Osteoporosis: An Age-Related and Gender-Specific Disease – A Mini-Review

Osteoporosis, a classical age-related disease and known to be more common in women than in men, has been reported increasingly often in men during the past few years. Although men at all ages after puberty have larger bones than women, resulting in greater bending strength, mortality after a hip fracture, one of the major complications of osteoporosis, is more common in men than in women. Sex hormone deficiency is associated with unrestrained osteoclast activity and bone loss. Even though estrogen deficiency is more pronounced in women, it appears to be a major factor in the pathogenesis of osteoporosis in both genders. In contrast to osteoporosis in postmenopausal women, the treatment of osteoporosis in men has been scarcely reported. Nevertheless, some drugs commonly used for the treatment of osteoporosis in women also appear to be effective in men. The aim of this study is to review primary osteoporosis in the elderly with particular emphasis on gender-related aspects.Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich

Glucocorticoids suppress Wnt16 expression in osteoblasts in vitro and in vivo

Glucocorticoid-induced osteoporosis is a frequent complication of systemic glucocorticoid (GC) therapy and mainly characterized by suppressed osteoblast activity. Wnt16 derived from osteogenic cells is a key determinant of bone mass. Here, we assessed whether GC suppress bone formation via inhibiting Wnt16 expression. GC treatment with dexamethasone (DEX) decreased Wnt16 mRNA levels in murine bone marrow stromal cells (mBMSCs) time- and dose-dependently. Similarly, Wnt16 expression was also suppressed after DEX treatment in calvarial organ cultures. Consistently, mice receiving GC-containing slow-release prednisolone pellets showed lower skeletal Wnt16 mRNA levels and bone mineral density than placebo-treated mice. The suppression of Wnt16 by GCs was GC-receptor-dependent as co-treatment of mBMSCs with DEX and the GR antagonist RU-486 abrogated the GC-mediated suppression of Wnt16. Likewise, DEX failed to suppress Wnt16 expression in GR knockout-mBMSCs. In addition, Wnt16 mRNA levels were unaltered in bone tissue of GC-treated GR dimerization-defective GRdim mice, suggesting that GCs suppress Wnt16 via direct DNA-binding mechanisms. Consistently, DEX treatment reduced Wnt16 promoter activity in MC3T3-E1 cells. Finally, recombinant Wnt16 restored DEX-induced suppression of bone formation in mouse calvaria. Thus, this study identifies Wnt16 as a novel target of GC action in GC-induced suppression of bone formation

Treatment of critical bone defects using calcium phosphate cement and mesoporous bioactive glass providing spatiotemporal drug delivery

Calcium phosphate cements (CPC) are currently widely used bone replacement materials with excellent bioactivity, but have considerable disadvantages like slow degradation. For critical-sized defects, however, an improved degradation is essential to match the tissue regeneration, especially in younger patients who are still growing. We demonstrate that a combination of CPC with mesoporous bioactive glass (MBG) particles led to an enhanced degradation in vitro and in a critical alveolar cleft defect in rats. Additionally, to support new bone formation the MBG was functionalized with hypoxia conditioned medium (HCM) derived from rat bone marrow stromal cells. HCM-functionalized scaffolds showed an improved cell proliferation and the highest formation of new bone volume. This highly flexible material system together with the drug delivery capacity is adaptable to patient specific needs and has great potential for clinical translation

Postembryonic development and aging of the appendicular skeleton in Ambystoma mexicanum

