Glucocorticoids and the osteoclast.
ABSTRACT 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.
- SourceAvailable from: Tara Clare Brennan-Speranza[Show abstract] [Hide abstract]
ABSTRACT: Glucocorticoids (GCs) are highly effective in the treatment of inflammatory and autoimmune conditions but their therapeutic use is limited by numerous adverse effects. Recent insights into the mechanisms of action of both endogenous and exogenous GCs on bone cells have unlocked new approaches to the development of effective strategies for the prevention and treatment of GC-induced osteoporosis. Furthermore, topical studies in rodents indicate that the osteoblast-derived peptide, osteocalcin, plays a central role in the pathogenesis of GC-induced diabetes and obesity. These exciting findings mechanistically link the detrimental effects of GCs on bone and energy metabolism. In this article we review the physiology and pathophysiology of GC action on bone cells, and discuss current and emerging concepts regarding the molecular mechanisms underlying adverse effects of GCs such as osteoporosis and diabetes.Trends in Endocrinology and Metabolism 01/2014; · 8.90 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: A variety of diseases of the jaws may present multinucleated giant cells. These diseases include central giant cell lesions (CGCL), peripheral giant cell lesions (PGCL), brown tumor of hyperparathyroidism (BTH), and cherubism. The multinucleated giant cells in these lesions are osteoclast-like. Since NFATc1 plays a significant role in osteoclast differentiation, the present study aimed to compare the expression of NFATc1 in CGCL, PGCL, BTH and cherubism. A total of 14 formalin-fixed and paraffin-embedded tissue samples of CGCL (n=4), PGCL (n=5), BTH (n=3) and cherubism (n=2) were included in the study. An immunohistochemical analysis was performed to investigate the NFATc1 protein. The majority of giant cells in all of the cases were positive for nuclear NFATc1 and the immunostaining pattern was similar in all of the groups. Although our study supports the hypothesis that giant cell accumulation in PGCL, CGCL, BTH and cherubism is mediated by NFATc1, functional studies are required to investigate this hypothesis.Oncology letters 05/2011; 2(3):571-573. · 0.24 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Objective This study aimed to evaluate the impact of concurrent administration of clinically relevant doses of zoledronic acid (ZA) and dexamethasone (DX) on bone healing after tooth extraction (EXO). Materials and Methods Forty-four Sprague–Dawley rats (6–8 month old) were randomized into five groups: ZA + DX = weekly injection of ZA with DX for 7 weeks; WD = ZA with DX for 3 weeks then DX alone for 4 weeks; C = control saline for 7 weeks; ZA = ZA alone for 7 weeks and DX = DX alone for 7 weeks. ZA was administered at 0.13 mg/kg/week and DX at 3.8 mg/kg/week and body weights recorded at the time of injection. All rats underwent extraction (EXO) of the mandibular and maxillary first molars at 3 weeks and were euthanized at 7 weeks. The extracted and non-extracted sides of both jaws were harvested for micro-CT analyses. Results All rats, particularly those injected with ZA, exhibited weight gain till EXO followed by decline then recovery. ZA + DX group demonstrated highest fractional bone to tissue volume (BV/TV) in the non-extracted side. ZA + DX rats exhibited also highest volume and surface of sequestra. Only sequestra volume was statistically higher in the WD group compared to C group. Conclusion Combined treatment with ZA and DX over a prolonged period inhibits bone remodeling and increased sequestra formation to a greater extent than either drug alone. Trauma caused by these sequestra cutting through the mucosa could play a key role in the development of BRONJ by potentially facilitating infection. ZA withdrawal may promote bone-remodeling reactivation following EXO.Oral Oncology 01/2014; · 2.70 Impact Factor