Fractures and injuries pertaining to bone tissue usually take prolonged periods for its natural healing. To overcome this problem, the field of bone tissue engineering (BTE) has acquired an efficient ...designing mechanism that incorporates cells, biomaterials and the corresponding growth factors to promote both osteogenesis as well as mineralization of the bone. Amidst the various techniques available for scaffold creation, electrospinning is considered superior as it paves the way for the creation of nanostructured scaffolds using biopolymers. Chitosan (CS) and Gelatin (Gel) are two of the cardinal natural biopolymers used in the field of biomaterials and tissue engineering. They can be used either exclusively or in combination with other biopolymers for the enhancement of bone regeneration. Hence, this review aims to render an elaborate study on the CS and Gel-based nanofibrous scaffolds with and without additional composites and the properties that they portray in terms of BTE.
Bone is a highly vascularized tissue that relies on a close spatial and temporal interaction between blood vessels and bone cells. As a result, angiogenesis is critical for bone formation and ...healing. The vascular system supports bone regeneration by delivering oxygen, nutrients, and growth factors, as well as facilitating efficient cell–cell contact. Most clinical applications of engineered bone grafts are hampered by insufficient vascularization after implantation. Over the last decade, a number of flavonoids have been reported to have osteogenic–angiogenic potential in bone regeneration because of their excellent bioactivity, low cost, availability, and minimal in vivo toxicity. During new bone formation, the osteoinductive nature of certain flavonoids is involved in regulating multiple signaling pathways contributing toward the osteogenic–angiogenic coupling. This review briefly outlines the osteogenic–angiogenic potential of those flavonoids and the mechanisms of their action in promoting bone regeneration. However, further studies are needed to investigate their delivery strategies and establish their clinical efficacy.
Flavonoids such as Icariin, Quercetin and few others exhibit angiogenic‐osteogenic coupling. These compounds stimulate the expression of genes regulating osteogenesis and operate as autocrine signals, promoting bone cell repair and survival while simultaneously stimulating angiogenesis in a paracrine manner. The angiogenic‐osteogenic potential of many such flavonoids is yet to be untapped and are scope for future research in the field of bone tissue engineering
Transforming growth factor beta 1 (TGF-β1) functions as a coupling factor between bone development and resorption. Matrix metalloproteinase 13 (MMP13) is important in bone remodeling, and skeletal ...dysplasia is caused by a deficiency in MMP13 expre-ssion. Runx2, a transcription factor is essential for bone development, and MMP13 is one of its target genes. TGF-β1 promoted Runx2 phosphorylation, which was necessary for MMP13 production in osteoblastic cells, as we previously shown. Since the phosphorylation of some proteins causes them to be degraded by the ubiquitin/proteasome pathway, we hypothesized that TGF-β1 might stabilize the phosphorylated Runx2 protein for its activity by other post-translational modification (PTM). This study demonstrated that TGF-β1-stimulated Runx2 acetylation in rat osteoblastic cells. p300, a histone acetyltransferase interacted with Runx2, and it promoted Runx2 acetylation upon TGF-β1-treatment in these cells. Knockdown of p300 decreased the TGF-β1-stimulated Runx2 acetylation and MMP13 expression in rat osteoblastic cells. TGF-β1-treatment stimulated the acetylated Runx2 bound at the MMP13 promoter, and knockdown of p300 reduced this effect in these cells. Overall, our studies identified the transcriptional regulation of MMP13 by TGF-β1 via Runx2 acetylation in rat osteoblastic cells, and these findings contribute to the knowledge of events presiding bone metabolism.
Bone tissue engineering is an alternative strategy to generate bone utilizing a combination of biomaterials and cells. Biomaterials that mimic the structure and composition of bone tissues at ...nanoscale are important for the development of bone tissue engineering applications. Natural or biopolymer-based composites containing chitin, chitosan, or collagen have advantages such as biocompatibility, biodegradability that are essential for bone tissue engineering. The inclusion of nanoparticles of hydroxyapatite (one of the most widely used bioceramic materials) into the biopolymer matrix improves the mechanical properties and incorporates the nanotopographic features that mimic the nanostructure of bone. This review summarizes the recent work on the development of biocomposites containing natural polymers with hydroxyapatite particles suitable for use in bone defects/bone regeneration.
