The Osteocyte: New Insights Robling, Alexander G; Bonewald, Lynda F
Annual review of physiology,
02/2020, Letnik:
82, Številka:
1
Journal Article
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Osteocytes are an ancient cell, appearing in fossilized skeletal remains of early fish and dinosaurs. Despite its relative high abundance, even in the context of nonskeletal cells, the osteocyte is ...perhaps among the least studied cells in all of vertebrate biology. Osteocytes are cells embedded in bone, able to modify their surrounding extracellular matrix via specialized molecular remodeling mechanisms that are independent of the bone forming osteoblasts and bone-resorbing osteoclasts. Osteocytes communicate with osteoclasts and osteoblasts via distinct signaling molecules that include the RankL OPG axis and the Sost Dkk1 Wnt axis, among others. Osteocytes also extend their influence beyond the local bone environment by functioning as an endocrine cell that controls phosphate reabsorption in the kidney, insulin secretion in the pancreas, and skeletal muscle function. These cells are also finely tuned sensors of mechanical stimulation to coordinate with effector cells to adjust bone mass, size, and shape to conform to mechanical demands.
When normal physiologic functions go awry, disorders and disease occur. This is universal; even for the osteocyte, a cell embedded within the mineralized matrix of bone. It was once thought that this ...cell was simply a placeholder in bone. Within the last decade, the number of studies of osteocytes has increased dramatically, leading to the discovery of novel functions of these cells. With the discovery of novel physiologic functions came the discoveries of how these cells can also be responsible for not only bone diseases and disorders, but also those of the kidney, heart, and potentially muscle.
Few investigators think of bone as an endocrine gland, even after the discovery that osteocytes produce circulating fibroblast growth factor 23 that targets the kidney and potentially other organs. ...In fact, until the last few years, osteocytes were perceived by many as passive, metabolically inactive cells. However, exciting recent discoveries have shown that osteocytes encased within mineralized bone matrix are actually multifunctional cells with many key regulatory roles in bone and mineral homeostasis. In addition to serving as endocrine cells and regulators of phosphate homeostasis, these cells control bone remodeling through regulation of both osteoclasts and osteoblasts, are mechanosensory cells that coordinate adaptive responses of the skeleton to mechanical loading, and also serve as a manager of the bone's reservoir of calcium. Osteocytes must survive for decades within the bone matrix, making them one of the longest lived cells in the body. Viability and survival are therefore extremely important to ensure optimal function of the osteocyte network. As we continue to search for new therapeutics, in addition to the osteoclast and the osteoblast, the osteocyte should be considered in new strategies to prevent and treat bone disease.
Sclerostin is a product of mature osteocytes embedded in mineralised bone and is a negative regulator of bone mass and osteoblast differentiation. While evidence suggests that sclerostin has an ...anti-anabolic role, the possibility also exists that sclerostin has catabolic activity. To test this we treated human primary pre-osteocyte cultures, cells we have found are exquisitely sensitive to sclerostin, or mouse osteocyte-like MLO-Y4 cells, with recombinant human sclerostin (rhSCL) and measured effects on pro-catabolic gene expression. Sclerostin dose-dependently up-regulated the expression of receptor activator of nuclear factor kappa B (RANKL) mRNA and down-regulated that of osteoprotegerin (OPG) mRNA, causing an increase in the RANK:OPG mRNA ratio. To examine the effects of rhSCL on resulting osteoclastic activity, MLO-Y4 cells plated onto a bone-like substrate were primed with rhSCL for 3 days and then either mouse splenocytes or human peripheral blood mononuclear cells (PBMC) were added. This resulted in cultures with elevated osteoclastic resorption (approximately 7-fold) compared to untreated co-cultures. The increased resorption was abolished by co-addition of recombinant OPG. In co-cultures of MLO-Y4 cells with PBMC, SCL also increased the number and size of the TRAP-positive multinucleated cells formed. Importantly, rhSCL had no effect on TRAP-positive cell formation from monocultures of either splenocytes or PBMC. Further, rhSCL did not induce apoptosis of MLO-Y4 cells, as determined by caspase activity assays, demonstrating that the osteoclastic response was not driven by dying osteocytes. Together, these results suggest that sclerostin may have a catabolic action through promotion of osteoclast formation and activity by osteocytes, in a RANKL-dependent manner.
: The target of bone systemic factors and therapeutics has been assumed to be primarily osteoblasts and/or osteoclasts and their precursors. All the action with regard to bone modeling or remodeling ...has been assumed to take place on the bone surface. In this scenario, cells below the bone surface, that is, osteocyte, are considered to be inactive placeholders in the bone matrix. New data show osteocytes are involved. In addition to the function of osteocytes translating mechanical strain into biochemical signals between osteocytes and cells on the bone surface to affect (re)modeling, new functions are emerging. Osteocytes are exquisitely sensitive to mechanical strain in the form of shear stress compared to osteoblasts or osteoclasts and communicate with each other, with cells on the bone surface, and with marrow cells. Osteocytes are able to move their cell body and their dendritic processes and appear to be able to modify their local microenvironment. A novel function now attributed to osteocytes includes regulation of phosphate metabolism. Therefore, in addition to osteoblasts and osteoclasts, osteocytes are also important for bone health.
