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Substrate topographical features induce osteogenic differentiation of bone marrow stem cells (BMSCs), but the underlying mechanisms are unclear. As microRNAs (miRNAs) play key roles in osteogenesis and bone regeneration, it would be meaningful to elucidate the roles of miRNAs in the intracellular signaling cascade of topographical cue‐induced osteogenic differentiation. In this study, the miRNA expression profile of the topographical feature‐induced osteogenic differentiation group is different from that of the chemical‐factors‐induced osteogenic differentiation group. miR‐193a‐3p is sensitive to substrate topographical features and its downregulation enhances osteogenic differentiation only in the absence of osteogenesis−inducing medium. Also, substrate topographical features specifically activate a nonclassical osteogenetic pathway—the mitogen‐activated protein kinase (MAPK) pathway. Loss‐ and gain‐of‐function experiments demonstrate that miR‐193a‐3p regulates the MAPK pathway by targeting the MAP3k3 gene. In conclusion, this data indicates that different osteogenic‐lineage‐related intracellular signaling cascades are triggered in BMSCs subjected to biophysical or chemical stimulation. Moreover, the miR‐193a‐3p‐MAP3k3 signaling axis plays a pivotal role in the transduction of biophysical cues from the substrate to regulate the osteogenic lineage specification of BMSCs, and hence may be a promising molecular target for bone regenerative therapies. Topographical feature‐induced bone marrow stem cells (BMSCs) lineage specification is different from that of chemical‐factors‐induced BMSCs lineage specification in terms of microRNA expression. MiR‐193a‐3p‐MAP3k3 signaling axis plays a pivotal role in the transduction of biophysical cues from the substrate to regulate the osteogenic differentiation of BMSCs. As an outlook, when designing implantable biomedical devices or orthopedic substitutes, more attention should be focused on their biophysical properties.

Circular RNA (circRNA) is a unique closed ring structure of noncoding RNA. Although many human diseases have been confirmed to be inextricably linked with circRNAs, whether circRNAs have a potential regulatory function in the osteogenic differentiation of bone marrow mesenchymal stem cells (BMMSCs) remains to be further elucidated. In a previous study by our team, all the differentially expressed circRNAs and messenger RNAs (mRNAs) involved in the osteogenic differentiation of BMMSCs were identified via high-throughput sequencing, and a competing endogenous RNA (ceRNA) regulatory network was constructed via bioinformatics analysis. The circRNA₁809/miR-370-3p/Kitlg axis may be involved in regulating the osteogenic differentiation of BMMSCs. In this study, gene knockdown/overexpression, small interfering RNA (siRNA) transfection and mimic/inhibitor treatment were used to evaluate the regulatory effects of circRNA₁809 on the miR-370-3p/Kitlg pathway and the osteogenic differentiation of rat bone marrow mesenchymal stem cells (rBMMSCs) in vitro. The results revealed that circRNA₁809 was upregulated and that miR-370-3p was downregulated during the osteogenic differentiation of rBMMSCs. The low expression of circRNA₁809 significantly downregulated the expression of Kitlg and decreased the protein expression of ALP and RUNX2. The expression of miR-370-3p was negatively correlated with the expression of Kitlg in rBMMSCs and the ability to undergo osteogenic differentiation. In addition, a dual-luciferase assay confirmed the binding of miR-370-3p and circRNA₁809, and si-circRNA₁809 + miR-370-3p inhibitor cotransfection reversed some of the downregulation of Kitlg induced by si-circRNA₁809, whereas si-circRNA₁809 + miR-370-3p mimic increased the downregulation of Kitlg. Therefore, circRNA₁809 may promote the expression of Kitlg by regulating miR-370-3p and subsequently promote the osteogenic differentiation of rBMMSCs.

