Research

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21 pages, 6093 KiB

Open AccessArticle

Modifications in Gene Expression in the Process of Osteoblastic Differentiation of Multipotent Bone Marrow-Derived Human Mesenchymal Stem Cells Induced by a Novel Osteoinductive Porous Medical-Grade 3D-Printed Poly(ε-caprolactone)/β-tricalcium Phosphate Composite

by Ivan López-González, Camilo Zamora-Ledezma, María Isabel Sanchez-Lorencio, Elena Tristante Barrenechea, José Antonio Gabaldón-Hernández and Luis Meseguer-Olmo

Int. J. Mol. Sci. 2021, 22(20), 11216; https://doi.org/10.3390/ijms222011216 - 18 Oct 2021

Cited by 13 | Viewed by 3174

Abstract

In this work, we evaluated the influence of a novel hybrid 3D-printed porous composite scaffold based on poly(ε-caprolactone) (PCL) and β-tricalcium phosphate (β-TCP) microparticles in the process of adhesion, proliferation, and osteoblastic differentiation of multipotent adult human bone marrow mesenchymal stem cells ( [...] Read more.

In this work, we evaluated the influence of a novel hybrid 3D-printed porous composite scaffold based on poly(ε-caprolactone) (PCL) and β-tricalcium phosphate (β-TCP) microparticles in the process of adhesion, proliferation, and osteoblastic differentiation of multipotent adult human bone marrow mesenchymal stem cells (ah-BM-MSCs) cultured under basal and osteogenic conditions. The in vitro biological response of ah-BM-MSCs seeded on the scaffolds was evaluated in terms of cytotoxicity, adhesion, and proliferation (AlamarBlue Assay^®) after 1, 3, 7, and 14 days of culture. The osteogenic differentiation was assessed by alkaline phosphatase (ALP) activity, mineralization (Alizarin Red Solution, ARS), expression of surface markers (CD73, CD90, and CD105), and reverse transcription–quantitative polymerase chain reaction (qRT-PCR) after 7 and 14 days of culture. The scaffolds tested were found to be bioactive and biocompatible, as demonstrated by their effects on cytotoxicity (viability) and extracellular matrix production. The mineralization and ALP assays revealed that osteogenic differentiation increased in the presence of PCL/β-TCP scaffolds. The latter was also confirmed by the gene expression levels of the proteins involved in the ossification process. Our results suggest that similar bio-inspired hybrid composite materials would be excellent candidates for osteoinductive and osteogenic medical-grade scaffolds to support cell proliferation and differentiation for tissue engineering, which warrants future in vivo research. Full article

(This article belongs to the Special Issue Osteoblast Differentiation and Activity in Skeletal Diseases)

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16 pages, 5062 KiB

Open AccessArticle

Modeling In Vitro Osteoarthritis Phenotypes in a Vascularized Bone Model Based on a Bone-Marrow Derived Mesenchymal Cell Line and Endothelial Cells

by Alessandro Pirosa, Esma Bahar Tankus, Andrea Mainardi, Paola Occhetta, Laura Dönges, Cornelia Baum, Marco Rasponi, Ivan Martin and Andrea Barbero

Int. J. Mol. Sci. 2021, 22(17), 9581; https://doi.org/10.3390/ijms22179581 - 03 Sep 2021

Cited by 9 | Viewed by 2548

Abstract

The subchondral bone and its associated vasculature play an important role in the onset of osteoarthritis (OA). Integration of different aspects of the OA environment into multi-cellular and complex human, in vitro models is therefore needed to properly represent the pathology. In this [...] Read more.

The subchondral bone and its associated vasculature play an important role in the onset of osteoarthritis (OA). Integration of different aspects of the OA environment into multi-cellular and complex human, in vitro models is therefore needed to properly represent the pathology. In this study, we exploited a mesenchymal stromal cell line/endothelial cell co-culture to produce an in vitro human model of vascularized osteogenic tissue. A cocktail of inflammatory cytokines, or conditioned medium from mechanically-induced OA engineered microcartilage, was administered to this vascularized bone model to mimic the inflamed OA environment, hypothesizing that these treatments could induce the onset of specific pathological traits. Exposure to the inflammatory factors led to increased network formation by endothelial cells, reminiscent of the abnormal angiogenesis found in OA subchondral bone, demineralization of the constructs, and increased collagen production, signs of OA related bone sclerosis. Furthermore, inflammation led to augmented expression of osteogenic (alkaline phosphatase (ALP) and osteocalcin (OCN)) and angiogenic (vascular endothelial growth factor (VEGF)) genes. The treatment, with a conditioned medium from the mechanically-induced OA engineered microcartilage, also caused increased demineralization and expression of ALP, OCN, ADAMTS5, and VEGF; however, changes in network formation by endothelial cells were not observed in this second case, suggesting a possible different mechanism of action in inducing OA-like phenotypes. We propose that this vascularized bone model could represent a first step for the in vitro study of bone changes under OA mimicking conditions and possibly serve as a tool in testing anti-OA drugs. Full article

(This article belongs to the Special Issue Osteoblast Differentiation and Activity in Skeletal Diseases)

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27 pages, 5214 KiB

Open AccessArticle

Comparative Proteomic and Metabolomic Analysis of Human Osteoblasts, Differentiated from Dental Pulp Stem Cells, Hinted Crucial Signaling Pathways Promoting Osteogenesis

by Slavomíra Nováková, Maksym Danchenko, Terézia Okajčeková, Eva Baranovičová, Andrej Kováč, Marián Grendár, Gábor Beke, Janka Pálešová, Ján Strnádel, Mária Janíčková, Erika Halašová and Henrieta Škovierová

Int. J. Mol. Sci. 2021, 22(15), 7908; https://doi.org/10.3390/ijms22157908 - 24 Jul 2021

Cited by 5 | Viewed by 2947

Abstract

Population aging has been a global trend for the last decades, which increases the pressure to develop new cell-based or drug-based therapies, including those that may cure bone diseases. To understand molecular processes that underlie bone development and turnover, we followed osteogenic differentiation [...] Read more.

