In addition to stimulating an increase in osteoclasts and bone resorption, Th 1 cytokines interact with osteoblast development and function. This illustrates the critical role of immunological factors, such as Th 1 cytokines, in bone biology. Th 2 cytokines, such as IL-4 and IL, are less well understood in the context of bone physiology.
Furthermore, IL transgenic knockout mice have low bone mass and increased fragility which alludes to an influential role of IL in regulating bone turnover There exist many other cytokines within the Th 1 and Th 2 classes and other subsets Th 9 , Th 17 , Th 22 , T fh that have roles not yet delineated in bone physiology, highlighting areas of future research.
Finally, the interaction of these cytokines with osteocytes has been minimally investigated. Osteocytes form when osteoblasts become buried in the mineral matrix of bone and develop distinct features. Residing within the lacuna of the mineralized bone matrix, osteocytes form dendritic processes that extend out from their cell bodies into spaces known as canaliculi. Through these dendritic processes, osteocytes form networks interfacing with other osteocytes, cells on bone surfaces, and the marrow Through these communication networks, osteocytes sense the local and systemic environment within the bone.
Osteocytes also coordinate the actions of osteoblasts and osteoclasts via several mechanisms. First, osteocytes express and release proteins that signal to osteoblasts, osteoclasts, and other bone-residing cells to respond to environmental changes. Additionally, osteocyte apoptosis signals to increase osteoclast activity driving targeted bone resorption 41 , 48 , Elucidating osteocyte function in the context of osteoimmunology may provide further insight to the imbalance of resorption vs.
In the past few decades, the central role of osteocytes in response to mechanical strains has been explored and identified.
Osteocytes sense mechanical strains through fluid flow shear stress through the lacuna-canalicular network and changes in interstitial hydrostatic pressure 50 — Decreased mechanical strains also induce osteocyte apoptosis leading to decreased bone mass and strength 53 , Some preliminary evidence suggests that high mobility group box 1 HMGB1 , an alarmin 55 , may be released during osteocyte apoptosis thereby triggering RANKL and other immune factors It is unknown what other immune-related factors may be released during apoptosis and the signaling cascades that follow.
Mechanosensory signals also trigger osteocytes to release various proteins that impact bone turnover. Prevention of osteocyte apoptosis in animal models of unloading mitigates increases in osteocyte RANKL 54 , Disuse is also characterized by elevated osteocyte sclerostin in conjunction with decreased bone formation rate 59 , Other mechanosensitive osteocyte proteins include insulin-like growth factor-I IGF-I and IL-6 which both are upregulated with loading 60 — The role of osteocytes in the mechanosensory capabilities of bone highlight the important role these cells play in bone adaptations to the environment.
Some osteocyte proteins known to have mechanosensory roles such as RANKL and IL-6 are also signaling molecules in the immune system and play key roles in inflammatory processes.
Burgeoning research has shown cytokines directly impact osteocyte apoptosis and cause the release of cytokines that influence bone turnover. Therefore, one mechanism of increased bone resorption in inflammatory conditions is through the direct effect of pro-inflammatory cytokines on osteocyte apoptosis which, in turn, increases osteoclastic driven resorption.
Osteocytes also express pro-inflammatory cytokines. Other cell culture osteocyte lines have increased expression of pro-inflammatory cytokines with exposure to monosodium urate crystals 73 , Brucella abortus infection 74 and orthopedic implant materials Therefore, osteocytes express cytokines that can increase osteoclastogenesis and inhibit osteoblast formation or activity.
Osteocytes themselves respond to circulating pro-inflammatory cytokines influencing their cytokine expression. Based on the supporting data from these in vitro studies, cytokines influence osteocytes in a positive-feedback mechanism leading to even greater cytokine expression.
This would suggest osteocytes may amplify an inflammatory bone state resulting in increased production of factors altering bone turnover and increasing bone loss.
Many cytokines also alter osteocyte signaling proteins. Osteocyte-to-osteoclast signaling is enhanced by multiple pro-inflammatory cytokines largely through RANKL signaling. Furthermore, RANKL-positive osteocytes are elevated in animal models of inflammatory conditions including periodontitis 80 — 82 , spinal cord injury 76 , and inflammatory bowel disease 68 , Furthermore, in rat models of inflammatory bowel disease and spinal cord injury, RANKL-positive osteocytes were associated with increases in osteoclast surfaces 68 , In rodent inflammatory bowel disease and spinal cord injury models, OPG-positive osteocytes were elevated 68 , 69 , Inflammatory signals also influence osteocyte proteins controlling bone formation.
Wnt proteins are key mediators of osteoblastogenesis and govern the formation of the skeletal development. Both sclerostin and Dickkopf-related-1 Dkk-1 inhibit the Wnt signaling pathway in bone. Interestingly, Dkk1 expression was inhibited in osteoblast cell culture treated with ILA; whether this is also true in osteocytes is unknown Beyond direct effects of pro-inflammatory cytokines on osteoblasts and bone formation, the inflammation-induced elevation of inhibitors of bone formation contributes to a state of low bone formation.