Bone scaffolds based on multi-components are the leading trend to address the multifaceted prerequisites to repair various bone defects. Chitosan is the most useable biopolymer, having excellent biological applications. Therefore, in the present study, the chitosan microsphere was prepared by the ion–gel method; transforming growth factor β (TGF-β1) and bone morphogenetic protein 2 (BMP-2) were loaded onto it and then combined with alginate/hyaluronic acid/collagen (Alg/HA/ICol) to construct a jawbones scaffold. The Alg/HA/ICol scaffolds were characterized by FTIR and SEM, and the water content, porosity, tensile properties, biocompatibility, and osteogenic-induced differentiation ability of the Alg/HA/ICol jawbones scaffolds were studied. The results indicate that a three-dimensional porous jawbone scaffold was successfully constructed having 100–250 μm of pore size and >90% of porosity without cytotoxicity against adipose-derived stem cells (ADSCs). Its ALP quantification, osteocalcin expression, and Von Kossamineralized nodule staining was higher than the control group. The jawbones scaffold constructed by TGF-β1 and BMP-2 loaded chitosan microsphere combining with Alg/HA/ICol has potential biomedical application in the future.

The aim of this study was to characterize the in vitro osteogenic differentiation of dental pulp stem cells (DPSCs) in 2D cultures and 3D biomaterials. DPSCs, separated from dental pulp by enzymatic digestion, and isolated by magnetic cell sorting were differentiated toward osteogenic lineage on 2D surface by using an osteogenic medium. During the differentiation process, DPSCs express specific bone proteins like Runx-2, Osx, OPN and OCN with a sequential expression, analogous to those occurring during osteoblast differentiation, and produce extracellular calcium deposits. In order to differentiate cells in a 3D space that mimes the physiological environment, DPSCs were cultured in two distinct bioscaffolds, Matrigel™ and Collagen sponge. With the addition of a third dimension, osteogenic differentiation and mineralized extracellular matrix production significantly improved. In particular, in Matrigel™ DPSCs differentiated with osteoblast/osteocyte characteristics and connected by gap junction, and therefore formed calcified nodules with a 3D intercellular network. Furthermore, DPSCs differentiated in collagen sponge actively secrete human type I collagen micro-fibrils and form calcified matrix containing trabecular-like structures. These neo-formed DPSCs-scaffold devices may be used in regenerative surgical applications in order to resolve pathologies and traumas characterized by critical size bone defects.

Chun-Yan Zheng,1,* Xiao-Yang Chu,2,* Chun-Yan Gao,1 Hua-Ying Hu,3 Xin He,1 Xu Chen,1 Kai Yang,4 Dong-Liang Zhang1 1Department of Orthodontics, Beijing Stomatological Hospital, Capital Medical University School of Stomatology, Capital Medical University, Beijing, People’s Republic of China; 2Department of Stomatology, Fifth Medical Center of Chinese PLA General Hospital, Beijing, People’s Republic of China; 3Birth Defects Prevention and Control Technology Research Center, Medical Innovation Research Division of Chinese PLA General Hospital, Beijing, People’s Republic of China; 4Prenatal Diagnosis Center, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Dong-Liang Zhang, Department of Orthodontics, Beijing Stomatological Hospital, Capital Medical University School of Stomatology, Capital Medical University, 11 Xilahutong Road, Beijing, 100040, People’s Republic of China, Email zhangdongliang@mail.ccmu.edu.cnBackground: Naringin is a naturally occurring flavanone that promotes osteogenesis. Owing to the high lipophilicity, poor in vivo bioavailability, and extensive metabolic alteration upon administration, the clinical efficacy of naringin is understudied. Additionally, information on the molecular mechanism by which it promotes osteogenesis is limited.Methods: In this study, we prepared TAT & RGD peptide-modified naringin-loaded nanoparticles (TAT-RGD-NAR-NPs), evaluated their potency on the osteogenic differentiation of human dental pulp stem cells (hDPSCs), and studied its mechanism of action through metabolomic analysis.Results: The particle size and zeta potential of TAT-RGD-NAR-NPs were 160.70± 2.05 mm and – 20.77± 0.47mV, respectively. The result of cell uptake assay showed that TAT-RGD-NAR-NPs could effectively enter hDPSCs. TAT-RGD-NAR-NPs had a more significant effect on cell proliferation and osteogenic differentiation promotion. Furthermore, in metabolomic analysis, naringin particles showed a strong influence on the glycerophospholipid metabolism pathway of hDPSCs. Specifically, it upregulated the expression of PLA2G3 and PLA2G1B (two isozymes of phospholipase A2, PLA2), increased the biosynthesis of lysophosphatidic acid (LPA).Conclusion: These results suggested that TAT-RGD-NPs might be used for transporting naringin to hDPSCs for modulating stem cell osteogenic differentiation. The metabolomic analysis was used for the first time to elucidate the mechanism by which naringin promotes hDPSCs osteogenesis by upregulating PLA2G3 and PLA2G1B.Keywords: nanoparticles, TAT, RGD, hDPSCs, osteogenic differentiation

