Enhanced osteoporotic bone regeneration by strontium-substituted calcium silicate bioactive ceramics.
TL;DR: In vivo experiments revealed that SrCS dramatically stimulated bone regeneration and angiogenesis in a critical sized OVX calvarial defect model, and the enhanced bone regeneration might be attributed to the modulation of osteogenic differentiation of endogenous mesenchymal stem cells (MSCs) and the inhibition of osteoclastogenesis, accompanying with the promotion of the angiogenic activity of endothelial cells (ECs).
About: This article is published in Biomaterials.The article was published on 2013-12-01. It has received 295 citations till now. The article focuses on the topics: Bone regeneration & Bone resorption.
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TL;DR: In this paper, the authors provide an overview of materials-design considerations for bone-tissue-engineering applications in both disease modelling and treatment of injuries and disease in humans, and highlight scalable technologies that can fabricate natural and synthetic biomaterials (polymers, bioceramics, metals and composites) into forms suitable for bone tissue engineering applications in human therapies and disease models.
Abstract: Successful materials design for bone-tissue engineering requires an understanding of the composition and structure of native bone tissue, as well as appropriate selection of biomimetic natural or tunable synthetic materials (biomaterials), such as polymers, bioceramics, metals and composites. Scalable fabrication technologies that enable control over construct architecture at multiple length scales, including three-dimensional printing and electric-field-assisted techniques, can then be employed to process these biomaterials into suitable forms for bone-tissue engineering. In this Review, we provide an overview of materials-design considerations for bone-tissue-engineering applications in both disease modelling and treatment of injuries and disease in humans. We outline the materials-design pathway from implementation strategy through selection of materials and fabrication methods to evaluation. Finally, we discuss unmet needs and current challenges in the development of ideal materials for bone-tissue regeneration and highlight emerging strategies in the field. Design of bone-tissue-engineering materials involves consideration of multiple, often conflicting, requirements. This Review discusses these considerations and highlights scalable technologies that can fabricate natural and synthetic biomaterials (polymers, bioceramics, metals and composites) into forms suitable for bone-tissue-engineering applications in human therapies and disease models.
630 citations
TL;DR: A comprehensive review of the state of the art of bone biomaterials and their interactions with stem cells is presented and the promising seed stem cells for bone repair are summarized, and their interaction mechanisms are discussed in detail.
Abstract: Bone biomaterials play a vital role in bone repair by providing the necessary substrate for cell adhesion, proliferation, and differentiation and by modulating cell activity and function. In past decades, extensive efforts have been devoted to developing bone biomaterials with a focus on the following issues: (1) developing ideal biomaterials with a combination of suitable biological and mechanical properties; (2) constructing a cell microenvironment with pores ranging in size from nanoscale to submicro- and microscale; and (3) inducing the oriented differentiation of stem cells for artificial-to-biological transformation. Here we present a comprehensive review of the state of the art of bone biomaterials and their interactions with stem cells. Typical bone biomaterials that have been developed, including bioactive ceramics, biodegradable polymers, and biodegradable metals, are reviewed, with an emphasis on their characteristics and applications. The necessary porous structure of bone biomaterials for the cell microenvironment is discussed, along with the corresponding fabrication methods. Additionally, the promising seed stem cells for bone repair are summarized, and their interaction mechanisms with bone biomaterials are discussed in detail. Special attention has been paid to the signaling pathways involved in the focal adhesion and osteogenic differentiation of stem cells on bone biomaterials. Finally, achievements regarding bone biomaterials are summarized, and future research directions are proposed.
464 citations
TL;DR: It is demonstrated that the application of hiPSC-MSC-Exos+β-TCP scaffolds promoted bone regeneration in critical-sized calvarial defects by enhancing angiogenesis and osteogenesis in an ovariectomized rat model.
