Osteogenic Factors
Recently Published Documents





Pharmaceutics ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1277
Daniel García-Sánchez ◽  
Alberto González-González ◽  
Patricia García-García ◽  
Ricardo Reyes ◽  
María Isabel Pérez-Núñez ◽  

Mesenchymal stem cell (MSC) transplantation has emerged as a promising approach for bone regeneration. Importantly, the beneficial effects of MSCs can be improved by modulating the expression levels of specific genes to stimulate MSC osteogenic differentiation. We have previously shown that Smurf1 silencing by using Locked Nucleic Acid-Antisense Oligonucleotides, in combination with a scaffold that sustainably releases low doses of BMP-2, was able to increase the osteogenic potential of MSCs in the presence of BMP-2 doses significantly smaller than those currently used in the clinic. This would potentially allow an important reduction in this protein in MSs-based treatments, and thus of the side effects linked to its administration. We have further improved this system by specifically targeting the Wnt pathway modulator Sfrp1. This approach not only increases MSC bone regeneration efficiency, but is also able to induce osteogenic differentiation in osteoporotic human MSCs, bypassing the need for BMP-2 induction, underscoring the regenerative potential of this system. Achieving successful osteogenesis with the sole use of LNA-ASOs, without the need of administering pro-osteogenic factors such as BMP-2, would not only reduce the cost of treatments, but would also open the possibility of targeting these LNA-ASOs specifically to MSCs in the bone marrow, allowing us to treat systemic bone loss such as that associated with osteoporosis.

Atsumu Kouketsu ◽  
Keiko Matsui ◽  
Tadashi Kawai ◽  
Yushi Ezoe ◽  
Tetsu Takahashi ◽  

Materials ◽  
2021 ◽  
Vol 14 (14) ◽  
pp. 3852
Federica Re ◽  
Luciana Sartore ◽  
Elisa Borsani ◽  
Matteo Ferroni ◽  
Camilla Baratto ◽  

Gelatin–dextran hydrogel scaffolds (G-PEG-Dx) were evaluated for their ability to activate the bone marrow human mesenchymal stromal cells (BM-hMSCs) towards mineralization. G-PEG-Dx1 and G-PEG-Dx2, with identical composition but different architecture, were seeded with BM-hMSCs in presence of fetal bovine serum or human platelet lysate (hPL) with or without osteogenic medium. G-PEG-Dx1, characterized by a lower degree of crosslinking and larger pores, was able to induce a better cell colonization than G-PEG-Dx2. At day 28, G-PEG-Dx2, with hPL and osteogenic factors, was more efficient than G-PEG-Dx1 in inducing mineralization. Scanning electron microscopy (SEM) and Raman spectroscopy showed that extracellular matrix produced by BM-hMSCs and calcium-positive mineralization were present along the backbone of the G-PEG-Dx2, even though it was colonized to a lesser degree by hMSCs than G-PEG-Dx1. These findings were confirmed by matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI), detecting distinct lipidomic signatures that were associated with the different degree of scaffold mineralization. Our data show that the architecture and morphology of G-PEG-Dx2 is determinant and better than that of G-PEG-Dx1 in promoting a faster mineralization, suggesting a more favorable and active role for improving bone repair.

2021 ◽  
Vol 22 (14) ◽  
pp. 7323
Na Young Shim ◽  
Jung Sun Heo

Graphene oxide (GO) is a biocompatible material considered a favorable stem cell culture substrate. In this study, GO was modified with polydopamine (PDA) to facilitate depositing GO onto a tissue culture polystyrene (PT) surface, and the osteogenic performance of the PDA/GO composite in pluripotent embryonic stem cells (ESCs) was investigated. The surface chemistry of the PDA/GO-coated PT surface was analyzed by scanning electron microscopy (SEM) and X-ray photoelectron spectroscopy (XPS). A high cell viability of ESCs cultured on the PDA/GO composite-coated surface was initially ensured. Then, the osteogenic differentiation of the ESCs in response to the PDA/GO substrate was assessed by alkaline phosphatase (ALP) activity, intracellular calcium levels, matrix mineralization assay, and evaluation of the mRNA and protein levels of osteogenic factors. The culture of ESCs on the PDA/GO substrate presented higher osteogenic potency than that on the uncoated control surface. ESCs cultured on the PDA/GO substrate expressed significantly higher levels of integrin α5 and β1, as well as bone morphogenetic protein receptor (BMPR) types I and II, compared with the control groups. The phosphorylation of extracellular signal-regulated kinase (ERK)1/2, p38, and c-Jun-N-terminal kinase (JNK) mitogen-activated protein kinases (MAPKs) was observed in ESCs culture on the PDA/GO substrate. Moreover, BMP signal transduction by SMAD1/5/8 phosphorylation was increased more in cells on PDA/GO than in the control. The nuclear translocation of SMAD1/5/8 in cells was also processed in response to the PDA/GO substrate. Blocking activation of the integrin α5/β1, MAPK, or SMAD signaling pathways downregulated the PDA/GO-induced osteogenic differentiation of ESCs. These results suggest that the PDA/GO composite stimulates the osteogenic differentiation of ESCs via the integrin α5/β1, MAPK, and BMPR/SMAD signaling pathways.

