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A systematic study was carried out in order to identify the optimum processing conditions for the preparation of PLA 3D porous structures applying foaming with supercritical C[O.sub.2] (sc-C[O.sub.2]). Both the depressurization rate and the C[O.sub.2] saturation pressure had a significant effect on the obtained sc-C[O.sub.2] PLA structures. When sc-C[O.sub.2] was instantaneously depressurized, a thin wall pore structure was formed, characterized by anisotropy with pores diameter ranging from 100 to 650 [micro]m, whereas the scaffold porosity varied between 85% and 95%. In this case, a decrease in the porosity percentage was observed with increasing saturation pressure. A trend of increase in the pores' size was recorded from 150 to 200 bar, followed by a decrease at 300 bar. Highly organized pore structures with thicker pore walls and pores with diameters within the range of 10-350 [micro]m and porosity and 74%-77% were fabricated when a slow depressurization rate was applied. An optimum porous structure, with average pore diameter 340 [micro]m and porosity 88% was prepared when [P.sub.sat] was maintained at 200 bar, followed by instantaneous depressurization. Although this scaffold included the biggest number of closed pores in its structure, it presented the highest degree of pore interconnectivity due to C[O.sub.2] bubbles' coalescence. KEYWORDS biodegradable scaffolds, foaming, micr[degrees]CT, poly(lactic acid), scanning electron microscopy, super critical C[O.sub.2], 1 | INTRODUCTION In many tissue-engineering applications, three-dimensional (3D), interconnected porous scaffolds, are broadly utilized as functional replacements for damaged tissues or organs. [1] Those scaffolds are required to be [...]

Bone marrow adipose tissue (BMAT) accrues in osteoporosis, whereas its contribution to the progression of bone resorption remains insufficiently understood. To understand the mechanisms that promote BMAT expansion in osteoporosis, in the present study, we performed extensive analysis of the spatiotemporal pattern of BMAT expansion during the progression of bone resorption in TgRANKL transgenic mouse models of osteoporosis expressing human RANKL (receptor activator of nuclear factor‐κB ligand). Our results showed that TgRANKL mice of both sexes developed dramatically increased BMAT expansion compared to wild‐type (WT) littermates, that was analogous to the levels of RANKL expression and the severity of the bone loss phenotype. BMAT was formed at close proximity to areas undergoing active bone remodelling and bone resorption, whereas bone resorption preceded BMAT development. Expression analysis in bone fractions demonstrated that BMAT constitutes a major source for RANKL production. Ex vivo analysis of isolated bone marrow stromal cells from TgRANKL mice showed an increased adipogenic differentiation capacity compared to WT, while osteoclast supernatants further exaggerated adipogenesis, supporting a critical role of the osteoclast‐derived secretome in the differentiation of bone marrow adipocytes. Furthermore, the effectiveness of an antiosteoporosis treatment in BMAT development was investigated upon treatment of TgRANKL models with the bisphosphonate alendronate. Notably, alendronate effectively improved bone mass and attenuated BMAT expansion, indicating a possible involvement of osteoclasts and bone resorption in BMAT development. On the contrary, inhibition of BMAT with PPARγ antagonists (GW9662 or BADGE) effectively ameliorated BMAT expansion but failed to reverse the osteoporotic phenotype of TgRANKL mice. Overall, our data demonstrate that TgRANKL mice constitute unique genetic mouse models for investigating the pathogenic mechanisms that regulate the development and expansion of BMAT in osteolytic diseases. [ABSTRACT FROM AUTHOR]

Mandible is a bony structure of neuroectodermal origin with unique characteristics that support dentition and jaw movements. In the present study, we investigated the effects of gestational exposure to a mixture of endocrine-disrupting chemicals (EDCs) on mandibular growth in mice. The mixture under study (Mixture N1) has been associated with neurodevelopmental effects in both a human cohort and animal studies. Pregnant mice were exposed throughout gestation to 0.5× (times of pregnant women's exposure levels), 10×, 100× and 500× of Mixture N1, or the vehicle, and the mandibles of the male offspring were studied in adulthood. Micro-CT analysis showed non-monotonic effects of Mixture N1 in the distances between specific mandibular landmarks and in the crown width of M1 molar, as well as changes in the mandibular bone characteristics. The alveolar bone volume was reduced, and the trabecular separation was increased in the 500× exposed mice. Bone volume in the condyle head was increased in all treated groups. Τhe Safranin-O-stained area of mature hypertrophic chondrocytes and the width of their zones were reduced in 0.5×, 10× and 100× exposed groups. This is the first indication that prenatal exposure to an epidemiologically defined EDC mixture, associated with neurodevelopmental impacts, can also affect mandibular growth in mammals. [ABSTRACT FROM AUTHOR]

