Diets rich in fruits and vegetables with many antioxidants can be very important in the prevention and treatment of osteoporosis. Studies show that oxidative stress, often due to lack of antioxidants, is involved in alteration of bone remodeling and reduction in bone density. This study demonstrates in human osteoblast-like SaOS-2 cells that blueberry juice (BJ), containing 7.5 or 15 μg∙mL−1 total soluble polyphenols (TSP), is able to prevent the inhibition of osteogenic differentiation and the mineralization process due to oxidative stress induced by glutathione depletion. This situation mimics a metabolic condition of oxidative stress that may occur during estrogen deficiency. The effect of BJ phytochemicals occurs through redox- and non-redox-regulated mechanisms. BJ protects from oxidative damage factors related to bone remodeling and bone formation, such as alkaline phosphatase and Runt-related transcription factor 2. It upregulates these factors by activation of sirtuin type 1 deacetylase expression, a possible molecular target for anti-osteoporotic drugs. Quantitative analysis of TSP in BJ shows high levels of anthocyanins with high antioxidant capacity and bioavailability. These novel data may be important to elucidate the molecular and cellular beneficial effects of blueberry polyphenols on bone regeneration, and they suggest their use as a dietary supplement for osteoporosis prevention and therapies.

Osteoporosis is characterized by the alteration of bone homeostasis due to an imbalance between osteoclastic bone resorption and osteoblastic bone formation. Estrogen deficiency causes bone loss and postmenopausal osteoporosis, the pathogenesis of which also involves oxidative stress, inflammatory processes, and the dysregulation of the expression of microRNAs (miRNAs) that control gene expression at post-transcriptional levels. Oxidative stress, due to an increase in reactive oxygen species (ROS), proinflammatory mediators and altered levels of miRNAs enhance osteoclastogenesis and reduce osteoblastogenesis through mechanisms involving the activation of MAPK and transcription factors. The present review summarizes the principal molecular mechanisms involved in the role of ROS and proinflammatory cytokines on osteoporosis. Moreover, it highlights the interplay among altered miRNA levels, oxidative stress, and an inflammatory state. In fact, ROS, by activating the transcriptional factors, can affect miRNA expression, and miRNAs can regulate ROS production and inflammatory processes. Therefore, the present review should help in identifying targets for the development of new therapeutic approaches to osteoporotic treatment and improve the quality of life of patients.

Classically, a secosteroid hormone, vitamin D, has been implicated in calcium and phosphate homeostasis and has been associated with the pathogenesis of rickets and osteomalacia in patients with severe nutritional vitamin D deficiency. The spectrum of known vitamin D-mediated effects has been expanded in recent years. However, the mechanisms of how exactly this hormone elicits its biological function are still not fully understood. The interaction of this metabolite with the vitamin D receptor (VDR) and, subsequently, with the vitamin D-responsive element in the region of specific target genes leading to the transcription of genes whose protein products are involved in the traditional function of calcitriol (known as genomic actions). Moreover, in addition to these transcription-dependent mechanisms, it has been recognized that the biologically active form of vitamin D3, as well as its immediate precursor metabolite, calcifediol, initiate rapid, non-genomic actions through the membrane receptors that are bound as described for other steroid hormones. So far, among the best candidates responsible for mediating rapid membrane response to vitamin D metabolites are membrane-associated VDR (VDRm) and protein disulfide isomerase family A member 3 (Pdia3). The purpose of this paper is to provide an overview of the rapid, non-genomic effects of calcifediol and calcitriol, whose elucidation could improve the understanding of the vitamin D3 endocrine system. This will contribute to a better recognition of the physiological acute functions of vitamin D3, and it could lead to the identification of novel therapeutic targets able to modulate these actions.

The discovery that osteocytes secrete phosphaturic fibroblast growth factor 23 (FGF23) has defined bone as an endocrine organ. However, the autocrine and paracrine functions of FGF23 are still unknown. The present study focuses on the cellular and molecular mechanisms involved in the complex control of FGF23 production and local bone remodeling functions. FGF23 was assayed using ELISA kit in the presence or absence of 17β–estradiol in starved MLO-Y4 osteocytes. In these cells, a relationship between oxidative stress-induced apoptosis and up-regulation of active FGF23 levels due to MAP Kinases activation with involvement of the transcriptional factor (NF-kB) has been demonstrated. The active FGF23 increase can be due to up-regulation of its expression and post-transcriptional modifications. 17β–estradiol prevents the increase of FGF23 by inhibiting JNK and NF-kB activation, osteocyte apoptosis and by the down-regulation of osteoclastogenic factors, such as sclerostin. No alteration in the levels of dentin matrix protein 1, a FGF23 negative regulator, has been determined. The results of this study identify biological targets on which drugs and estrogen may act to control active FGF23 levels in oxidative stress-related bone and non-bone inflammatory diseases.

Several recent studies have demonstrated that the direct precursor of vitamin D3, the calcifediol [25(OH)D3], through the binding to the nuclear vitamin D receptor (VDR), is able to regulate the expression of many genes involved in several cellular processes. Considering that itself may function as a VDR ligand, although with a lower affinity, respect than the active form of vitamin D, we have assumed that 25(OH)D3 by binding the VDR could have a vitamin’s D3 activity such as activating non-genomic pathways, and in particular we selected mesenchymal stem cells derived from human adipose tissue (hADMSCs) for the in vitro assessment of the intracellular Ca2+ mobilization in response to 25(OH)D3. Our result reveals the ability of 25(OH)D3 to activate rapid, non-genomic pathways, such as an increase of intracellular Ca2+ levels, similar to what observed with the biologically active form of vitamin D3. hADMSCs loaded with Fluo-4 AM exhibited a rapid and sustained increase in intracellular Ca2+ concentration as a result of exposure to 10−5 M of 25(OH)D3. In this work, we show for the first time the in vitro ability of 25(OH)D3 to induce a rapid increase of intracellular Ca2+ levels in hADMSCs. These findings represent an important step to better understand the non-genomic effects of vitamin D3 and its role in endocrine system.