2021 ◽  
Vol 22 (13) ◽  
pp. 6811
Masako Tabuchi ◽  
Kosuke Hamajima ◽  
Miyuki Tanaka ◽  
Takeo Sekiya ◽  
Makoto Hirota ◽  

It is a significant challenge for a titanium implant, which is a bio-inert material, to recruit osteogenic factors, such as osteoblasts, proteins and blood effectively when these are contained in a biomaterial. The objective of this study was to examine the effect of ultraviolet (UV)-treatment of titanium on surface wettability and the recruitment of osteogenic factors when they are contained in an atelocollagen sponge. UV treatment of a dental implant made of commercially pure titanium was performed with UV-light for 12 min immediately prior to the experiments. Superhydrophilicity on dental implant surfaces was generated with UV-treatment. The collagen sponge containing blood, osteoblasts, or albumin was directly placed on the dental implant. Untreated implants absorbed only a little blood from the collagen sponge, while the UV-treated implants absorbed blood rapidly and allowed it to spread widely, almost over the entire implant surface. Blood coverage was 3.5 times greater for the UV-treated implants (p < 0.001). Only 6% of the osteoblasts transferred from the collagen sponge to the untreated implants, whereas 16% of the osteoblasts transferred to the UV-treated implants (p < 0.001). In addition, a weight ratio between transferred albumin on the implant and measured albumin adsorbed on the implant was 17.3% in untreated implants and 38.5% in UV-treated implants (p < 0.05). These results indicated that UV treatment converts a titanium surface into a superhydrophilic and bio-active material, which could recruite osteogenic factors even when they were contained in a collagen sponge. The transfer and subsequent diffusion and adsorption efficacy of UV-treated titanium surfaces could be useful for bone formation when titanium surfaces and osteogenic factors are intervened with a biomaterial.

2021 ◽  
Kai Tie ◽  
Jinghang Cai ◽  
Jun Qin ◽  
Hao Xiao ◽  
Yangfan Shangguan ◽  

Abstract Background: Bone formation plays an important role in early tendon-bone healing after anterior cruciate ligament reconstruction (ACLR). Dedifferentiated osteogenic bone marrow mesenchymal stem cells (De-BMSCs) have enhanced osteogenic potential. This study aimed to investigate the effect of De-BMSCs transplantation on the promotion of bone formation at the tendon-bone interface after ACLR and to further explore the molecular mechanism of the enhanced osteogenic potential of De-BMSCs.Methods: BMSCs from the femurs and tibias of New Zealand White rabbits were subjected to osteogenic induction and then cultured in medium without osteogenic factors; the obtained cell population was termed De-BMSCs. De-BMSCs were induced to undergo osteo-, chondro- and adipo-differentiation in vitro to examine the characteristics of primitive stem cells. An ACLR model with a semitendinosus tendon was established in rabbits, and the animals were divided into a control group, BMSCs group and De-BMSCs group. At 12 weeks after surgery, the rabbits in each group were sacrificed to evaluate tendon-bone healing by histologic staining, micro–computed tomography (micro-CT) examination, and biomechanical testing. During osteogenic differentiation of De-BMSCs, an siRNA targeting nuclear factor of activated T cells 1 (NFATc1) was used to verify the molecular mechanism of the enhanced osteogenic potential of De-BMSCs.Results: De-BMSCs exhibited some properties similar to BMSCs, including multiple differentiation potential and cell surface markers. Bone formation at the tendon-bone interface in the De-BMSCs group was significantly increased, and biomechanical strength was significantly improved. During the osteogenic differentiation of De-BMSCs, the expression of Nanog and NFATc1 was synergistically increased, which promoted the interaction of NFATc1 and Osterix, resulting in increased expression of osteoblast marker genes such as COL1A, OCN, and OPN.Conclusions: De-BMSCs transplantation could promote bone formation at the tendon-bone interface after ACLR and improve the biomechanical strength of the reconstruction. The Nanog/NFATc1/Osterix signaling pathway mediated the enhanced osteogenic differentiation efficiency of De-BMSCs.