Background: The axolotl is a key model to study appendicular regeneration. The limb complexity resembles that of humans in structure and tissue components; however, axolotl limbs develop postembryonically. In this work, we evaluated the postembryonic development of the appendicular skeleton and its changes with aging. Results: The juvenile limb skeleton is formed mostly by Sox9/Col1a2 cartilage cells. Ossification of the appendicular skeleton starts when animals reach a length of 10 cm, and cartilage cells are replaced by a primary ossification center, consisting of cortical bone and an adipocyte-filled marrow cavity. Vascularization is associated with the ossification center and the marrow cavity formation. We identified the contribution of Col1a2-descendants to bone and adipocytes. Moreover, ossification progresses with age toward the epiphyses of long bones. Axolotls are neotenic salamanders, and still ossification remains responsive to l-thyroxine, increasing the rate of bone formation. Conclusions: In axolotls, bone maturation is a continuous process that extends throughout their life. Ossification of the appendicular bones is slow and continues until the complete element is ossified. The cellular components of the appendicular skeleton change accordingly during ossification, creating a heterogenous landscape in each element. The continuous maturation of the bone is accompanied by a continuous body growth.Fil: Riquelme Guzmán, Camilo. Technische Universität Dresden; AlemaniaFil: Schuez, Maritta. Technische Universität Dresden; AlemaniaFil: Böhm, Alexander. Technische Universität Dresden; AlemaniaFil: Knapp, Dunja. Technische Universität Dresden; AlemaniaFil: Edwards Jorquera, Sandra. Technische Universität Dresden; AlemaniaFil: Ceccarelli, Alberto Sebastián. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física de Líquidos y Sistemas Biológicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física de Líquidos y Sistemas Biológicos; ArgentinaFil: Chara, Osvaldo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Argentina de la Empresa; Argentina. Technische Universität Dresden; AlemaniaFil: Rauner, Martina. Universitätsklinikum Carl Gustav Carus; AlemaniaFil: Sandoval Guzmán, Tatiana. Universitätsklinikum Carl Gustav Carus; Alemania. Technische Universität Dresden; Alemani

Osteoprotegerin production by breast cancer cells is suppressed by dexamethasone and confers resistance against TRAIL-induced apoptosis

ABSTRACT Osteoprotegerin (OPG) is a decoy receptor for receptor activator of NF-kB ligand (RANKL) and TNF-related apoptosis-inducing ligand (TRAIL). While RANKL is essential for osteoclastogenesis and facilitates breast cancer migration into bone, TRAIL promotes breast cancer apoptosis. We analyzed the expression of OPG and TRAIL and its modulation in estrogen receptor-positive MCF-7 cells and receptor-negative MDA-MB-231 cells. In both cells, OPG mRNA levels and protein secretion were dose-and time-dependently enhanced by interleukin (IL)-1b and suppressed by dexamethasone. In contrast to MCF-7 cells, MDA-MB-231 abundantly expressed TRAIL mRNA, which was enhanced by IL-1b and inhibited by dexamethasone. TRAIL activated pro-apoptotic caspase-3, -7, and poly-ADP-ribose polymerase and decreased cell numbers of MDA-MB-231, but had no effect on MCF-7 cells. Gene silencing siRNA directed against OPG resulted in a 31% higher apoptotic rate compared to non-target siRNA-treated MDA-MB-231 cells. Furthermore, TRAIL induced significantly less apoptosis in cells cultured in conditioned media (containing OPG) compared to cells exposed to TRAIL in fresh medium lacking OPG ( P < 0.01) and these protective effects were reversed by blocking OPG with its specific ligand RANKL ( P < 0.05). The association between cancer cell survival and OPG production by MDA-MB-231 cells was further supported by the finding, that modulation of OPG secretion using IL-1b or dexamethasone prior to TRAIL exposure resulted in decreased and increased rate of apoptosis, respectively ( P < 0.05). Thus, OPG secretion by breast cancer cells is modulated by cytokines and dexamethasone, and may represent a critical resistance mechanism that protects against TRAIL-induced apoptosis

Aspalathin from Aspalathus linearis (rooibos) reduces osteoclast activity and increases osteoblast activity in vitro

Bone remodelling in a healthy body is in constant balance, maintaining an adaptive and robust skeletal system. In osteoporosis this balance is disrupted with the rates of osteoclastic bone resorption exceeding osteoblastic bone formation, resulting in lower bone mineral density. Rooibos tea, is a popular South African drink made from Aspalathus linearis leaves grown in the Western Cape. This tea is rich in phenolic compounds which have been widely investigated in recent years as a potential treatment for many ailments. In this study, aspalathin, a phenolic compound found exclusively in rooibos, increases osteoblast formation and function including increased osteoblast marker expression and mineralisation. In addition, aspalathin decreased differentiation and function of osteoclasts as well as reducing osteoclast formation in an osteoclast/osteoblast co-culture model. These results illustrate bone-protective effects of aspalathin in vitro through the reduction of osteoclast activity and promotion of osteoblast activity, with potential applications in the maintenance of bone density.The University of Pretoria Postgraduate Study Abroad Bursary Program, the Institute for Food, Nutrition, and Well-being, University of Pretoria, and Biocom Biotech, Centurion, South Africa.https://www.elsevier.com/locate/jffam2020Human NutritionPhysiolog

Increased pore size of scaffolds improves coating efficiency with sulfated hyaluronan and mineralization capacity of osteoblasts