Muscle and bone are closely associated in both anatomy and function, but the mechanisms that coordinate their synergistic action remain poorly defined. Myostatin, a myokine secreted by muscles, has ...been shown to inhibit muscle growth, and the disruption of the myostatin gene has been reported to cause muscle hypertrophy and increase bone mass. Extracellular vesicle-exosomes that carry microRNA (miRNA), mRNA, and proteins are known to perform an important role in cell-cell communication. We hypothesized that myostatin may play a crucial role in muscle-bone interactions and may promote direct effects on osteocytes and on osteocyte-derived exosomal miRNAs, thereby indirectly influencing the function of other bone cells. We report herein that myostatin promotes expression of several bone regulators such as sclerostin (SOST), DKK1, and RANKL in cultured osteocytic (Ocy454) cells, concomitant with the suppression of miR-218 in both parent Ocy454 cells and derived exosomes. Exosomes produced by Ocy454 cells that had been pretreated with myostatin could be taken up by osteoblastic MC3T3 cells, resulting in a marked reduction of Runx2, a key regulator of osteoblastic differentiation, and in decreased osteoblastic differentiation via the down-regulation of the Wnt signaling pathway. Importantly, the inhibitory effect of myostatin-modified osteocytic exosomes on osteoblast differentiation is completely reversed by expression of exogenous miR-218, through a mechanism involving miR-218-mediated inhibition of SOST. Together, our findings indicate that myostatin directly influences osteocyte function and thereby inhibits osteoblastic differentiation, at least in part, through the suppression of osteocyte-derived exosomal miR-218, suggesting a novel mechanism in muscle-bone communication.
Osteocytes are derived from osteoblasts and make up over 90% of the cells in bone. However, the mechanisms that control the differentiation of osteoblasts into osteocytes embedded in bone matrix are ...not well understood. With the recent developments of transgenic models for manipulating gene expression in osteocytes and of transgenic mice carrying lineage reporters for osteoblasts and osteocytes, unprecedented new insights are becoming possible. In this article we review recent advances, such as comparative gene and protein expression studies, that are delineating the changes in gene and protein expression that accompany osteocyte differentiation. We also review recent studies in which time‐lapse dynamic imaging approaches have been used to visualize osteoblast and osteocyte populations within bone. These approaches reveal the key role of cell motility in bone cell function and highlight the dynamic nature of mineralized tissues. Changes in motile properties of the cell may be key in the transition from osteoblast to osteocyte, as reflected in the altered expression of many molecules involved in cytoskeletal function.
Osteocytes embedded in bone have been postulated to orchestrate bone homeostasis by regulating both bone-forming osteoblasts and bone-resorbing osteoclasts. We find here that purified osteocytes ...express a much higher amount of receptor activator of nuclear factor-κB ligand (RANKL) and have a greater capacity to support osteoclastogenesis in vitro than osteoblasts and bone marrow stromal cells. Furthermore, the severe osteopetrotic phenotype that we observe in mice lacking RANKL specifically in osteocytes indicates that osteocytes are the major source of RANKL in bone remodeling in vivo.
Abstract The majority of bone cell biology focuses on activity on the surface of the bone with little attention paid to the activity that occurs below the surface. However, with recent new ...discoveries, osteocytes, cells embedded within the mineralized matrix of bone, are becoming the target of intensive investigation. In this article, the distinctions between osteoblasts and their descendants, osteocytes, are reviewed. Osteoblasts are defined as cells that make bone matrix and osteocytes are thought to translate mechanical loading into biochemical signals that affect bone (re)modeling. Osteoblasts and osteocytes should have similarities as would be expected of cells of the same lineage, yet these cells also have distinct differences, particularly in their responses to mechanical loading and utilization of the various biochemical pathways to accomplish their respective functions. For example, the Wnt/β-catenin signaling pathway is now recognized as an important regulator of bone mass and bone cell functions. This pathway is important in osteoblasts for differentiation, proliferation and the synthesis bone matrix, whereas osteocytes appear to use the Wnt/β-catenin pathway to transmit signals of mechanical loading to cells on the bone surface. New emerging evidence suggests that the Wnt/β-catenin pathway in osteocytes may be triggered by crosstalk with the prostaglandin pathway in response to loading which then leads to a decrease in expression of negative regulators of the pathway such as Sost and Dkk1. The study of osteocyte biology is becoming an intense area of research interest and this review will examine some of the recent findings that are reshaping our understanding of bone/bone cell biology.
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