Yan Huang ◽  
Yongqiang Xu ◽  
Siyin Feng ◽  
Pan He ◽  
Bing Sheng ◽  

AbstractBone marrow mesenchymal stem cell (BMSC)-derived exosomes have been found to enhance fracture healing. In addition, microRNAs contributing to the healing of various bone fractures have attracted widespread attention in recent years, but knowledge of the mechanisms by which they act is still very limited. In this study, we clarified the function of altered microRNA-19b (miR-19b) expression in BMSCs in fracture healing. We modulated miR-19b expression via mimics/inhibitors in BMSCs and via agomirs in mice to explore the effects of these changes on osteogenic factors, bone cell mineralization and the healing status of modeled fractures. Through gain- and loss-of function assays, the binding affinity between miR-19b and WWP1/Smurf2 was identified and characterized to explain the underlying mechanism involving the KLF5/β-catenin signaling pathway. miR-19b promoted the differentiation of human BMSCs into osteoblasts by targeting WWP1 and Smurf2. Overexpression of WWP1 or Smurf2 degraded the target protein KLF5 in BMSCs through ubiquitination to inhibit fracture healing. KLF5 knockdown delayed fracture healing by modulating the Wnt/β-catenin signaling pathway. Furthermore, miR-19b enhanced fracture healing via the KLF5/β-catenin signaling pathway by targeting WWP1 or Smurf2. Moreover, miR-19b was found to be enriched in BMSC-derived exosomes, and treatment with exosomes promoted fracture healing in vivo. Collectively, these results indicate that mesenchymal stem cell-derived exosomal miR-19b represses the expression of WWP1 or Smurf2 and elevates KLF5 expression through the Wnt/β-catenin signaling pathway, thereby facilitating fracture healing.

2021 ◽  
Yan Deng ◽  
Honghong Luo ◽  
Yixuan Deng ◽  
Yuanyuan Yang ◽  
Xintong Yao ◽  

Abstract Background: Bone morphogenetic protein 9 (BMP9) is one of excellent osteogenic factors, but it can also initiate adipogenesis concomitantly. Thus, the osteogenic potential of BMP9 may be enhanced if the adipogenesis were reduced. It was reported that lysyl oxidase (Lox) may function as a critical switcher for adipogenesis. Up to date, the role of Lox in BMP9-induced osteoblastic differentiation remains unknown.Methods: The effect and possible mechanism of Lox on the osteogenic function of BMP9 were evaluated with RT-PCR, western blotting, immunofluorescent and histochemical staining. The same results were also confirmed with the in vivo BMP9-induced ectopic bone formation model.Results: The mRNA and protein of Lox are both detectable in progenitor cells, and it was increased by BMP9 in 3T3-L1 cells. BMP9-induced Runx2, OPN and mineralization were all enhanced by inhibiting or silencing Lox, but reduced by exogenous Lox. BMP9 increased the mRNA level of c-Myc, which was enhanced by inhibiting Lox, so did the protein level of β-catenin. Effects of Lox specific inhibitor on BMP9-induced Runx2, OPN and mineralization were reduced obviously by silencing β-catenin. HIF-1α was up-regulated by BMP9, which was enhanced by inhibiting or silencing Lox, but decreased by Lox over-expression. The effects of Lox specific inhibitor on increasing BMP9-induced osteogenic markers were reduced greatly by silencing HIF-1α. On the contrary, the inhibitory effect of Lox on BMP9-induced osteoblastic markers was almost abolished by HIF-1α over-expression. BMP9-induced bone formation was increased by silencing Lox or over-expressing HIF-1α. The effect of silencing Lox on potentiating BMP9-induced bone formation was attenuated by silencing HIF-1α. Lox specific inhibitor increased the level of β-catenin and decreased that of SOST, but these effects were almost reversed by silencing HIF-1α.Conclusions: Lox may reducing the osteoblastic-induction function of BMP9 through inhibiting Wnt/β-catenin signal via down-regulation of HIF-1α partly.