[This corrects the article DOI: 10.3389/fphar.2021.736301.].

Vascular calcification (VC), which is categorized by intimal and medial calcification, depending on the site(s) involved within the vessel, is closely related to cardiovascular disease. Specifically, medial calcification is prevalent in certain medical situations, including chronic kidney disease and diabetes. The past few decades have seen extensive research into VC, revealing that the mechanism of VC is not merely a consequence of a high-phosphorous and -calcium milieu, but also occurs via delicate and well-organized biologic processes, including an imbalance between osteochondrogenic signaling and anticalcific events. In addition to traditionally established osteogenic signaling, dysfunctional calcium homeostasis is prerequisite in the development of VC. Moreover, loss of defensive mechanisms, by microorganelle dysfunction, including hyper-fragmented mitochondria, mitochondrial oxidative stress, defective autophagy or mitophagy, and endoplasmic reticulum (ER) stress, may all contribute to VC. To facilitate the understanding of vascular calcification, across any number of bioscientific disciplines, we provide this review of a detailed updated molecular mechanism of VC. This encompasses a vascular smooth muscle phenotypic of osteogenic differentiation, and multiple signaling pathways of VC induction, including the roles of inflammation and cellular microorganelle genesis.

Approximately 10% of bone fractures do not heal satisfactorily, leading to significant clinical and socioeconomic implications. Recently, the role of macrophages in regulating bone marrow stem cell (BMSC) differentiation through the osteogenic pathway during fracture healing has attracted much attention. : The tibial monocortical defect model was employed to determine the critical role of macrophage scavenger receptor 1 (MSR1) during intramembranous ossification (IO) . The potential functions and mechanisms of MSR1 were explored in a co-culture system of bone marrow-derived macrophages (BMDMs), RAW264.7 cells, and BMSCs using qPCR, Western blotting, immunofluorescence, and RNA sequencing. : In this study, using the tibial monocortical defect model, we observed delayed IO in MSR1 knockout (KO) mice compared to MSR1 wild-type (WT) mice. Furthermore, macrophage MSR1 mediated PI3K/AKT/GSK3β/β-catenin signaling increased ability to promote osteogenic differentiation of BMSCs in the co-culture system. We also identified proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) as the target gene for macrophage MSR1-activated PI3K/AKT/GSK3β/β-catenin pathway in the co-culture system that facilitated M2-like polarization by enhancing mitochondrial oxidative phosphorylation. : Our findings revealed a previously unrecognized function of MSR1 in macrophages during fracture repair. Targeting MSR1 might, therefore, be a new therapeutic strategy for fracture repair.

Bone marrow mesenchymal stem cells (MSCs) are multipotent stem cells with the ability to differentiate into bone-producing cells, which is essential for bone formation. Magnesium biomedical materials, such as biodegradable matters with osteoinductive properties, play a vital role in the osteogenic differentiation of MSCs. International and Chinese studies have shown that magnesium ions, which are produced by biodegradation, mainly achieve this effect by regulating the expression of genes and proteins associated with osteogenesis, activating multiple signal pathways, elevating autophagic activities, and adjusting the pH in the microenvironment. It is of great significance to study the regulatory mechanisms and identify the optimal conditions that how magnesium ions promote osteogenic differentiation of MSCs. In this study, we summarized the regulatory mechanisms noted above.