Receptor activator of nuclear factor-κB ligand (RANKL) has been actively pursued as a therapeutic target for osteoporosis, given that RANKL is the master mediator of bone resorption as it promotes osteoclast differentiation, activity and survival. We employed a structure-based virtual screening approach comprising two stages of experimental evaluation and identified 11 commercially available compounds that displayed dose-dependent inhibition of osteoclastogenesis. Their inhibitory effects were quantified through TRAP activity at the low micromolar range (IC50 < 5 μΜ), but more importantly, 3 compounds displayed very low toxicity (LC50 > 100 μΜ). We also assessed the potential of an N-(1-aryl-1H-indol-5-yl)aryl-sulfonamide scaffold that was based on the structure of a hit compound, through synthesis of 30 derivatives. Their evaluation revealed 4 additional hits that inhibited osteoclastogenesis at low micromolar concentrations; however, cellular toxicity concerns preclude their further development. Taken together with the structure–activity relationships provided by the hit compounds, our study revealed potent inhibitors of RANKL-induced osteoclastogenesis of high therapeutic index, which bear diverse scaffolds that can be employed in hit-to-lead optimization for the development of therapeutics against osteolytic diseases. [ABSTRACT FROM AUTHOR]

A systematic study was carried out in order to identify the optimum processing conditions for the preparation of PLA 3D porous structures applying foaming with supercritical CO2 (sc‐CO2). Both the depressurization rate and the CO2 saturation pressure had a significant effect on the obtained sc‐CO2 PLA structures. When sc‐CO2 was instantaneously depressurized, a thin wall pore structure was formed, characterized by anisotropy with pores diameter ranging from 100 to 650 μm, whereas the scaffold porosity varied between 85% and 95%. In this case, a decrease in the porosity percentage was observed with increasing saturation pressure. A trend of increase in the pores' size was recorded from 150 to 200 bar, followed by a decrease at 300 bar. Highly organized pore structures with thicker pore walls and pores with diameters within the range of 10–350 μm and porosity and 74%–77% were fabricated when a slow depressurization rate was applied. An optimum porous structure, with average pore diameter 340 μm and porosity 88% was prepared when Psat was maintained at 200 bar, followed by instantaneous depressurization. Although this scaffold included the biggest number of closed pores in its structure, it presented the highest degree of pore interconnectivity due to CO2 bubbles' coalescence. [ABSTRACT FROM AUTHOR]

Glucocorticoids are used widely on a long-term basis in autoimmune and inflammatory diseases. Their adverse effects include the development of hyperglycemia and osteoporosis, whose molecular mechanisms have been only partially studied in preclinical models. Both these glucocorticoid-induced pathologies have been shown to be mediated at least in part by oxidative stress. The transcription factor nuclear erythroid factor 2-like 2 (NRF2) is a central regulator of antioxidant and cytoprotective responses. Thus, we hypothesized that NRF2 may play a role in glucocorticoid-induced metabolic disease and osteoporosis. To this end, WT and Nrf2 knockout (Nrf2KO) mice of both genders were treated with 2 mg/kg dexamethasone or vehicle 3 times per week for 13 weeks. Dexamethasone treatment led to less weight gain during the treatment period without affecting food consumption, as well as to lower glucose levels and high insulin levels compared to vehicle-treated mice. Dexamethasone also reduced cortical bone volume and density. All these effects of dexamethasone were similar between male and female mice, as well as between WT and Nrf2KO mice. Hepatic NRF2 signaling and gluconeogenic gene expression were not affected by dexamethasone. A 2-day dexamethasone treatment was also sufficient to increase insulin levels without affecting body weight and glucose levels. Hence, dexamethasone induces hyperinsulinemia, which potentially leads to decreased glucose levels, as well as osteoporosis, both independently of NRF2. [ABSTRACT FROM AUTHOR]