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1.
ZNF521 Represses Osteoblastic Differentiation in Human Adipose-Derived Stem Cells.
Chiarella, E, Aloisio, A, Scicchitano, S, Lucchino, V, Montalcini, Y, Galasso, O, Greco, M, Gasparini, G, Mesuraca, M, Bond, HM, et al
International journal of molecular sciences. 2018;(12)
Abstract
Human adipose-derived stem cells (hADSCs) are multipotent mesenchymal cells that can differentiate into adipocytes, chondrocytes, and osteocytes. During osteoblastogenesis, the osteoprogenitor cells differentiate into mature osteoblasts and synthesize bone matrix components. Zinc finger protein 521 (ZNF521/Zfp521) is a transcription co-factor implicated in the regulation of hematopoietic, neural, and mesenchymal stem cells, where it has been shown to inhibit adipogenic differentiation. The present study is aimed at determining the effects of ZNF521 on the osteoblastic differentiation of hADSCs to clarify whether it can influence their osteogenic commitment. The enforced expression or silencing of ZNF521 in hADSCs was achieved by lentiviral vector transduction. Cells were cultured in a commercial osteogenic medium for up to 20 days. The ZNF521 enforced expression significantly reduced osteoblast development as assessed by the morphological and molecular criteria, resulting in reduced levels of collagen I, alkaline phosphatase, osterix, osteopontin, and calcium deposits. Conversely, ZNF521 silencing, in response to osteoblastic stimuli, induced a significant increase in early molecular markers of osteogenesis and, at later stages, a remarkable enhancement of matrix mineralization. Together with our previous findings, these results show that ZNF521 inhibits both adipocytic and osteoblastic maturation in hADSCs and suggest that its expression may contribute to maintaining the immature properties of hADSCs.
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2.
Bone metabolic responses to low energy availability achieved by diet or exercise in active eumenorrheic women.
Papageorgiou, M, Martin, D, Colgan, H, Cooper, S, Greeves, JP, Tang, JCY, Fraser, WD, Elliott-Sale, KJ, Sale, C
Bone. 2018;:181-188
Abstract
PURPOSE We aimed to explore the effects of low energy availability (EA)[15 kcal·kg lean body mass (LBM)-1·d-1] achieved by diet or exercise on bone turnover markers in active, eumenorrheic women. METHODS By using a crossover design, ten eumenorrheic women (VO2 peak: 48.1 ± 3.3 ml·kg-1·min-1) completed all three, 3-day conditions in a randomised order: controlled EA (CON; 45 kcal·kgLBM-1·d-1), low EA through dietary energy restriction (D-RES; 15 kcal·kgLBM-1·d-1) and low EA through increasing exercise energy expenditure (E-RES; 15 kcal·kgLBM-1·d-1), during the follicular phase of three menstrual cycles. In CON, D-RES and E-RES, participants consumed diets providing 45, 15 and 45 kcal·kgLBM-1·d-1. In E-RES only, participants completed supervised running sessions (129 ± 10 min·d-1) at 70% of their VO2 peak that resulted in an exercise energy expenditure of 30 kcal·kg LBM-1·d-1. Blood samples were collected at baseline (BASE) and at the end of the 3-day period (D6) and analysed for bone turnover markers (β-CTX and P1NP), markers of calcium metabolism (PTH, albumin-adjusted Ca, Mg and PO4) and hormones (IGF-1, T3, insulin, leptin and 17β-oestradiol). RESULTS In D-RES, P1NP concentrations at D6 decreased by 17% (BASE: 54.8 ± 12.7 μg·L-1, D6: 45.2 ± 9.3 μg·L-1, P < 0.001, d = 0.91) and were lower than D6 concentrations in CON (D6: 52.5 ± 11.9 μg·L-1, P = 0.001). P1NP did not change significantly in E-RES (BASE: 55.3 ± 14.4 μg·L-1, D6: 50.9 ± 15.8 μg·L-1, P = 0.14). β-CTX concentrations did not change following D-RES (BASE: 0.48 ± 0.18 μg·L-1, D6: 0.55 ± 0.17 μg·L-1) or E-RES (BASE: 0.47 ± 0.24 μg·L-1, D6: 0.49 ± 0.18 μg·L-1) (condition × time interaction effect, P = 0.17). There were no significant differences in P1NP (P = 0.25) or β-CTX (P = 0.13) responses between D-RES and E-RES. Both conditions resulted in reductions in IGF-1 (-13% and - 23% from BASE in D-RES and E-RES, both P < 0.01) and leptin (-59% and - 61% from BASE in D-RES and E-RES, both P < 0.001); T3 decreased in D-RES only (-15% from BASE, P = 0.002) and PO4 concentrations decreased in E-RES only (-9%, P = 0.03). CONCLUSIONS Low EA achieved through dietary energy restriction resulted in a significant decrease in bone formation but no change in bone resorption, whereas low EA achieved through exercise energy expenditure did not significantly influence bone metabolism. Both low EA conditions elicited significant and similar changes in hormone concentrations.
