Background: Although antiretroviral agents trigger bone loss in human immunodeficiency virus patients, tenofovir disoproxil fumarate (TDF) induces more severe bone damage, such as osteoporosis. While, the mechanisms are unclear, probiotic supplements may be effective against osteoporosis. Methods: C57BL6/J mice were administered with Lactobacillus rhamnosus GG (LGG)+TDF, TDF, and zoledronic acid+TDF, respectively. Bone morphometry and biomechanics were evaluated using microcomputed tomography, bone slicing, and flexural tests. The lymphocyte, proinflammatory cytokines, and intestinal permeability levels were detected using enzyme-linked immunosorbent assays, quantitative real-time polymerase chain reaction, and flow cytometry. The gut microbiota composition and metabolomics were analyzed using 16S recombinant deoxyribonucleic acid pyrosequencing and ultra-performance liquid-chromatography–quadrupole time-of-flight mass spectrometry. Results: LGG administered orally induced marked increases in trabecular bone microarchitecture, cortical bone volume, and biomechanical properties in the LGG+TDF group compared with that in the TDF-only group. Moreover, LGG treatment increased intestinal barrier integrity, expanded regulatory T cells, decreased Th17 cells, and downregulated osteoclastogenesis-related cytokines in the bone marrow, spleen, and gut. Furthermore, LGG reconstructed the gut microbiota and changed the metabolite composition, especially lysophosphatidylcholine levels. However, the amount of N-acetyl-leukotriene E4 was the highest in the TDF-only group. Conclusion: LGG reconstructed the community structure of the gut microbiota, promoted the expression of lysophosphatidylcholines, and improved intestinal integrity to suppress the TDF-induced inflammatory response, which resulted in attenuation of TDF-induced bone loss in mice. LGG probiotics may be a safe and effective strategy to prevent and treat TDF-induced osteoporosis.
Introduction To repair bone defects, a variety of bone substitution materials have been used, such as ceramics, metals, natural and synthetic polymers, and combinations thereof. In recent decades, a wide range of synthetic polymers have been used for bone regeneration. These polymers have the advantages of biocompatibility, biodegradability, good mechanical properties, low toxicity, and ease of processing. However, when used alone, they are unable to achieve ideal bone formation. Incorporating zinc (Zn) into synthetic polymers has been considered, as previous studies have shown that Zn2+ promotes stem cell osteogenesis and mineral deposition. The purpose of this systematic review was to provide an overview of the application and effectiveness of Zn in synthetic polymers for bone regeneration, whether used alone or in combination with other biomaterials. This study was performed according to the PRISMA guidelines. Materials and methods A search of the PubMed, Embase, and the Cochrane Library databases for articles published up to June 2020 revealed 153 relevant studies. After screening the titles, abstracts, and full texts, 13 articles were included in the review; 9 of these were in vitro, 3 were in vivo, and 1 included both in vitro and in vivo experiments. Results At low concentrations, Zn2+ promoted cell proliferation and osteogenic differentiation, while high-dose Zn2+ resulted in cytotoxicity and inhibition of osteogenic differentiation. Additionally, one study showed that Zn2+ reduced apatite formation in simulated body fluid. In all of the in vivo experiments, Zn-containing materials enhanced bone formation. Conclusions At appropriate concentrations, Zn-doped synthetic polymer materials are better able to promote bone regeneration than materials without Zn.
Poly-ε-caprolactone (PCL) is a promising synthetic material in bone tissue engineering (BTE). Particularly, the introduction of rapid prototyping (RP) represents the possibility of manufacturing PCL scaffolds with customized appearances and structures. Bio-Oss is a natural bone mineral matrix with significant osteogenic effects; however, it has limitations in being constructed and maintained into specific shapes and sites. In this study, we used RP and fabricated a hollow-structured cage-shaped PCL scaffold loaded with Bio-Oss to form a hybrid scaffold for BTE. Moreover, we adopted NaOH surface treatment to improve PCL hydrophilicity and enhance cell adhesion. The results showed that the NaOH-treated hybrid scaffold could enhance the osteogenesis of human bone marrow-derived mesenchymal stem cells (hBMMSCs) both in vitro and in vivo. Altogether, we reveal a novel hybrid scaffold that not only possesses osteoinductive function to promote bone formation but can also be fabricated into specific forms. This scaffold design may have great application potential in bone tissue engineering.
