Osteocytes: A proposed multifunctional bone cell
Most cell types are ascribed a single function. The osteoclast holds the unique distinction of performing only one function in the body - that of resorbing bone. The osteoblast has been ascribed the major function of bone matrix production. Other less well-defined cell types include progenitor cells and the nebulous cell type that can support osteoclast formation upon stimulation with various bone resorbing cytokines. Obviously, these cells could have other functions. The definition of an osteocyte is descriptive of its location - cells surrounded by mineralized matrix - not its function. For this year's Sun Valley Workshop on osteocytes, several proposed functions will be presented. First, a general consensus exists that osteocytes are most likely sensitive to mechanotransduction and translate mechanical strain into biochemical signals. Consensus does not exist on the nature of the mechanical strain, the form of the biochemical signals, the target cell(s), or the viability status of the osteocyte. Second, it is also proposed that this cell is incredibly adaptable and expresses plasticity in response to mechanical stimuli. In other words, this cell can readjust its responses to strain in the presence of other bone agents such as hormones and bone factors. Third, it will also be presented that osteocytes maintain systemic mineral homeostasis by regulating mineral release and deposition over the enormous surface area over which these cells interface with the surrounding matrix. Although osteocytes are terminally differentiated osteoblasts, they appear to have separate and distinct properties from their predecessors. Bone cell biologists loaded with an arsenal of bone anabolic and catabolic factors are examining the expression and effects of these factors on osteocytes. Engineers trained in mathematical modeling have generated new models of strain and connectivity to be tested. The unique morphology of osteocytes suggests that the cytoskeleton in these cells may function differently from osteoblasts and other cell types. Osteocytes may consist of different subpopulations; some that possess receptors for parathyroid hormone (PTH) and others that only express receptors for carboxyl terminal PTH suggesting different functions and responses. Osteocytes may respond rapidly to strain through glutamate receptor-like mechanisms, through calcium influxes, through gap junctions, and less rapidly through the production of small molecules and factors. Strain may take the form of substrate stretching and/or fluid flow. Osteocytes may communicate with other osteocytes and/or bone surface cells such as lining cells, stromal cells, osteoblasts, and/or osteoclasts and their precursors. The viability status of the osteocyte may determine the type of signals sent from these cells. If the cells are deprived of oxygen or nutrients, the apoptotic cells may send signals for initiation of resorption. If the cells and/or their dendritic process are ripped or torn by microdamage, they may send signals of both resorption and formation. If the majority of these theories are correct, then the osteocyte is the 'smart' cell that can direct or orchestrate the bone resorbing and bone forming cells even in its death and dying.
Available from: Graham Peter Riley
- "Osteocytes are now known to play key roles in calcium and phosphate homeostasis and are versatile orchestrators of bone remodelling in response to load-bearing (Bonewald, 2002; Franz-Odendaal et al., 2006; Pitsillides et al., 1995; Quarles, 2003). Most models of osteocyte formation (osteocytogenesis) propose a predominantly passive role, during which an osteoblast destined for osteocytogenesis slows extracellular matrix (ECM) production and becomes surrounded by the osteoid synthesised by neighbouring osteoblasts (Franz-Odendaal et al., 2006; Nefussi et al., 1991; Palumbo et al., 2004). "
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ABSTRACT: Osteocytes within bone differentiate from osteoblast precursors which reside in a mineralised extracellular matrix (ECM). Fully differentiated osteocytes are critical for bone development and function but the factors that regulate this differentiation process are unknown. The enzymes primarily responsible for ECM remodelling are matrix metalloproteinases (MMP) however, the expression and role of MMPs during osteocytogenesis is undefined. Here we used MLO-A5 cells to determine the temporal gene expressions of the MMP family and their endogenous inhibitors - tissue inhibitors of metalloproteinases (TIMPs) during osteocytogenesis. RT-qPCR revealed expression of 14 Mmps and 3 Timps in MLO-A5 cells. Mmp2, Mmp23 and Mmp28 were decreased concurrent with mineralisation onset (P<0.05*). Mmp14 and Mmp19 mRNAs were also significantly increased at day 3 (P<0.05*) before returning to baseline levels at day 6. Decreased expressions of Timp1, Timp2 and Timp3 mRNA was observed by day 6 compared to day 0 (P<0.05*). To examine whether these changes are linked to osteocytogenesis, we determined Mmp/Timp mRNA expressions in mineralisation-limited conditions. RT-qPCR revealed that the previously observed decreases in Mmp2, Mmp23 and Mmp28 were not observed in these mineralisation-limited cultures, therefore closely linking these MMPs with osteocyte differentiation. Similarly, we found differential expression of Timp1, Timp2 and Timp3 mRNA in mineralisation-restricted cultures (P<0.05*). In conclusion, we have identified several members of the MMP/TIMP families as regulators of ECM remodelling necessary for the acquisition of the osteocyte phenotype.
