environment.
Cx43 is vital for animal embryogenesis and bone development. Global deletion of Cx43 in mice resulted in both neural crest cell defects and osteoblast dysfunctions, leading to animal death immediately after birth.
Moreover, Cx43 is involved in aging-related bone loss. Furthermore, mice carrying a G60S mutation in Cx43 exhibited severe bone mass loss and decreased strength, highly similar to the symptoms of the human disease oculodentodigital dysplasia, which is caused by Cx43 mutation.
Unlike those with global deletion of Cx43 in osteoblasts and osteocytes, mice with conditional deletion of Cx43 in osteoblasts and osteocytes were viable but developed osteopenia. Cx43 haploinsufficiency in osteoblasts 2. Moreover, more osteoclasts were observed at the site of apoptotic osteocytes. Together, these observations suggest that Cx43 regulates osteocyte apoptosis and target protein expression. Therefore, together, these data indicate that Cx43 deficiency desensitizes bone to the effects of mechanical loading and unloading.
In addition to its role in mechanical stimulation, Cx43 in osteocytes plays a role in hormone stimulation. In addition to its role in PTH signaling, Cx43 is involved in the estrogen pathway. These observations suggest that Cx43 in GJs and hemichannels may have different roles in regulating osteocyte and osteoclast activities and that intact Cxassociated channels are essential for protection of the bone against catabolic effects resulting from estrogen deficiency.
Together, these in vivo observations demonstrate that Cx43 is not required for early osteogenesis but plays important roles in regulating anabolic responses in response to hormone treatment and mechanical stimulation in osteoblasts and osteoclasts Table 6. In addition to in vivo studies, in vitro studies have revealed the detailed molecular contribution of Cx43 to osteocyte mechanotransduction Fig.
In addition to Cxmediated GJs, osteocytes use Cxdependent hemichannels in response to extracellular stimuli Fig. When MLO-Y4 cells were plated at a low density in culture, Cx43 formed hemichannels instead of cell-cell contact GJs in individual cells. These data suggest that hemichannels regulate PGE 2 release in osteocyte mechanotransduction. Interestingly, Cx43 also participates in osteocyte autocrine effects. When PGE 2 was depleted from the fluid flow conditioned medium, the stimulatory effect on GJs was partially but significantly decreased.
These data suggest that Cx43 can regulate osteocyte autocrine effects under conditions of mechanical stimulation and that released PGE 2 further enhances osteocyte Cx43 expression in a positive feedback loop, eventually resulting in broader and more intense responses. The function of Cx43 in osteocyte mechanobiology seems to be related to FAs, especially Integrins. MLO-Y4 cells cultured on a soft substrate expressed less Cx43, Vinculin, Paxillin , and Fibronectin than cells cultured on a stiff substrate.
In addition to Integrins, GJIC and the activity of hemichannels, which are mediated through Cx43, are closely regulated by other cellular components. In summary, Cxmediated GJs and hemichannels play a crucial role in regulating bone homeostasis, especially in responses to hormone and mechanical stimulation.
Second, Cxmediated hemichannels contribute to autocrine or even endocrine effects. Third, Cx43 directly regulates osteocyte apoptosis, which further influences local osteoblast and osteoclast activity. Finally, Cx43 is in direct and indirect contact with FAs, structural proteins and protein kinases in osteocytes, which further facilitates bone homeostasis. Illustration of ion channels involved in osteocyte mechanobiology.
Piezo1 is a curved channel that is highly engaged with the cell membrane. This process further changes the plasma membrane charge balance and induces the opening of VSCs. Discovery of the molecular structure of Piezo1 showed that Piezo1 is a large ion channel with a special and highly curved blade-like shape , Figs.
This curved channel is highly engaged with the cell membrane, amplifying the sensitivity of Piezo1 to changes in membrane tension. Upon MSIC opening, ions, especially cations, are exchanged between the cytoplasmic and extracellular environments. This process further changes the plasma membrane charge balance and induces the opening of voltage-sensitive calcium channels VSCs.
Interestingly, the calcium that undergoes flux induced by mechanical stimulation is derived from not only external fluid and the medium but also stored internal calcium, such as that in the endoplasmic reticulum ER. On the one hand, when cells were cultured in medium lacking calcium, bone cells lost the ability to activate calcium flux upon fluid flow. These results further show that calcium mobilization in osteocytes is a quantitative response to mechanical loading.
Moreover, calcium mobilization also regulated ATP release in osteocytes upon mechanical stimulation. In rat ulnar loading experiments, pretreatment with two L-type VSC antagonists nifedipine and verapamil reduced load-induced bone formation and ATP signaling. Calcium, the release of which is a very early event in osteocyte mechanotransduction, serves as a powerful second messenger, providing essential information for mechanical responses and participating in downstream regulation.
The primary ECM components in bone are organic collagen and inorganic hydroxyapatite. Even though osteocytes are embedded in the LCS, which allows fluid flow and nutrient exchange for these cells, the space between the LCS wall and the osteocyte plasma membrane is not empty.
As discussed, and as presented in Fig. In these spaces, together, the ECM components proteoglycans, glycoproteins, and hyaluronic acid form a mesh of PCM, called the glycocalyx. In summary, ECM components, especially the glycocalyx in the pericellular space, actively contribute to osteocyte mechanotransduction. These glycocalyx molecules act as a tether or ligand for osteocyte membrane receptors, conveying mechanical signals due to either ECM deformation or fluid shear to the osteocyte surface.