Background As the representative of fenamic acids, an important group of NSAIDs, flufenamic acid (FFA) has been used for anti-inflammation and analgesia in the clinic. Recently, researches have focused on the role of some members of NSAIDs in promoting osteogenesis. However, little attention has been paid to the subgroup of fenamic acids, and it remains unclear whether FFA and other fenamic acids could regulate mesenchymal stem cells’ (MSCs) lineage commitment and bone regeneration. Methods Here we treated two kinds of human MSCs with FFA at different concentrations in vitro and examined the effect of FFA on osteogenic differentiation of human MSCs. This was followed by heterotopic bone formation assay in nude mice. In addition, ovariectomized and aged mice were used as osteoporotic models to test the effect of FFA on osteoporosis. Besides, activators and inhibitor of nuclear factor-κB (NF-κB) signaling pathway and western blot were used to clarify the mechanism of the promoting effect of low concentration FFA on osteogenesis. Results Our results indicated that low concentrations of FFA could significantly enhance osteogenic differentiation of human MSCs in vitro, as well as in vivo. In addition, FFA treatment suppressed bone loss in ovariectomized and aged mice. Mechanistically, FFA at low concentrations promoted osteogenesis differentiation of human MSCs by inhibition of the NF-κB signaling pathway. Conclusions Collectively, our study suggested that low concentration FFA could be used in bone tissue engineering or osteoporosis by promoting osteogenic differentiation of human MSCs. Electronic supplementary material The online version of this article (10.1186/s13287-019-1321-y) contains supplementary material, which is available to authorized users.
Background: D-mannose exhibits strong anti-inflammatory properties, but whether it has beneficial effects on preventing and treating osteoporosis remains unknown. Methods: Female, 12-month-old senile C57BL6/J mice (s-Man group) and 8-week-old ovariectomized C57BL6/J mice (OVX-Man group) were treated with D-mannose in drinking water for 2 months (six mice/group). Microcomputed tomography analysis and hematoxylin and eosin staining were performed to investigate the effect of D-mannose on attenuation of bone loss. Tartrate-resistant acid phosphatase staining of tissue sections, flow cytometry, enzyme-linked immunosorbent assay, quantitative real-time polymerase chain reaction, and gut microbiome biodiversity tests were used to explore the underlying mechanisms. Results: D-mannose-induced marked increases in cortical bone volume and trabecular bone microarchitecture in the s-Man and OVX-Man group compared with that in the s-CTRL (senile control) and OVX group, respectively. Moreover, D-mannose downregulated osteoclastogenesis-related cytokines in the bone marrow and expanded regulatory T cells in the spleen of mice. Furthermore, D-mannose reconstructed the gut microbiota and changed the metabolite composition. Conclusion: D-mannose attenuated bone loss induced by senility and estrogen deficiency in mice, and this effect may be mediated by D-mannose-induced proliferation of regulatory T cells and gut microbiota-dependent anti-inflammatory effects.
Background: Bone defects are a common clinical condition that has gained an increasing amount of attention in recent years. Causes of bone defect include tumors, inflammation, and fractures. Bone tissue engineering is a novel treatment of bone defect, and human mesenchymal stem cells (hMSCs) are the ideal seed cells for bone tissue engineering due to their multi-lineage differentiation potential and immunogenicity. The laminin α2 (LAMA2) gene encodes the α2 subunit of laminins. Mutations in this gene have been reported to cause muscular dystrophy, but thus far no studies have elucidated the role of LAMA2 in the fate choices of MSCs. Here, we aimed to investigate the critical role of LAMA2 in the osteogenesis and adipogenesis of mesenchymal stem cells (MSCs). Methods: We investigated LAMA2 function in osteogenic and adipogenic differentiation of MSCs in vitro and in vivo through loss-and gain-of-function experiments. In addition, molecular mechanism was clarified by Western blot and siRNA. Results: Our results demonstrated that LAMA2 was a critical regulator for fate commitment of MSCs. Both in vitro and in vivo studies indicate that LAMA2 inhibits osteogenesis and promotes adipogenesis. Mechanistically, we found that LAMA2 regulated osteogenesis and adipogenesis of MSCs by modulating the hedgehog signaling pathway. Conclusions: The present work confirms that LAMA2 is a new molecular target for MSC-based bone regeneration.
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