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3.
Proliferative and osteogenic differentiation capacity of mesenchymal stromal cells: Influence of harvesting site and donor age.
Prall, WC, Saller, MM, Scheumaier, A, Tucholski, T, Taha, S, Böcker, W, Polzer, H
Injury. 2018;(8):1504-1512
Abstract
Human mesenchymal stromal cells (hMSCs) are the cellular source of new bone formation and an essential component of autologous bone grafts. Autologous bone graft harvesting is routinely conducted at the iliac crest, although alternative donor sites with lower complication rates are available. Thus, the aim of this study was to compare hMSCs harvested from the iliac crest and the proximal tibia regarding their proliferative and osteogenic differentiation capacity. Furthermore, we investigated the influence of donor age on these biological properties. HMSCs were isolated from iliac crest or proximal tibia bone grafts of 46 patients. Proliferative capacity was assessed by cumulative population doublings, population doubling time, colony forming units and cell proliferation assays. Osteogenic capacity was assessed by quantification of extracellular calcium deposition and marker gene expression levels. The number of hMSCs per gram harvested tissue was determined. Furthermore, the adipogenic and chondrogenic differentiation capacity were quantified using BODIPY and Safranin Orange staining, respectively. Additional analyses were carried out after grouping young (18-49 years) and aged (≥50 years) donors. HMSCs derived from the proximal tibia featured a comparable proliferative and osteogenic differentiation capacity. No significant differences were found for any analysis conducted, when compared to hMSCs obtained from the iliac crest. Furthermore, no significant differences could be revealed when comparing young and aged donors. This was equally true for hMSCs from both donor sites after comparison within the same age group. Our study demonstrates comparable biological properties of hMSCs derived from both donor sites, the iliac crest and the proximal tibia. Furthermore, aging does not alter proliferative and osteogenic differentiation capacity. Consequently, the proximal tibia should be considered more closely as an alternative donor site in patients of all age groups.
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4.
Cyclic uniaxial compression of human stem cells seeded on a bone biomimetic nanocomposite decreases anti-osteogenic commitment evoked by shear stress.