Abstract: Bone defects caused by trauma, severe infection, tumor resection and skeletal abnormalities are common osteoporotic conditions and major challenges in orthopedic surgery, and there is still no effective solution to this problem. Consequently, new treatments are needed to develop regeneration procedures without side effects. Exosomes secreted by mesenchymal stem cells (MSCs) derived from human induced pluripotent stem cells (hiPSCs, hiPSC-MSC-Exos) incorporate the advantages of both MSCs and iPSCs with no immunogenicity. However, there are no reports on the application of hiPSC-MSC-Exos to enhance angiogenesis and osteogenesis under osteoporotic conditions. HiPSC-MSC-Exos were isolated and identified before use. The effect of hiPSC-MSC-Exos on the proliferation and osteogenic differentiation of bone marrow MSCs derived from ovariectomized (OVX) rats (rBMSCs-OVX) in vitro were investigated. In vivo, hiPSC-MSC-Exos were implanted into critical size bone defects in ovariectomized rats, and bone regeneration and angiogenesis were examined by microcomputed tomography (micro-CT), sequential fluorescent labeling analysis, microfil perfusion and histological and immunohistochemical analysis. The results in vitro showed that hiPSC-MSC-Exos enhanced cell proliferation and alkaline phosphatase (ALP) activity, and up-regulated mRNA and protein expression of osteoblast-related genes in rBMSCs-OVX. In vivo experiments revealed that hiPSC-MSC-Exos dramatically stimulated bone regeneration and angiogenesis in critical-sized calvarial defects in ovariectomized rats. The effect of hiPSC-MSC-Exos increased with increasing concentration. In this study, we showed that hiPSC-MSC-Exos effectively stimulate the proliferation and osteogenic differentiation of rBMSCs-OVX, with the effect increasing with increasing exosome concentration. Further analysis demonstrated that the application of hiPSC-MSC-Exos+β-TCP scaffolds promoted bone regeneration in critical-sized calvarial defects by enhancing angiogenesis and osteogenesis in an ovariectomized rat model.
352 citations
Cites methods from "Enhanced osteoporotic bone regenera..."
...Next, the sections were stained with van Gieson’s picrofuchsin to evaluate new bone formation, with red areas representing new bone formation, and black areas representing β-TCP [37]....
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...At 2, 4 and 6 weeks after the craniotomies, the rats were intraperitoneally injected with tetracycline (TE, 25 mg/kg of body weight), alizarin red (AL, 30 mg/kg of body weight) and calcein (CA, 20 mg/kg of body weight), and the mineralized tissue was observed by the trichromatic sequential fluorescent labeling method [37]....
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...Sp) were automatically determined to confirm the osteoporotic model, while the BMD and BV/TV values in the defect regions were used to evaluate new bone formation using the auxiliary software (Scanco) [37]....
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TL;DR: A review of recent literature has revealed that several ions are uniquely capable of inducing stem cell differentiation down desired lineages and there exists enormous promise for these ions to be used in bone regenerative medicine.
228 citations
TL;DR: The results are the first to elucidate the specific effect of each ion from bioceramics on osteogenesis, osteoclastogenesis and angiogenesis for osteoporotic bone regeneration, paving the way for the design of functional biomaterials with complex compositions for tissue engineering and regenerative medicine.
194 citations
Cites background or methods or result from "Enhanced osteoporotic bone regenera..."
...Moreover, patients with osteoporosis exhibit low bone mass, poor bone strength and microarchitectural deterioration of bone, which may increase the risks of fractures and bone defects [5-7]....
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...16-week-old female Sprague-Dawley (SD) rats and confirmed by measurements of body weight and bone mineral density (BMD) of lumbar at 3 months postoperatively as described in previous studies [7, 23, 24]....
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...Recent studies also showed that Sr-substituted calcium silicate (SrCS) bioceramics displayed the improved in vitro and in vivo osteogenesis [7]....
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...It has been reported that the proliferation and osteogenic differentiation of osteoblasts could be increased by Sr and Si ions released from Sr-substituted bioactive glasses and bioceramics [7]....
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...days, CCK8 assay was performed as described in previous studies [7, 24]....
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References
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TL;DR: Vascular endothelial growth factor (VEGF) is a key regulator of physiological angiogenesis during embryogenesis, skeletal growth and reproductive functions and is implicated in pathologicalAngiogenesis associated with tumors, intraocular neovascular disorders and other conditions.
Abstract: Vascular endothelial growth factor (VEGF) is a key regulator of physiological angiogenesis during embryogenesis, skeletal growth and reproductive functions. VEGF has also been implicated in pathological angiogenesis associated with tumors, intraocular neovascular disorders and other conditions. The biological effects of VEGF are mediated by two receptor tyrosine kinases (RTKs), VEGFR-1 and VEGFR-2, which differ considerably in signaling properties. Non-signaling co-receptors also modulate VEGF RTK signaling. Currently, several VEGF inhibitors are undergoing clinical testing in several malignancies. VEGF inhibition is also being tested as a strategy for the prevention of angiogenesis, vascular leakage and visual loss in age-related macular degeneration.