Transforming growth factor‐beta1 (TGF‐β1), a highly abundant growth factor in skeletal tissues, stimulates matrix metalloproteinase‐13 (MMP‐13) expression in osteoblastic cells. MMP‐13 plays a ...critical role in bone remodeling. Runx2, a bone transcription factor, is required for TGF‐β1‐mediated stimulation of MMP‐13 expression in osteoblastic cells. In this study, the molecular mechanism responsible for TGF‐β1‐stimulation of MMP‐13 expression via Runx2 in osteoblastic cells was elucidated. TGF‐β1 stimulated the phosphorylation of Runx2 at serine amino acids, and ERK inhibition blocked this effect in rat (UMR106‐01) and human (MG‐63) osteoblastic cells. Pretreatment with okadaic acid, a serine‐threonine phosphatase inhibitor, increased Runx2 serine phosphorylation in osteoblastic cells. When cells were pretreated with an ERK inhibitor, TGF‐β1‐mediated stimulation of MMP‐13 mRNA expression decreased. Nano‐ESI/LC/MS analysis identified that TGF‐β1 stimulates Runx2 phosphorylation at three serine amino acids. Transient transfection of mouse mesenchymal stem cells (C3H10T1/2) with Runx2 serine mutant constructs decreased TGF‐β1‐mediated Runx2 serine phosphorylation. A luciferase reporter assay identified that TGF‐β1 stimulated MMP‐13 promoter activity in these cells only in the presence of the wild Runx2 construct, and not with mutant Runx2. Thus, TGF‐β1 stimulates the phosphorylation of Runx2 at three serine amino acids, and this event is required for MMP‐13 expression in osteoblastic cells. Hence, this study contributes to the knowledge of events governing bone remodeling and bone‐related diseases.
A schematic diagram representing the TGF‐β1‐induced stimulation of ERK‐dependent Runx2 phosphorylation, with the corresponding sites, required for MMP‐13 promoter activation in human osteoblast cells.
Parathyroid hormone (PTH) acts on osteoblasts and functions as an essential regulator of calcium homeostasis and as a mediator of bone remodeling. We previously reported that PTH stimulates the ...expression of matrix metalloproteinase‐13 (MMP‐13) in rat osteoblasts and that MMP‐13 plays a key role in bone remodeling, endochondral bone formation, and bone repair. Recent evidence indicated that microRNAs (miRNAs) have regulatory functions in bone metabolism. In this study, we hypothesized that the down‐regulation of miRNAs that target MMP‐13 by PTH leads to the stimulation of MMP‐13 expression in osteoblasts. We used various bioinformatic tools to identify miRNAs that putatively target rat MMP‐13. Among these miRNAs, the expression of miR‐532‐5p in rat osteoblasts decreased at 4 h of PTH‐treatment, whereas MMP‐13 mRNA expression was maximal at the same time point. When an miR‐532‐5p mimic was transiently transfected into UMR‐106‐01 cells, MMP‐13 mRNA and protein expression decreased. Using a luciferase reporter assay system, we also identified that miR‐532‐5p directly targeted the 3′ UTRs of MMP‐13 gene. Based on these results, we suggest that PTH‐induced down‐regulation of miR‐532‐5p resulted in the stimulation of MMP‐13 expression in rat osteoblasts. This study identified a significant role of miRNA in controlling bone remodeling via PTH‐stimulated MMP‐13 expression. This finding enhances our understanding of bone metabolism and bone‐related diseases and it could provide information regarding the usage of miRNAs as therapeutic agents or biomarkers.
PTH‐induced down‐regulation of miR‐532‐5p resulted in the stimulation of MMP‐13 expression in rat osteoblasts. This study identified a significant role of miRNA in controlling bone remodeling via PTH‐stimulated MMP‐13 expression.
Nanogels are cross-linked hydrogel nanoparticles with a three-dimensional, tunable porous structure that merges the best features of hydrogels and nanoparticles, including the ability to retain their ...hydrated nature and to swell and shrink in response to environmental changes. Nanogels have attracted increasing attention for use in bone tissue engineering as scaffolds for growth factor transport and cell adhesion. Their three-dimensional structures allow the encapsulation of a wide range of hydrophobic and hydrophilic drugs, enhance their half-life, and impede their enzymatic breakdown
in vivo
. Nanogel-based scaffolds are a viable treatment modality for enhanced bone regeneration. They act as carriers for cells and active ingredients capable of controlled release, enhanced mechanical support, and osteogenesis for enhanced bone tissue regeneration. However, the development of such nanogel constructs might involve combinations of several biomaterials to fabricate active ingredients that can control release, enhance mechanical support, and facilitate osteogenesis for more effective bone tissue regeneration. Hence, this review aims to highlight the potential of nanogel-based scaffolds to address the needs of bone tissue engineering.