Baumgartner, W, Schneider, I, Hess, SC, Stark, WJ, Märsmann, S, Brunelli, M, Calcagni, M, Cinelli, P, Buschmann, J
Journal of the mechanical behavior of biomedical materials. 2018;:84-93
Abstract
OBJECTIVE Chemical supplementation of culture media to induce differentiation of adult stem cells seeded on a scaffold may mask other differentiation triggers such as scaffold stiffness, chemical composition or mechanical stimulation. However, stem cells can be differentiated towards osteoblasts without any supplementation given an appropriate osteogenic scaffold and an adequate mechanical stimulation. MATERIALS AND METHODS Electrospun meshes of poly-lactic-co-glycolic acid and amorphous calcium phosphate nanoparticles (PLGA/aCaP) in a weight ratio of 60:40 were seeded with human adipose-derived stem cells (ASCs) and cultured in DMEM. After two weeks of static cultivation, they were either further cultivated statically for another two weeks (group 1), or placed in a Bose® bioreactor with a flow rate per area of 0.16 mL cm-2 min1 (group 2). Furthermore, group 3 was also cultivated under perfusion, however, with an additional uniaxial cyclic compression. Stiffness of the scaffolds was assessed as a function of time. After a total of four weeks, minimum stem cell criteria markers as well as typical markers for osteogenesis, endothelial cell differentiation, adipogenesis and chondrogenesis were analyzed by quantitative real-time PCR, cell distribution within the scaffolds by histology and protein expression by immunohistochemistry. RESULTS Dynamic conditions (perfusion ± uniaxial cyclic compression) significantly upregulated gene and protein expression of PPAR-γ-2 compared to static cultivation, while osteogenic markers were slightly downregulated. However, the compression in the perfusion bioreactor favored osteogenesis compared to mere perfusion as indicated by upregulation of ALP, Runx2 and collagen I. This behavior was not only attributed to the compressive load, but also to the significant increase in stiffness of the scaffold. Furthermore, CD105 was significantly upregulated under compression. CONCLUSIONS Although an osteogenic electrospun composite material with an organic (PLGA) and an inorganic phase (aCaP nanoparticles) was used as scaffold, the dynamic cultivation as realized by either perfusion alone or an additional compression did not upregulate typical osteogenic genes when compared to static cultivation. In contrast, there was a significant upregulation of the adipogenic gene PPAR-γ-2. However, this anti-osteogenic starting point evoked by mere perfusion was partially reversed by an additional compression. Our findings exemplify that bone tissue engineering using adult stem cells should consider any other differentiations that may be triggered and overwhelm the desired differentiation, although experimental conditions theoretically provide cues to achieve it - like an osteogenic scaffold and mechanical stimulation.
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5.
Osteoporosis in primary biliary cholangitis.
Danford, CJ, Trivedi, HD, Papamichael, K, Tapper, EB, Bonder, A
World journal of gastroenterology. 2018;(31):3513-3520
Abstract
Primary biliary cholangitis (PBC) is an autoimmune cholestatic liver disease with multiple debilitating complications. Osteoporosis is a common complication of PBC resulting in frequent fractures and leading to significant morbidity in this population, yet evidence for effective therapy is lacking. We sought to summarize our current understanding of the pathophysiology of osteoporosis in PBC, as well as current and emerging therapies in order to guide future research directions. A complete search with a comprehensive literature review was performed with studies from PubMed, EMBASE, Web of Science, Cochrane database, and the Countway Library. Osteoporosis in PBC is driven primarily by decreased bone formation, which differs from the increased bone resorption seen in postmenopausal osteoporosis. Despite this fundamental difference, current treatment recommendations are based primarily on experience with postmenopausal osteoporosis. Trials specific to PBC-related osteoporosis are small and have not consistently demonstrated a benefit in this population. As it stands, prevention of osteoporosis in PBC relies on the mitigation of risk factors such as smoking and alcohol use, as well as encouraging a healthy diet and weight-bearing exercise. The primary medical intervention for the treatment of osteoporosis in PBC remains bisphosphonates though a benefit in terms of fracture reduction has never been shown. This review outlines what is known regarding the pathogenesis of bone disease in PBC and summarizes current and emerging therapies.
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6.
Transcriptional Mechanisms of Secondary Fracture Healing.
Roberts, JL, Paglia, DN, Drissi, H
Current osteoporosis reports. 2018;(2):146-154
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Abstract
PURPOSE OF REVIEW Growing evidence supports the critical role of transcriptional mechanisms in promoting the spatial and temporal progression of bone healing. In this review, we evaluate and discuss new transcriptional and post-transcriptional regulatory mechanisms of secondary bone repair, along with emerging evidence for epigenetic regulation of fracture healing. RECENT FINDINGS Using the candidate gene approach has identified new roles for several transcription factors in mediating the reactive, reparative, and remodeling phases of fracture repair. Further characterization of the different epigenetic controls of fracture healing and fracture-driven transcriptome changes between young and aged fracture has identified key biological pathways that may yield therapeutic targets. Furthermore, exogenously delivered microRNA to post-transcriptionally control gene expression is quickly becoming an area with great therapeutic potential. Activation of specific transcriptional networks can promote the proper progression of secondary bone healing. Targeting these key factors using small molecules or through microRNA may yield effective therapies to enhance and possibly accelerate fracture healing.