8,942 citations
TL;DR: Nonenzymatic mechanisms that impact MAP kinase functions and findings from gene disruption studies are highlighted and particular emphasis is on ERK1/2.
Abstract: Mitogen-activated protein (MAP) kinases comprise a family of ubiquitous proline-directed, protein-serine/threonine kinases, which participate in signal transduction pathways that control intracellular events including acute responses to hormones and major developmental changes in organisms. MAP kinases lie in protein kinase cascades. This review discusses the regulation and functions of mammalian MAP kinases. Nonenzymatic mechanisms that impact MAP kinase functions and findings from gene disruption studies are highlighted. Particular emphasis is on ERK1/2.
4,040 citations
"Enhanced osteoporotic bone regenera..." refers background in this paper
...The ERK and p38 are considered to control multiple cellular processes, such as cell proliferation, division, differentiation, apoptosis and embryogenesis [47,48], and have not been reported as the involved molecular mechanisms for bone regeneration induced by Sr- and Sicomponents under osteoporotic animal model....
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TL;DR: Multicellular organisms have three well-characterized subfamilies of mitogen-activated protein kinases (MAPKs) that control a vast array of physiological processes, and inhibitors of these enzymes are being explored as anticancer agents.
Abstract: Multicellular organisms have three well-characterized subfamilies of mitogen-activated protein kinases (MAPKs) that control a vast array of physiological processes. These enzymes are regulated by a characteristic phosphorelay system in which a series of three protein kinases phosphorylate and activate one another. The extracellular signal-regulated kinases (ERKs) function in the control of cell division, and inhibitors of these enzymes are being explored as anticancer agents. The c-Jun amino-terminal kinases (JNKs) are critical regulators of transcription, and JNK inhibitors may be effective in control of rheumatoid arthritis. The p38 MAPKs are activated by inflammatory cytokines and environmental stresses and may contribute to diseases like asthma and autoimmunity.
3,999 citations
"Enhanced osteoporotic bone regenera..." refers background in this paper
...The ERK and p38 are considered to control multiple cellular processes, such as cell proliferation, division, differentiation, apoptosis and embryogenesis [47,48], and have not been reported as the involved molecular mechanisms for bone regeneration induced by Sr- and Sicomponents under osteoporotic animal model....
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TL;DR: Novel treatment strategies have been developed that aim to inhibit excessive bone resorption and increase bone formation and the most promising novel treatments include denosumab, a monoclonal antibody for receptor activator of NF-κB ligand; odanacatib, a specific inhibitor of the osteoclast protease cathepsin K; and antibodies against the proteins sclerostin and dickkopf-1, two endogenous inhibitors of bone formation.
1,792 citations
TL;DR: Treatment of postmenopausal osteoporosis with strontium ranelate leads to early and sustained reductions in the risk of vertebral fractures.
Abstract: background Osteoporotic structural damage and bone fragility result from reduced bone formation and increased bone resorption. In a phase 2 clinical trial, strontium ranelate, an orally active drug that dissociates bone remodeling by increasing bone formation and decreasing bone resorption, has been shown to reduce the risk of vertebral fractures and to increase bone mineral density. methods To evaluate the efficacy of strontium ranelate in preventing vertebral fractures in a phase 3 trial, we randomly assigned 1649 postmenopausal women with osteoporosis (low bone mineral density) and at least one vertebral fracture to receive 2 g of oral strontium ranelate per day or placebo for three years. We gave calcium and vitamin D supplements to both groups before and during the study. Vertebral radiographs were obtained annually, and measurements of bone mineral density were performed every six months. results New vertebral fractures occurred in fewer patients in the strontium ranelate group than in the placebo group, with a risk reduction of 49 percent in the first year of treatment and 41 percent during the three-year study period (relative risk, 0.59; 95 percent confidence interval, 0.48 to 0.73). Strontium ranelate increased bone mineral density at month 36 by 14.4 percent at the lumbar spine and 8.3 percent at the femoral neck (P<0.001 for both comparisons). There were no significant differences between the groups in the incidence of serious adverse events. conclusions Treatment of postmenopausal osteoporosis with strontium ranelate leads to early and sustained reductions in the risk of vertebral fractures.
1,582 citations