Copyright © 2015. Published by Elsevier B.V.
Gene Expression Patterns 05/2015; 18(1-2). DOI:10.1016/j.gep.2015.04.004 · 1.38 Impact Factor
Available from: Harish K Datta
- "Osteocytes are fully differentiated osteoblasts and lie in lacunae in the mineralized matrix and osteoid tissue of bone . Osteocytes are able to detect changes in bone morphology, particularly micro-fractures through their sensitivity to mechanical forces, acting like bone mechanoreceptors . They regulate bone turnover both through direct physical contact with other bone cells and by producing various factors which affect bone formation and can be measured in blood such as, sclerostin (SCL), dickkopf-related protein 1 (DKK1), dentin matrix protein 1 (DMP1) and matrix extracellular phosphoglycoprotein (MEPE). "
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ABSTRACT: Osteoporosis is characterised by low bone mass and structural deterioration of bone tissue, resulting in increased fragility and susceptibility to fracture. Osteoporotic fractures are a significant cause of morbidity and mortality. Direct medical costs from such fractures in the UK are currently estimated at over two billion pounds per year, resulting in a substantial healthcare burden that is expected to rise exponentially due to increasing life expectancy. Currently bone mineral density is the WHO standard for diagnosis of osteoporosis, but poor sensitivity means that potential fractures will be missed if it is used alone. During the past decade considerable progress has been made in the identification and characterisation of specific biomarkers to aid the management of metabolic bone disease. Technological developments have greatly enhanced assay performance producing reliable, rapid, non-invasive cost effective assays with improved sensitivity and specificity. We now have a greater understanding of the need to regulate pre-analytical sample collection to minimise the effects of biological variation. However, bone turnover markers (BTMs) still have limited clinical utility. It is not routinely recommended to use BTMs to select those at risk of fractures, but baseline measurements of resorption markers are useful before commencement of anti-resorptive treatment and can be checked 3--6 months later to monitor response and adherence to treatment. Similarly, formation markers can be used to monitor bone forming agents. BTMs may also be useful when monitoring patients during treatment holidays and aid in the decision as to when therapy should be recommenced. Recent recommendations by the Bone Marker Standards Working Group propose to standardise research and include a specific marker of bone resorption (CTX) and bone formation (P1NP) in all future studies. It is hoped that improved research in turn will lead to optimised markers for the clinical management of osteoporosis and other bone diseases.
Journal of Translational Medicine 08/2013; 11(1):201. DOI:10.1186/1479-5876-11-201 · 3.93 Impact Factor
Available from: Anita V Neutzsky-Wulff
- "Osteocytes are often the forgotten cells in bones, although there is evidence supporting that they are central regulators of bone remodeling  . An important role for the osteocytes is to respond to mechanical stress, which, as well as high bone turnover pathologies, is known to lead to microcracks . "
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ABSTRACT: Bone remodeling is required for healthy calcium homeostasis and for repair of damage occurring with stress and age. Osteoclasts resorb bone and osteoblasts form bone. These processes normally occur in a tightly regulated sequence of events, where the amount of formed bone equals the amount of resorbed bone, thereby restoring the removed bone completely. Osteocytes are the third cell type playing an essential role in bone turnover. They appear to regulate activation of bone remodeling, and they exert both positive and negative regulation on both osteoclasts and osteoblasts. In this review, we consider the intricate communication between these bone cells in relation to bone remodeling, reviewing novel data from patients with mutations rendering different cell populations inactive, which have shown that these interactions are more complex than originally thought. We highlight the high probability that a detailed understanding of these processes will aid in the development of novel treatments for bone metabolic disorders, i.e. we discuss the possibility that bone resorption can be attenuated pharmacologically without a secondary reduction in bone formation.
Bone 05/2009; 44(6):1026-33. DOI:10.1016/j.bone.2009.03.671 · 3.97 Impact Factor
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