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7.
Polydatin, Natural Precursor of Resveratrol, Promotes Osteogenic Differentiation of Mesenchymal Stem Cells.
Di Benedetto, A, Posa, F, De Maria, S, Ravagnan, G, Ballini, A, Porro, C, Trotta, T, Grano, M, Muzio, LL, Mori, G
International journal of medical sciences. 2018;(9):944-952
Abstract
Bone loss and fractures are consequences of aging, diseases or traumas. Furthermore the increased number of aged people, due to the rise of life expectancy, needs more strategies to limit the bone loss and regenerate the lost tissue, ameliorating the life quality of patients. A great interest for non-pharmacological therapies based on natural compounds is emerging and focusing on the oligostilbene Polydatin, present in many kinds of fruits and vegetables, when resveratrol particularly in red wines. These molecules have been extensively studied due to their antioxidant and anti-inflammatory effects, showing more recently Resveratrol the ability to enhance osteogenic differentiation and bone formation. However, the clinical applications of Resveratrol are limited due to its low bioavailability and rapid metabolism, while its natural glycosilated precursor Polydatin shows better metabolic stability and major abundance in fresh fruits and vegetables. Nevertheless the role of Polydatin on osteogenic differentiation is still unexplored. Mesenchymal stem cells (MSCs) from dental tissues, such as dental bud stem cells (DBSCs), are able to differentiate toward osteogenic lineage: thus we investigated how Resveratrol and Polydatin influence the differentiation of DBSCs, eventually affecting bone formation. Our results showed that Polydatin increases MSCs osteogenic differentiation sharing similar properties with Resveratrol. These results encourage to deepen the effects of this molecule on bone health and its associated mechanisms of action, wishing for the future a successful use in bone loss prevention and therapy.
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Variation of bone acquisition during growth hormone treatment in children can be explained by proteomic biomarkers, bone formation markers, body composition and nutritional factors.
Swolin-Eide, D, Andersson, B, Hellgren, G, Magnusson, P, Albertsson-Wikland, K
Bone. 2018;:144-153
Abstract
OBJECTIVE Growth hormone (GH) regulates both longitudinal growth and bone acquisition in children, and has profound metabolic effects. The aim was to investigate the association between proteomic biomarkers, body fat, nutrition and bone formation markers, and longitudinal growth in response to GH during the first year of treatment. The degree to which changes in these factors could explain variations in GH-dependent longitudinal growth and bone mineralization was also assessed. METHODS The individualized GH dose trial included 128 short prepubertal children with either normal (non-GH-deficient) or reduced levels of GH secretion (GH-deficient) (mean age ± SD, 8.6 ± 2.6 years; 90 boys), i.e., with a broad range of GH-secretion and GH-responsiveness, receiving GH treatment (mean 43 μg/kg/day). Blood samples were taken and dual-energy X-ray absorptiometry (DXA) measured at baseline and 1 year of treatment. Step-wise multiple regression models were constructed including three steps with different independent variables added at each step to explain the variance in outcome variables (heightSDS, bone mineral content (BMC) and bone mineral density (BMD). Independent variables included in Step I were previously identified proteomic markers related to GH treatment response, bone formation markers (intact PINP, bone-specific alkaline phosphatase and osteocalcin), variables at treatment start (GH dose mU/kg/day, GH maximum secretion, and difference between child's current and mid-parental heightSDS). Step II explored the added influence of body composition data (body mass index or DXA). Step III explored the added influence of serum nutritional markers and hormones. RESULTS Step I variables explained 71% of the variation in first year heightSDS gain, median (minimum-maximum) 0.8 (0.24-1.67); and the proportion explained rose to 73% following inclusion of step II variables and 75% following step III. Corresponding values for total body BMC were 58%, 78%, and 80%, respectively. Proportions fell by approximately 20% when BMC was adjusted for height; 33%, 57%, and 57% for steps I, II, and III, respectively. Corresponding values for total body BMD were 29%, 39%, and 45%, respectively. CONCLUSION For total BMC, as much as 80% of the variation during the first year of GH treatment could be explained by proteomic biomarkers, body fat, nutrition and bone formation markers, whereas for height-adjusted BMC 57% could be explained. The inclusion of information about either body composition (fat/lean mass) or nutritional markers contributed with approximately 20%. The variation in heightSDS gain could be explained to 75%. Hence, information of fat or nutrition markers was needed for explaining the variation in bone acquisition to the same magnitude as explaining the variation in height response.