This review summarizes the potential of nanogel-based scaffolds to address the needs of bone tissue engineering.
The microporous films comprised of chitosan (CS), gelatin (Gel) and magnesium oxide nanoparticles (MgO NPs) were developed as a wound-healing material using the lyophilization technique. The chemical ...structure, composition and morphology of the films were evaluated by FTIR, XRD, EDX and SEM. Also, the swelling, mechanical, biodegradation, cell viability, antimicrobial property, bioactivity and cell migration capability of the porous films were determined to evaluate their suitability as a wound-dressing material. The average diameter of pores and porosity of the films were in the range of 73 − 103 μm and 57 − 78%, respectively, based on the content of MgO NPs. Compared to control CS/Gel film, the CS/Gel/MgO films presented improved swelling behavior, mechanical strength, antimicrobial activity against the strains of bacteria and fungi and controlled in vitro degradation. Among the developed films, CS/Gel/MgO films containing 1 wt. % of MgO NPs demonstrated an increased biocompatibility, bioactivity and cell migration ability. These results indicated that the porous films based on CS/Gel/MgO could be a competent dermal substitute for wound healing application.
Matrix metalloproteinase‐13 (MMP‐13) plays a predominant role in endochondral bone formation and bone remodeling. Parathyroid hormone (PTH) stimulates the expression of MMP‐13 via Runx2, a bone ...transcription factor in rat osteoblastic cells (UMR106‐01), and histone deacetylase 4 (HDAC4) acts as a corepressor of Runx2. Moreover, microRNAs (miRNAs) play an important role in regulating genes posttranscriptionally. Here, we hypothesized that PTH upregulates the miRNAs targeting HDAC4, which could lead to increased Runx2 activity and MMP‐13 expression in rat osteoblastic cells. We identified several miRNAs that putatively target rat HDAC4 using bioinformatics tools. miR‐873‐3p was significantly upregulated by PTH in rat osteoblasts. miR‐873‐3p overexpression downregulated HDAC4 protein expression, increased Runx2 binding at the MMP‐13 promoter, and increased MMP‐13 messenger RNA expression in UMR106‐01 cells. A luciferase reporter assay identified the direct targeting of miR‐873‐3p at the 3′‐untranslated region of HDAC4. Thus, miR‐873‐3p targeted HDAC4 and relieved the corepressor effect of HDAC4 on Runx2 for MMP‐13 expression in rat osteoblasts. This study advances our knowledge of posttranscriptional gene regulation occurring in bone and bone‐related diseases and clarifies the role of miRNAs as diagnostic biomarkers.
Parathyroid hormone stimulates the expression of matrix metalloproteinase‐13 (MMP‐13) via Runx2, a bone transcription factor in rat osteoblasts, and histone deacetylase 4 (HDAC4) acts as a corepressor of Runx2. miR‐873‐3p targeted HDAC4 and relieved the corepressor effect of HDAC4 on Runx2 for MMP‐13 expression in rat osteoblasts.
Bone is a flexible and electro active tissue that is vulnerable to various traumatic injuries. The self-healing of damaged bone tissue towards reconstruction is limited due to the lack of proper ...niche compliances. Nevertheless, the classical grafting techniques like autograft/allograft for bone repair pose challenges like bacterial infections and donor-site morbidity with unsatisfactory outcomes. The use of appropriate biomaterial with osteogenic potential can meet these challenges. In this regard, bioactive glass ceramics is widely used as a bone filler or graft material because of its bonding affinity to bone leading towards bone reconstruction applications without the challenge of post implant infections. Hence, the current study is aimed at addressing this potentiality of zinc (Zn) for doped the bioglass at nano-scale advantages for bone tissue repair. Since, Zn has been demonstrated to have not only antibacterial property but also the stimulatory effect on osteoblasts differentiation, mineralization by enhancing the osteogenic genes expression. In view of these, the present study is focused on sol–gel synthesis and pysico-chemical characterization of Zinc-doped bioglass nanoparticles (Zn-nBGC) and also analyzing its biological implications. The surface morphological and physiochemical characterizations using SEM, EDX, FT-IR and XRD analysis has shown the increased surface area of Zn-nBGC particles providing a great platform for biomolecular interaction, cytocompatibility, cell proliferation and osteogenic differentiation. The obtaining hydroxy apatite groups have initiated in vitro mineralization towards osteogenic lineage formation. Zn has not only involved in enhancing cellular actions but also strengthen the ceramic nanoparticles towards antibacterial application. Hence the finding suggests a biomaterial synthesis of better biomaterial for bone tissue engineering application by preventing post-operative bacterial infection.
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