Glucocorticoids and the Osteoclast
Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO 63110, USA.Annals of the New York Academy of Sciences (Impact Factor: 4.38). 12/2007; 1116(1):335-9. DOI: 10.1196/annals.1402.057
Glucocorticoid (GC)-induced bone loss is the most common cause of secondary osteoporosis but its pathogenesis is controversial. GCs clearly suppress bone formation in vivo but the means by which they impact osteoblasts is unclear. Because bone remodeling is characterized by tethering of the activities of the two cells, the osteoclast is a potential modulator of the effect of GCs on osteoblasts. To address this issue we compared the effects of dexamethasone on wild-type (WT) osteoclasts with those derived from mice with disruption of the GC receptor in osteoclast lineage cells and found that the bone-degrading capacity of GC-treated WT cells is suppressed. The inhibitory effect of dexamethasone on bone resorption reflects failure of osteoclasts to organize their cytoskeleton in response to M-CSF. Dexamethasone specifically arrests M-CSF activation of RhoA, Rac, and Vav3, each of which regulate the osteoclast cytoskeleton. In all circumstances, mice lacking the GC receptor in osteoclast lineage cells are spared the impact of dexamethasone on osteoclasts and their precursors. Consistent with osteoclasts modulating the osteoblast-suppressive effect of dexamethasone, GC receptor-deficient mice are protected from the steroid's inhibition of bone formation.
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ABSTRACT: The osteoclast is the giant cell of bone phylogenically evolved to resorb the bone matrix. It contributes to both the bone modeling and remodeling processes through a complex extracellular mechanism, termed bone resorption, which removes the mineral and the organic bone matrix components. Primary osteoclast pathologies occur both in children and adults, and are very common in elderly. Reduced bone resorption is typically responsible of osteopetrosis, in which both bone modeling and remodeling are altered, and the primary bone persists reducing strength and causing spontaneous fractures, failure in hematopoiesis and impairment of sensory and motor systems. In children, bone resorption can be increased secondary to other pathological conditions due for instance to mechanical failure or inflammatory diseases. Excess bone resorption over formation is typical of post-menopausal women and elderly men, and the net result of this unbalanced bone cell activity is osteoporosis, which affects millions of people worldwide with high costs for management. This article will expand the concepts associated with the pathophysiology of the osteoclasts, providing up-to-date information on their function and involvement in bone diseases. KeywordsOsteoclast–Bone resorption–Bone remodeling–Osteopetrosis–OsteoporosisClinical Reviews in Bone and Mineral Metabolism 06/2011; 10(2):1-27. DOI:10.1007/s12018-011-9086-6
Article: Osteoclast receptors and signaling[Show abstract] [Hide abstract]
ABSTRACT: Osteoclasts are bone-resorbing cells derived from hematopoietic precursors of the monocyte-macrophage lineage. Besides the well known Receptor Activator of Nuclear factor-kappaB (RANK), RANK ligand and osteoprotegerin axis, a variety of factors tightly regulate osteoclast formation, adhesion, polarization, motility, resorbing activity and life span, maintaining bone resorption within physiological ranges. Receptor-mediated osteoclast regulation is rather complex. Nuclear receptors, cell surface receptors, integrin receptors and cell death receptors work together to control osteoclast activity and prevent both reduced or increased bone resorption. Here we will discuss the signal transduction pathways activated by the main osteoclast receptors, integrating their function and mechanisms of action.Archives of Biochemistry and Biophysics 06/2008; 473(2):147-60. DOI:10.1016/j.abb.2008.01.011 · 3.02 Impact Factor
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ABSTRACT: Osteoporosis is the most common metabolic disease characterized by loss of the normal density of bone, resulting in fragile bone and a higher risk of fractures. Patients under glucocorticoids treatment are susceptible to glucocorticoid-induced osteoporosis (GIO). The normal bone turnover depends on a balance between osteoblasts and osteoclasts. The skeletal cells including osteoblasts, osteoclasts, osteocytes and their precursors demonstrate altered features while they are cocultured with different extracellular glucocorticoids, or their intracytoplasmic glucocorticoids modified by genetic manipulation of 11beta-HSD isozyme. However, recent studies have also demonstrated different or even contradictive outcomes on whether the glucocorticoids inhibit or increase biological activity of these skeletal cells. Focusing on the roles of extracellular glucorticoids, intracytoplasmic glucocorticoids and the mechanism of transmembrane passage of the glucocorticoids, this review reveals that glucocorticoids may exert either inhibitive or enhancing influence on these skeletal cells, but relying on the difference in cell origins, methodology, and types of glucocorticoids. In addition, the effects of glucocorticoids may be dose- and time-dependent.The Journal of Steroid Biochemistry and Molecular Biology 09/2008; 111(3-5):164-70. DOI:10.1016/j.jsbmb.2008.06.015 · 3.63 Impact Factor
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