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Comparing the Effects of Chitosan Scaffolds Containing Various Divalent Metal Phosphates on Osteogenic Differentiation of Stem Cells from Human Exfoliated Deciduous Teeth.
Huang, TY, Su, WT, Chen, PH
Biological trace element research. 2018;(2):316-326
Abstract
Inducing the differentiation of stem cells from human exfoliated deciduous teeth (SHEDs) proceeds with low efficiency, which greatly limits clinical applications. Divalent metal elements play an important role in osteoinductivity for bone remodeling because they can simulate bone formation and decrease bone resorption. The purpose of this study was to investigate the effect of some divalent metal phosphates on osteogenic differentiation from human exfoliated deciduous teeth. These divalent metal ions can be gradually released from the scaffold into the culture medium and continually induce osteoblastic differentiation. Experimental results revealed that SHEDs cultured in chitosan scaffolds containing divalent metal phosphates had notably increased osteoblastic differentiation compared with cells cultured without divalent metal phosphates. This effect was due to the high activity of alkaline phosphatase, as well as the bone-related gene expression of collagen type I, Runx2, osteopontin, osteocalcin, VEGF, and Ang-1, shown through RT-PCR and bone-related protein immunocytochemistry stains. A calcium-content assay further revealed significant enhancement of deposited minerals on the scaffolds after 21 days of culture, particularly for magnesium phosphate and zinc phosphate. Thus, divalent metals, except for barium phosphate, effectively promoted SHED cell differentiation and osteoblastic cell maturation. This study demonstrated that the divalent metal elements magnesium, strontium, and zinc could effectively induce SHED osteoblastic differentiation for use in tissue engineering and bone repair.
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Dissolution behavior of CaO-MgO-SiO2 -based multiphase bioceramic powders and effects of the released ions on osteogenesis.
Zhang, M, Chen, X, Pu, X, Liao, X, Huang, Z, Yin, G
Journal of biomedical materials research. Part A. 2017;(11):3159-3168
Abstract
In the present study, the dissolution behavior of the CaO-MgO-SiO2 -based multiphase bioceramic powders as well as the effects of released ions on osteogenesis was investigated. In the dissolution process, Ca, Mg, and Si ions could be dissolved out from the powders. The incorporation of Mg could slow down the degradation rate of the powders so that to reduce the local concentration of Ca and Si ions. In return, the dissolution of Ca and Si ions leading to the formation of a porous SiO2 -rich layer could enhance the readsorption of free Mg ions in solution and thus down-regulate the concentration of Mg ions. In addition, the released ions exhibited both positive and negative synergistic effects on osteogenesis with a concentration-dependent manner. Trace amount of released Si ions could stimulate cell proliferation and osteogenic differentiation in the presence of Ca and Mg ions. The optimal concentration of Ca-Mg-Si ion combination to promote osteogenesis was existed in the 1/4 diluted extract, whereas a slightly inhibitory effect on cell proliferation and ALP activity was observed in the 1/2 diluted extract with higher concentration of Ca and Si ions . All above results suggested that the ion dissolution behavior of the CaO-MgO-SiO2 -based multiphase bioceramic could be regulated via adjustment of the composition so that released ions could be maintained at an appropriate composite concentration to cooperatively regulate the osteogenesis. This research provided an experimental basis for further optimization and application of CaO-MgO-SiO2 -based multiphase bioceramics with controlled ion dissolution and excellent physicochemical and biological properties. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 3159-3168, 2017.