All of these important functions make the glycocalyx in the ECM an essential osteocyte mechanosensor during force adaptation. During skeletal development, multiple classical signaling pathways have been shown to play indispensable roles in bone formation through both genetic modification of experimental animals and human genomic studies. Receptors on the plasma membrane are activated through direct binding to specific ligands, leading to the activation of sequential signaling cascades and expression of downstream target genes.
Interestingly, Notch signaling has dual effects on osteogenesis and osteoclastogenesis. In addition to traditional pathways in bone development, several classical and new pathways that regulate bone homeostasis during osteocyte mechanotransduction have emerged Fig.
Signaling pathways involved in osteocyte mechanobiology. Appropriate mechanical stimulation prevents osteocyte apoptosis, whereas aging, damage-inducing loading and disuse induce osteocyte apoptosis and senescence through several different pathways. The Wnt signaling pathway, the major regulator of the transition of stem cells into mature osteoblasts, has been proven to be a key regulator of bone mass. Mutations of WNT1 in humans cause early-onset osteoporosis and osteogenesis imperfecta.
In addition to its functions in bone development, the Wnt pathway is an important osteocyte mechanotransduction pathway. As a major receptor in the Wnt pathway, Lrp5 has been shown to be highly important in osteocyte mechanotransduction. In humans, loss-of-function mutations in LRP5 are tightly associated with osteoporosis—pseudoglioma syndrome, which is characterized by low BMD and skeletal fragility, and gain-of-function mutations in LRP5 lead to a high bone mass phenotype.
Bonewald et al. Sensing of the external environment and stimulation by osteocytes is largely dependent on the connects between cells and the ECM—Integrin-based FAs. As discussed above Fig. These signals activate internal signaling pathways that determine cell migration, survival and differentiation. With this bidirectional transmission between the intracellular environment and intercellular status, Integrins carry out dynamic, spatial, and temporal regulation in osteocytes Fig.
Another FA-binding protein, Pinch, is also involved in osteogenesis and osteocyte mechanosensation. Global Pinch2 deletion and conditional Pinch1 deletion in osteocytes resulted in significant bone loss in mice, whereas single deletion of one isoform of Pinch did not cause any marked skeletal phenotypes.
Taken together, these results show that the Integrin-centered FA signaling pathway is essential for skeletogenesis and tightly associated with bone mechanobiology. More studies focused on individual components of the adhesome are required, and osteocyte mechanobiology should be studied in more detail. Osteocyte apoptosis, a form of programmed cell death, and senescence, a death-resistance cell fate program, are common features of aging bone tissue Fig.
Both in vitro and in vivo studies have shown that appropriate mechanical stimulation prevents osteocyte apoptosis. The results from in vitro culture studies further suggested that mechanical stimulation induces Erk activation through Integrin and the cytoskeleton in osteocytes and supports osteocyte survival. Compared with osteocyte apoptosis, less is known about senescence.
Both apoptosis and senescence appear to be tightly associated with age-related bone loss through two independent pathways. Senescent cells can release various cytokines, known as the proinflammatory secretome or senescence-associated secretory phenotype, causing significant damage to the surrounding tissues.
In osteocytes, sclerostin is detected in the cell body as well as cell processes. Together, these data demonstrate that Sclerostin participates in osteocyte mechanobiology through Wnt signaling and potentially other pathways. With rapidly increasing attention on osteocyte mechanobiology, increasingly more players in mechanosensation and mechanotransduction are being discovered.
A better understanding of the details of osteocyte mechanobiology will provide promising treatments for disease-, disuse-, and age-related bone loss. These treatments could be science-based advice regarding daily activities, noninvasive machine-based mechanical stimulation, or simply small molecules or peptides that regulate important players in osteocyte mechanobiology.
One exciting example is the approval of romosozumab, a Sclerostin monoclonal antibody drug, for the clinical treatment of osteogenesis imperfecta and low BMD in postmenopausal women and patients with a high risk of fracture. The importance of osteocyte mechanobiology is related to not only bone health but also the homeostasis of other organs.
On the one hand, as important endocrine cells, osteocytes can regulate the functions of multiple organs, such as muscle growth, memory in the brain, and fertility in the testis.
For example, adipocyte-specific Kindlin-2 deletion caused a severe lipodystrophy phenotype. These results suggest interorgan communication between bone and distal organs, which indicates that the mechanotransductive properties and abilities of osteocytes can influence multiple cell types from different organs, including the surrounding bone cells and distal cells.
Moreover, changes in possible ECM components and the morphology of osteocytes due to the influence of other organs can also affect osteocyte mechanobiology. Therefore, osteocytes residing in bone and other cells from various organs form a continuous loop that regulates whole-body homeostasis. From the perspective of osteocytes, how these cells coordinate different mechanosensors and pathways in a complex stimulating environment, such as during daily physical activities, such as running, walking, and jogging, remains intriguing.
Complex stimulation triggers more than one mechanosensor and activates more than one pathway, necessitating interactions between different players in the process. Therefore, considering osteocyte mechanobiology in a systematic way is a future direction for both basic research and potential clinical utilization. Moreover, osteocytes are not the only mechanosensitive cells in bone.
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