Osteocytes: a proposed multifunctional bone cell.
ABSTRACT 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.
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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 · 4.46 Impact Factor
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ABSTRACT: Biomechanical theories to predict bone remodelling have used either mechanical strain or microdamage as the stimulus driving cellular responses. Even though experimental data have implicated both stimuli in bone cell regulation, a mechano-regulatory system incorporating both stimuli has not yet been proposed. In this paper, we test the hypothesis that bone remodelling may be regulated by signals due to both strain and microdamage. Four mechano-regulation algorithms are studied where the stimulus is: strain, damage, combined strain/damage, and either strain or damage with damage-adaptive remodelling prioritised when damage is above a critical level. Each algorithm is implemented with both bone lining cell (surface) sensors and osteocyte cell (internal) sensors. Each algorithm is applied to prediction of a bone multicellular unit (BMU) remodelling on the surface of a bone trabecula. It is predicted that a regulatory system capable of responding to changes in either strain or microdamage but which prioritises removal of damaged bone when damage is above a critical level, is the only one that provides a plausible prediction of BMU behaviour. A mechanism for this may be that, below a certain damage threshold, osteocyte processes can sense changes in strain and fluid flow but above the threshold damage interferes with the signalling mechanism, or causes osteocyte apoptosis so that a remodelling response occurs to remove the dead osteocytes.Journal of Biomechanics 02/2007; 40(6):1381-91. DOI:10.1016/j.jbiomech.2006.05.007 · 2.50 Impact Factor
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ABSTRACT: The osteocyte is often considered to be a cell that is hardly active, yet it turns out to have a central role in bone remodeling. It functions as a mechanoreceptor that translates mechanical stimuli into biochemical signals. The expression of PGE2 by loaded osteocytes and the consequent activation of the cAMP/PKA pathway, together with stabilization of β-catenin, may permit cross talk with the canonical Wnt/β-catenin pathway, the activation of which is increased by the load-dependent reduction of the expression of DKK1 and of sclerostin (Sost, the secretion product of old osteocytes). These signal pathways, as well as TGF-β and BMP expression, stimulate the differentiation and activity of osteoblasts, reduce their apoptosis, and enhance bone formation. The expressions of MEPE, FGF-23 and DMP-1 further contribute to the osteocytic control of bone metabolism. Periosteocytic osteolysis, if definitively demonstrated, would constitute another fundamental function of osteocytes. A thorough understanding of the osteocyte’s activities could open up new strategies in the therapy of metabolic bone diseases.Rendiconti Lincei. Scienze Fisiche e Naturali 09/2009; 20(3):237-254. DOI:10.1007/s12210-009-0051-y · 0.76 Impact Factor