RESUMO
Short-term studies have shown that histamine is involved, via its H2 receptors (H2R), in the mediator network regulating trabecular bone loss in long bones of ovariectomized (OVX) rats. It is not known whether this effect of histamine persists over time or involves other skeletal sites. In this study, rats were maintained for 6 months postOVX and treated daily with saline or famotidine (10 mg kg(-1)), an H2R antagonist. At the end of the experimental period, femur trabecular bone mass was markedly decreased in OVX rats, whether or not they were treated with famotidine. In contrast, in the fourth lumbar vertebra, where bone loss starts later than in the femur, famotidine treatment attenuated the decline in trabecular bone volume, protected the trabecular architecture, maintained the thickness of the cortices and reduced the numbers of osteoclasts and tartrate-resistant acid phosphatase-positive preosteoclasts, whereas it had no influence on bone formation parameters. In vertebral bone marrow of OVX rats, the numbers of mast cells (MCs) and non-MC histamine-producing cells increased, while famotidine treatment significantly diminished both cell populations. These data show that H2R antagonism does not protect trabecular bone mass in the long term, and that short-term protection involves all bones. Histamine is involved during the early phase of strong osteoclastic resorption but not during the late phase of slower resorption, suggesting that different mediator networks control the two phases of destruction. Histamine would be part of the network mediating the early phase.
Assuntos
Reabsorção Óssea/patologia , Reabsorção Óssea/fisiopatologia , Antagonistas dos Receptores H2 da Histamina/administração & dosagem , Histamina/metabolismo , Osteoclastos/metabolismo , Ovariectomia , Animais , Famotidina/administração & dosagem , Feminino , Osteoclastos/efeitos dos fármacos , Osteoclastos/patologia , Ratos , Ratos Wistar , Cloreto de Sódio/administração & dosagemRESUMO
We have previously postulated that mast cells participate in the cellular network involved in osteoclastic resorption, probably through histamine release. In this study, we examined mast cell activation and histamine release during origination of resorption. Groups of 10 rats were killed 0, 0.5, 1, 1.5, 3, 6, 9, 12 and 18 h after induction of resorption in a synchronized model of cortical resorption along the mandible. The total number of mast cells was transiently decreased by about one-third at 1 and 9 h. Mast cell activation was monitored by Alcian blue-safranin staining. Early after induction, mast cells started to release their mediator stores; complete release led to the apparent disappearance of the cells with the staining technique used. Histamine immunostaining confirmed the release of histamine and its diffusion in the extracellular environment. Massive degranulation was observed at 1.5 and 9 h with toluidine blue staining. Cell recovery, assessed in terms of histidine decarboxylase expression, occurred gradually. The number of ED1+ osteoclast precursors strongly increased from 12 h up to 18 h. Most parameters had returned to baseline at 18 h, except the ED1+ cells. H2 receptor inhibition with famotidine strongly decreased ED1+ osteoclast precursors at 12 h and subsequently osteoclasts at the peak of resorption. These data support a role of mast cells in resorption origination. They show an early and transient intervention of mast cells in the events regulating the recruitment of circulating osteoclast precursors and ultimately of resorption. Mast cell activation and degranulation induce the release of mediators, particularly histamine acting through its H2 receptors, which are likely involved in these reactions.
Assuntos
Reabsorção Óssea , Degranulação Celular , Mastócitos/efeitos dos fármacos , Mastócitos/fisiologia , Animais , Famotidina/farmacologia , Antagonistas dos Receptores H2 da Histamina/farmacologia , Liberação de Histamina/efeitos dos fármacos , Histidina Descarboxilase/metabolismo , Histocitoquímica , Cinética , Masculino , Mandíbula/citologia , Mandíbula/efeitos dos fármacos , Mandíbula/enzimologia , Mandíbula/metabolismo , Mandíbula/fisiologia , Mastócitos/enzimologia , Osteoclastos/efeitos dos fármacos , Ratos , Ratos Wistar , Receptores Histamínicos H2/metabolismoRESUMO
We have previously reported that cimetidine, a reference H2 receptor antagonist, attenuates the initial osteoclastic burst and subsequent trabecular bone loss induced by ovariectomy (ovx) in rats. This study was designed to determine whether these effects are specific to H2 antagonism. To this end, we compared the effects of two H2 receptor antagonists, cimetidine and famotidine. In addition, we analyzed the response of histamine-producing cells to these inhibitors. Seventy-two 90-day-old female Sprague-Dawley rats were ovariectomized or sham-operated, and received single daily intramuscular injections of cimetidine (125 mg/kg), famotidine (10 mg/kg), or vehicle. The animals were killed 14 days after surgery and their femurs were processed for histomorphometry. Trabecular bone volume was reduced by 30% in ovx rats and by 15% in cimetidine- and famotidine-treated rats. Architectural parameters were reduced by about 20% in ovx rats. Cimetidine and famotidine attenuated these consequences of ovx by about 50%. Trabecular connectivity was deteriorated by ovx, while cimetidine and famotidine attenuated this effect. Resorption parameters were increased by ovx, while cimetidine and famotidine prevented this increase. Kinetic bone formation parameters were increased by ovx, while cimetidine and famotidine had no influence. Neither cimetidine nor famotidine had any observable effect in sham-treated rats. Mast cell numbers increased by 250% in ovx rats and by only 40% in H2 antagonists-treated ovx rats. A resident histamine-positive, non-mast cell, population found in bone marrow was increased by 25% by ovx. Interestingly, cimetidine and famotidine reduced this population in both sham-operated and ovx rats, famotidine being more potent than cimetidine. These results show that H(2) receptor blockade partially prevents the consequences of castration on cancellous bone resorption in female rats, and strongly suggest that histamine participates in the mediator network regulating estrogen deficiency induced bone resorption. A large population of histamine-producing cells, which differ morphologically from mast cells and belong to an immature marrow population, may be a source of histamine in this model. The H(2) blockers targeted this population, and this effect appeared to explain the anti-resorptive action of the two drugs.