Effects of Insulin Resistance Induced by Dexamethasone on Bone Mass in Ovariectomized Rats
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Abstract:
Glucocorticoids therapy is the most common cause of secondary iatrogenic osteoporosis.The bone loss occurs predominantly due to a decrease in bone formation, although increased bone resorption also occurs. Insulin resistance is the key pathology in type 2 diabetes negatively influence bone remodeling and leads to reduced bone strength. Loss of sex steroids, particularly oestradiol, as in ovariectomized rats,leads to increased skeletal remodeling over and above the age-related increment, together with excessive osteoclast activity. In this study, ovariectomy DEX group has highly significant increase in relative cortical resorptioncompared to ovaiectomy and sham DEX groups, also ovariectomy and DEX group has highly significant decrease in bone thickness compared to ovariectomy and sham DEX groups. The consequent increase in remodeling activation increases the overall resorption rate without a compensatory increase in formation, leading to rapid bone loss.This negative effect on bone which is due to the glucocorticoid excess is also mediated by indirect mechanisms such as the calcium malabsorption and hypercalciuria. In response to the enhanced supply of calcium from the skeleton, PTH secretion tends to be diminished, thereby reducing vitamin D [1,25(OH)2 cholecalciferol] concentration with a consequent reduction in calcium absorption.Keywords:
Bone remodeling
Osteopenia
Abstract Excessive RANKL signaling leads to superfluous osteoclast formation and bone resorption, is widespread in the pathologic bone loss and destruction. Therefore, targeting RANKL or its signaling pathway has been a promising and successful strategy for this osteoclast-related diseases. In this study, we examined the effects of xanthohumol (XN), an abundant prenylflavonoid from hops plant, on osteoclastogenesis, osteoclast resorption and RANKL-induced signaling pathway using both in vitro and in vivo assay systems. In mouse and human, XN inhibited osteoclast differentiation and osteoclast formation at the early stage. Furthermore, XN inhibited osteoclast actin-ring formation and bone resorption in a dose-dependent manner. In ovariectomized-induced bone loss mouse model and RANKL-injection-induced bone resorption model, we found that administration of XN markedly inhibited bone loss and resorption by suppressing osteoclast activity. At the molecular level, XN disrupted the association of RANK and TRAF6, resulted in the inhibition of NF-κB and Ca 2+ /NFATc1 signaling pathway during osteoclastogenesis. As a results, XN suppressed the expression of osteoclastogenesis-related marker genes, including CtsK, Nfatc1, Trap, Ctr . Therefore, our data demonstrated that XN inhibits osteoclastogenesis and bone resorption through RANK/TRAF6 signaling pathways. XN could be a promising drug candidate in the treatment of osteoclast-related diseases such as postmenopausal osteoporosis.
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There are accumulating studies reporting that vitamin E in general exhibits bone protective effects. This systematic review, however discusses the effects of a group of vitamin E isomers, tocotrienols in preventing bone loss through osteoclast differentiation and activity suppression.This review is aimed to discuss the literature reporting the effects of tocotrienols on osteoclasts, the cells specialized for resorbing bone.Out of the total 22 studies from the literature search, only 11 of them were identified as relevant, which comprised of eight animal studies, two in vitro studies and only one combination of both. The in vivo studies indicated that tocotrienols improve the bone health and reduce bone loss via inhibition of osteoclast formation and resorption activity, which could be through regulation of RANKL and OPG expression as seen from their levels in the sera. This is well supported by data from the in vitro studies demonstrating the suppression of osteoclast formation and resorption activity following treatment with tocotrienol isomers.Thus, tocotrienols are suggested to be potential antioxidants for prevention and treatment of bone-related diseases characterized by increased bone loss.
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A screening method for anti-osteoporotics using ovariectomized rats was designed using a compact method to monitor the bone density. It was found that ovariectomy (OVX) of Wister female rats (11 weeks old) induced acute and focal osteopenia within 2 weeks, which responded well to intermittent salmon calcitonin (SCT : 5 and 20 U/kg, s.c., every other day) employed as the standard anti-osteoporotic and injected up to 4 weeks with or without a delay of 2 weeks after OVX.
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