Background: Delayed bone regeneration of fractures in osteoporosis patients or of critical-size bone defects after tumor resection are a major medical and socio-economic challenge. Therefore, the development of more effective and osteoinductive biomaterials is crucial. Methods: We examined the osteogenic potential of macroporous scaffolds with varying pore sizes after biofunctionalization with a collagen/high-sulfated hyaluronan (sHA3) coating in vitro. The three-dimensional scaffolds were made up from a biodegradable three-armed lactic acid-based macromer (TriLA) by cross-polymerization. Templating with solid lipid particles that melt during fabrication generates a continuous pore network. Human mesenchymal stem cells (hMSC) cultivated on the functionalized scaffolds in vitro were investigated for cell viability, production of alkaline phosphatase (ALP) and bone matrix formation. Statistical analysis was performed using student's t-test or two-way ANOVA. Results: We succeeded in generating scaffolds that feature a significantly higher average pore size and a broader distribution of individual pore sizes (HiPo) by modifying composition and relative amount of lipid particles, macromer concentration and temperature for cross-polymerization during scaffold fabrication. Overall porosity was retained, while the scaffolds showed a 25% decrease in compressive modulus compared to the initial TriLA scaffolds with a lower pore size (LoPo). These HiPo scaffolds were more readily coated as shown by higher amounts of immobilized collagen (+ 44%) and sHA3 (+ 25%) compared to LoPo scaffolds. In vitro, culture of hMSCs on collagen and/or sHA3-coated HiPo scaffolds demonstrated unaltered cell viability. Furthermore, the production of ALP, an early marker of osteogenesis (+ 3-fold), and formation of new bone matrix (+ 2.5-fold) was enhanced by the functionalization with sHA3 of both scaffold types. Nevertheless, effects were more pronounced on HiPo scaffolds about 112%. Conclusion: In summary, we showed that the improvement of scaffold pore sizes enhanced the coating efficiency with collagen and sHA3, which had a significant positive effect on bone formation markers, underlining the promise of using this material approach for in vivo studies. © 2019 The Author(s)

Transferrin receptor 2 controls bone mass and pathological bone formation via BMP and Wnt signalling

Transferrin receptor 2 (Tfr2) is mainly expressed in the liver and controls iron homeostasis. Here, we identify Tfr2 as a regulator of bone homeostasis that inhibits bone formation. Mice lacking Tfr2 display increased bone mass and mineralization independent of iron homeostasis and hepatic Tfr2. Bone marrow transplantation experiments and studies of cell-specific Tfr2 knockout mice demonstrate that Tfr2 impairs BMP-p38MAPK signaling and decreases expression of the Wnt inhibitor sclerostin specifically in osteoblasts. Reactivation of MAPK or overexpression of sclerostin rescues skeletal abnormalities in Tfr2 knockout mice. We further show that the extracellular domain of Tfr2 binds BMPs and inhibits BMP-2-induced heterotopic ossification by acting as a decoy receptor. These data indicate that Tfr2 limits bone formation by modulating BMP signaling, possibly through direct interaction with BMP either as a receptor or as a co-receptor in a complex with other BMP receptors. Finally, the Tfr2 extracellular domain may be effective in the treatment of conditions associated with pathological bone formation

Exploiting Mass Spectrometry to Unlock the Mechanism of Nanoparticle-Induced Inflammasome Activation

Nanoparticles (NPs) elicit sterile inflammation, but the underlying signaling pathways are poorly understood. Here, we report that human monocytes are particularly vulnerable to amorphous silica NPs, as evidenced by single-cell-based analysis of peripheral blood mononuclear cells using cytometry by time-of-flight (CyToF), while silane modification of the NPs mitigated their toxicity. Using human THP-1 cells as a model, we observed cellular internalization of silica NPs by nanoscale secondary ion mass spectrometry (nanoSIMS) and this was confirmed by transmission electron microscopy. Lipid droplet accumulation was also noted in the exposed cells. Furthermore, time-of-flight secondary ion mass spectrometry (ToF-SIMS) revealed specific changes in plasma membrane lipids, including phosphatidylcholine (PC) in silica NP-exposed cells, and subsequent studies suggested that lysophosphatidylcholine (LPC) acts as a cell autonomous signal for inflammasome activation in the absence of priming with a microbial ligand. Moreover, we found that silica NPs elicited NLRP3 inflammasome activation in monocytes, whereas cell death transpired through a non-apoptotic, lipid peroxidation-dependent mechanism. Together, these data further our understanding of the mechanism of sterile inflammation