Fluoxetine treatment increases trabecular bone formation in mice
ABSTRACT Mounting evidence exists for the operation of a functional serotonin (5-HT) system in osteoclasts and osteoblasts, which involves both receptor activation and 5-HT reuptake. In previous work we showed that the serotonin transporter (5-HTT) is expressed in osteoclasts and that its activity is required by for osteoclast differentiation in vitro. The purpose of the current study was to determine the effect of treatment with fluoxetine, a specific serotonin reuptake inhibitor, on bone metabolism in vivo. Systemic administration of fluoxetine to Swiss-Webster mice for 6 weeks resulted in increased trabecular BV and BV/TV in femurs and vertebrae as determined by micro-computed tomography (microCT). This correlated with an increase in trabecular number, connectivity, and decreased trabecular spacing. Fluoxetine treatment also resulted in increased volume in vertebral trabecular bone. However, fluoxetine-treated mice were not protected against bone loss after ovariectomy, suggesting that its anabolic effect requires the presence of estrogen. The effect of blocking the 5-HTT on bone loss following an LPS-mediated inflammatory challenge was also investigated. Subcutaneous injections of LPS over the calvariae of Swiss-Webster mice for 5 days resulted in increased numbers of osteoclasts and net bone loss, whereas new bone formation and a net gain in bone mass was seen when LPS was given together with fluoxetine. We conclude that fluoxetine treatment in vivo leads to increased bone mass under normal physiologic or inflammatory conditions, but does not prevent bone loss associated with estrogen deficiency. These data suggest that commonly used anti-depressive agents may affect bone mass.
- SourceAvailable from: Joaquim Evencio-Neto
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- "Other experimental evidence has also revealed that 5-HT may influence embryogenesis and growth 23 . Battaglino et al. (2007) 24 reported reduced cortical bone and trabecular bone mass in rats treated with fluoxetine, and concluded that fluoxetine inhibits normal bone growth in rats. Those authors claimed that 5-HT plays an important role in the differentiation of osteoblasts and osteocytes, and that interference of 5-HT by fluoxetine could reduce bone mass. "
ABSTRACT: AIM: To evaluate the morphological aspects of coronal dentinogenesis in the first molars of 1- and 5-day-old rats whose mothers were treated with fluoxetine hydrochloride during pregnancy.METHODS: Twelve pregnant Wistar rats were divided randomly into three groups: group C (control), group FL (fluoxetine administered at 10 mg/kg bodyweight), and group FX (fluoxetine administered at 20 mg/kg bodyweight). Saline (0.9%) solution or fluoxetine hydrochloride was administered subcutaneously for the first 21 days of pregnancy. Subsequently, the offspring of these animals was subdivided into subgroups according to age of tooth germ development to be studied: 1 and 5 days of life. C1 and C5 (control group 1 and 5 days of age); FL1 and FL5 (groups treated with 10 mg/kg fluoxetine at 1 and 5 days of age); FX5 and FX1 (groups treated with 20 mg/ kg fluoxetine at 1 and 5 days of age).RESULTS: No structural changes in the dentin-pulp complex of rats whose mothers were treated with fluoxetine hydrochloride were observed at either dose.CONCLUSIONS: Fluoxetine, at the doses administered during pregnancy in this study, did not alter the morphological development of the coronal dentin-pulp complex in their offspring.Brazilian Journal of Oral Sciences 03/2013; 12(1):30-36. DOI:10.1590/S1677-32252013000100007
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- "Although correlative in nature, these studies showed that an increase in extracellular concentration of blood serotonin in patients on SSRI's may explain their often observed low bone mass phenotype . However, the influence of this gut-bone axis on bone mass could not explain the increase in bone mass observed in another study with SSRI's . In our quest to understand the serotonin regulation of bone mass in vertebrates we inactivatedTph2, the gene that catalyzes the rate-limiting step in the biosynthesis of BDS. "
ABSTRACT: The adipocyte-derived hormone leptin inhibits appetite and bone mass accrual. To fulfill these two functions leptin requires the integrity of hypothalamic neurons but not the expression of its receptor, ObRb on these neurons. These results suggested that leptin acts first elsewhere in the brain to mediate these functions. However, this neuroanatomical site of leptin action in the brain remained elusive. Recent mouse genetic, electrophysiological and neuroanatomical studies provide evidence that leptin inhibits appetite and bone mass accrual through a two-step pathway: it decreases synthesis and the release by brainstem neurons of serotonin that in turn targets hypothalamic neurons to regulate appetite and bone mass accrual.Aging 11/2009; 1(11):954-6. · 6.43 Impact Factor
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- "For mCT imaging, fixed calvaria were imaged and analyzed using a compact fan-beam-type tomograph (mCT 40, Scanco Medical AG, Brüttisellen, Switzerland) as previously described (Battaglino et al., 2007). Samples were located in an airtight cylindrical sample holder filled with formalin. "
ABSTRACT: High [HCO(3)(-)] inhibits and low [HCO(3)(-)] stimulates bone resorption, which mediates part of the effect of chronic acidosis or acid feeding on bone. Soluble adenylyl cyclase (sAC) is a bicarbonate sensor that can potentially mediate the effect of bicarbonate on osteoclasts. Osteoclasts were incubated in 0, 12, and 24 mM HCO(3)(-) at pH 7.4 for 7-8 days and assayed for tartrate-resistant acid phosphatase (TRAP) and vacuolar-ATPase expression, and H+ accumulation. Total number and area of TRAP (+) multinucleated osteoclasts was decreased by HCO(3)(-) in a dose-dependent manner. V-ATPase expression and H+ accumulation normalized to cell cross-sectional area or protein were not significantly changed. The HCO(3)(-) -induced inhibition of osteoclast growth and differentiation was blocked by either 2-hydroxyestradiol, an inhibitor of sAC or sAC knockdown by sAC specific siRNA. The model of HCO(3)(-) inhibiting osteoclast via sAC was further supported by the fact that the HCO(3)(-) dose-response on osteoclasts is flat when cells were saturated with 8-bromo-cAMP, a permeant cAMP analog downstream from sAC thus simulating sAC activation. To confirm our in vitro findings in intact bone, we developed a 1-week mouse calvaria culture system where osteoclasts were shown to be viable. Bone volume density (BV/TV) determined by micro-computed tomography (microCT), was higher in 24 mM HCO(3)(-) compared to 12 mM HCO(3)(-) treated calvaria. This HCO(3)(-) effect on BV/TV was blocked by 2-hydroxyestradiol. In summary, sAC mediates the inhibition of osteoclast function by HCO(3)(-), by acting as a HCO(3)(-) sensor.Journal of Cellular Physiology 08/2009; 220(2):332-40. DOI:10.1002/jcp.21767 · 3.84 Impact Factor