While outside the scope of this review, additional osteocyte proteins involved in mineral homeostasis and metabolism are influenced by inflammatory signals. Fibroblast growth factor 23 FGF23 , a phosphate regulator synthesized by osteocytes, has increased expression in inflammatory conditions 72 , 88 , ILA has been shown to decrease various genes of osteocyte proteins involved in mineral metabolism including Dmp1 and Phex Therefore, it is clear that osteocytes respond to inflammatory signals through various mechanisms including increased expression of cytokines and altered expression of regulatory proteins.
Crucial to osteocyte function is sensing and responding to bone interstitial fluid shear stress and mechanical strains. What is not fully understood is if mechanosensing is tied with osteocyte inflammatory responses and vice versa. With aging, osteocytes develop morphological adaptations and changes in the lacunocanalicular system that may impair their mechanosensory function and ability to communicate 91 , In addition, osteocytes of aged mice also express a senescence-associated secretory-phenotype, expressing multiple pro-inflammatory cytokines including ILA, IL-1A, and IL-6, likely contributing to age-related bone loss Prevention of the pro-inflammatory secretome of senescent cells in aged mice with a JAK inhibitor improved bone mass and strength It has been hypothesized that exercise to increase mechanical strain on bone could improve the senescent phenotype in aging It remains to been seen whether a lack of mechanical loading and a lack of adequate mechanosensory ability or pro-inflammatory senescent markers occurs first during aging in osteocytes.
To our knowledge, there are no investigations directly assessing the influence of mechanical loading on osteocyte-related proteins in animal models of inflammatory conditions to determine the mechanical loading effects on osteocyte inflammatory changes.
However, it is possible that in inflammatory pathologies, such as spinal cord injury where both chronic systemic inflammation and disuse are present, the inflammatory status with the lack of mechanical loading on osteocytes could exacerbate bone loss.
Further work needs to be done on the interaction of inflammation and mechanical strains in osteocytes. 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. In inflammatory conditions, bone-specific treatments like bisphosphonates, anti-RANKL, and anti-sclerostin, all improve bone outcomes, but have no effect on inflammatory measures 96 — Anti-inflammatory treatments, like anti-TNF, may improve bone mass 99 , but potentially have negative side effects , Therefore, viable treatments for inflammatory conditions are still needed.
By directly impacting osteocytes via senolytic treatment or a JAK inhibitor in aged mice prevented the inflammatory senescent osteocyte phenotype Additionally, in rodent models of inflammatory bowel disease, a soy protein diet and treatment with exogenous irisin decreased the inflammatory status of osteocytes and improved bone turnover 69 , Other anti-inflammatory treatments that improve bone in inflammatory conditions, like resolvin E1 , need to be examined for their impact on osteocytes.
Furthermore, low-grade inflammation may be beneficial in some conditions like fracture healing The role of other cytokines in bone physiology still needs to be elucidated as well as the relative contribution of osteocytic pro-inflammatory cytokines vs. Finally, the magnitude and duration of mechanical forces that could influence osteocyte-immune crosstalk has yet to be examined. Osteocytes play a central role in orchestrating changes in bone turnover.
In this review, we present literature that supports an overlap between classical osteocyte regulatory proteins with known mechanosensory functions RANKL, OPG, sclerostin, etc. Pro-inflammatory signals stimulate osteocyte apoptosis, increase osteocyte cytokine production, and alter osteocytic proteins controlling bone turnover.
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Interleukin inhibits osteoclastogenesis by reducting NFATc1 expression and preventing its translocation to the nucleus. The osteocytes are oval-shaped, multi-protuberant cells, and contain a single nucleus that is located toward the vascular side and has one or two nucleoli and a membrane. Under the electron microscope, there were a few lysosomes, mitochondria, and rough endoplasmic reticulum in the cytoplasm, and the Golgi complex was also underdeveloped.
Bone cells are sandwiched between adjacent two layers of bone plates or dispersed within the bone plate. There are gap junctions between the projections of adjacent bone cells. In the bone matrix, the small oval cavity occupied by the bone cell body is called the bone lacunae, and the space where the protrusions are located is called the bony canaliculus.
Adjacent bone lacunae are interconnected by bone canals. Although osteocytes are relatively inert cells, they are capable of molecular synthesis and modification, as well as transmission of signals over long distances, in a way analogous to the nervous system.
They are the most common cell type in bone. Most of the receptor activities that play an important role in bone function are present in the mature osteocyte. Osteocytes contain glutamate transporters that produce nerve growth factors after bone fracture, which provides evidence of a sensing and information transfer system.
When osteocytes were experimentally destroyed, the bones showed a significant increase in bone resorption, decreased bone formation, trabecular bone loss, and loss of response to unloading. Osteocytes are thought to be mechanisation cells that control the activity of osteoblasts and osteoclasts within a basic multicellular unit BMU , a temporary anatomic structure where bone remodeling occurs.
Osteocytes generate an inhibitory signal that is passed through their cell processes to osteoblasts for recruitment to enable bone formation. So the osteocyte is an important regulator of bone mass and a key endocrine regulator of phosphate metabolism. Twitter Facebook. Research Area.
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