2021 ◽  
Bin Wang ◽  
Yanming Cao ◽  
Caiyuan Mai ◽  
Ram Ishwar Yadav ◽  
Jianliang Gao ◽  

Abstract Objective: To investigate the variations in the expressions of LRP5, Runx2, Osterix, and RANKL factors in bone tissues associated with postmenopausal osteoporotic fractures (PMOPF). Method: Postmenopausal patients with femur fractures were initially divided into control (31 cases) and PMOPF groups (83 cases). All control group patients were operated within 1 day after injury. The patients with PMOPF were operated based on the time after fracture in the respective groups (patients were divided into groups A, B, and C based on the time after fracture). Samples were collected from femurs at fracture sites during the operation. The expression level of each factor in bone tissues was detected using RT-qPCR, and the bone mass samples were decalcified and then histologically analyzed by immunohistochemistry. We subsequently analyzed significant differences in the expressions of factors (LRP5, Runx2, Osterix, and RANKL) between PMOPF and control groups. Results: (1) LRP5, β-catenin, Runx2, and Osterix were under-expressed in patients with PMOPF relative to the controls (P<0.05). In contrast, RANKL was over-expressed in the PMOPF group when compared to the control group (P<0.05); (2) the expressions of LRP5 and Runx2 were lowest in Group A patients (1–3 days after fracture). Osterix expression was lowest in Group C patients (8–14 days after fracture). Conversely, RANKL expression was highest in Group B patients (4–7 days after fracture). Conclusion: The inhibition or reduction in the expressions of osteogenic factors including LRP5, Runx2, and Osterix of the Wnt/β-catenin and BMP-2/Runx2/Osterix signaling pathways are associated with PMOPF incidence. Specifically, upregulation of RANKL in the RANKL/RANK signaling pathway is associated with the incidence of PMOPF. LRP5 and Runx2 expressions decreased considerably within 1-3 days after fracture; Osterix expression decreased considerably within 8-14 days after fracture; RANKL expression was highest within 4-7 days after fracture, which could be associated with bone repair in PMOPF. The expression level of the aforementioned factors affects the development and progression of PMOPF.

Fatchiyah Fatchiyah ◽  
Bambang Setiawan ◽  
Tomohiko Sasase ◽  
Takeshi Ohta

We investigated the potential anti-glycation and anti-osteoporosis properties of Caprine milk CSN1S2 protein on the serum AGEs and sRAGE level, osteogenic factors expressions, femoral bone mesostructure, histomorphometry, and hydroxyapatite crystals changes in T2DM rats. Varying doses of Caprine milk CSN1S2 protein (0, 375, 750, and 1500mg/kg BW) were used to treat the control and T2DM rats. We measured AGEs and sRAGE level; RUNX2, OSX, BMP2, and Caspase-3 expressions in rats using ELISA and immunohistochemistry, respectively. The mesostructure and histomorphometry of femoral bone was analyzed using SEM Microscope and BoneJ software, then hydroxyapatite crystal size was determined using SEM-XRD. T2DM rats showed a high level of AGEs and a low level of sRAGE, the RUNX2, OSX, & BMP2 expression was down regulated, BV, BV.TV, Tb.Th, Tb.Sp, increased and SMI levels declined, respectively. Vice versa, after administration of the CSN1S2 protein to T2DM rats, improvement in all levels of molecular and cellular markers was achieved. In the CSN1S2 highest dose, AGEs level declined and sRAGE level elevated in T2DM rats. The 375 and 750 mg/kgBW of CSN1S2 protein was able to upregulate the RUNX2, OSX, and BMP2 expression in T2DM rats, thus improving the normalization of osteoclasts and osteoblasts number. The whole dose of CSN1S2 triggered the thickening of trabecular bone wall, granule formation, and normalized the trabecular thickness (Tb.Th) parameter of T2DM rats. The hydroxyapatite crystal size was increased in the highest dose of CSN1S2-treated T2DM rats. This study indicated that CSN1S2 protein had a protective effect against osteoporosis in the T2DM rat bones by means of glycation pathway inhibition, bone histomorphometry and mesostructure improvement via bone morphometric protein signaling.

Sign in / Sign up

Export Citation Format

Share Document