Population aging has been a global trend for the last decades, which increases the pressure to develop new cell-based or drug-based therapies, including those that may cure bone diseases. To understand molecular processes that underlie bone development and turnover, we followed osteogenic differentiation of human dental pulp stem cells (DPSCs) using a specific induction medium. The differentiation process imitating in vivo osteogenesis is triggered by various signaling pathways and is associated with massive proteome and metabolome changes. Proteome was profiled by ultrahigh-performance liquid chromatography and comprehensively quantified by ion mobility-enhanced mass spectrometry. From 2667 reproducibly quantified and identified proteins, 432 were differentially abundant by strict statistic criteria. Metabolome profiling was carried out by nuclear magnetic resonance. From 27 detected metabolites, 8 were differentially accumulated. KEGG and MetaboAnalyst hinted metabolic pathways that may be involved in the osteogenic process. Enrichment analysis of differentially abundant proteins highlighted PPAR, FoxO, JAK-STAT, IL-17 signaling pathways, biosynthesis of thyroid hormones and steroids, mineral absorption, and fatty acid metabolism as processes with prominent impact on osteoinduction. In parallel, metabolomic data showed that aminoacyl-tRNA biosynthesis, as well as specific amino acids, likely promote osteodifferentiation. Targeted immunoassays validated and complemented omic results. Our data underlined the complexity of the osteogenic mechanism. Finally, we proposed promising targets for future validation in patient samples, a step toward the treatment of bone defects. Full article

(This article belongs to the Special Issue Osteoblast Differentiation and Activity in Skeletal Diseases)

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15 pages, 3032 KiB

Open AccessArticle

Photobiomodulation by Near-Infrared 980-nm Wavelengths Regulates Pre-Osteoblast Proliferation and Viability through the PI3K/Akt/Bcl-2 Pathway

by Dimitrios Agas, Reem Hanna, Stefano Benedicenti, Nicola De Angelis, Maria Giovanna Sabbieti and Andrea Amaroli

Int. J. Mol. Sci. 2021, 22(14), 7586; https://doi.org/10.3390/ijms22147586 - 15 Jul 2021

Cited by 17 | Viewed by 2735

Abstract

Background: bone tissue regeneration remains a current challenge. A growing body of evidence shows that mitochondrial dysfunction impairs osteogenesis and that this organelle may be the target for new therapeutic options. Current literature illustrates that red and near-infrared light can affect the key [...] Read more.

Background: bone tissue regeneration remains a current challenge. A growing body of evidence shows that mitochondrial dysfunction impairs osteogenesis and that this organelle may be the target for new therapeutic options. Current literature illustrates that red and near-infrared light can affect the key cellular pathways of all life forms through interactions with photoacceptors within the cells’ mitochondria. The current study aims to provide an understanding of the mechanisms by which photobiomodulation (PBM) by 900-nm wavelengths can induce in vitro molecular changes in pre-osteoblasts. Methods: The PubMed, Scopus, Cochrane, and Scholar databases were used. The manuscripts included in the narrative review were selected according to inclusion and exclusion criteria. The new experimental set-up was based on irradiation with a 980-nm laser and a hand-piece with a standard Gaussian and flat-top beam profile. MC3T3-E1 pre-osteoblasts were irradiated at 0.75, 0.45, and 0.20 W in continuous-wave emission mode for 60 s (spot-size 1 cm²) and allowed to generate a power density of 0.75, 0.45, and 0.20 W/cm² and a fluence of 45, 27, and 12 J/cm², respectively. The frequency of irradiation was once, three times (alternate days), or five times (every day) per week for two consecutive weeks. Differentiation, proliferation, and cell viability and their markers were investigated by immunoblotting, immunolabelling, fluorescein-FragELTM-DNA, Hoechst staining, and metabolic activity assays. Results and conclusions: The 980-nm wavelength can photobiomodulate the pre-osteoblasts, regulating their metabolic schedule. The cellular signal activated by 45 J/cm², 0.75 W and 0.75 W/cm² consist of the PI3K/Akt/Bcl-2 pathway; differentiation markers were not affected, nor do other parameters seem to stimulate the cells. Our previous and present data consistently support the window effect of 980 nm, which has also been described in extracted mitochondria, through activation of signalling PI3K/Akt/Bcl-2 and cyclin family, while the Wnt and Smads 2/3-β-catenin pathway was induced by 55 J/cm², 0.9 W and 0.9 W/cm². Full article

(This article belongs to the Special Issue Osteoblast Differentiation and Activity in Skeletal Diseases)

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12 pages, 1833 KiB

Open AccessArticle

Calvaria Bone Transcriptome in Mouse Models of Osteogenesis Imperfecta

by Pierre Moffatt, Iris Boraschi-Diaz, Juliana Marulanda, Ghalib Bardai and Frank Rauch

Int. J. Mol. Sci. 2021, 22(10), 5290; https://doi.org/10.3390/ijms22105290 - 18 May 2021

Cited by 7 | Viewed by 2479

Abstract

Osteogenesis imperfecta (OI) is a bone fragility disorder that is usually caused by mutations affecting collagen type I. We compared the calvaria bone tissue transcriptome of male 10-week-old heterozygous Jrt (Col1a1 mutation) and homozygous oim mice (Col1a2 mutation) to their respective [...] Read more.

Osteogenesis imperfecta (OI) is a bone fragility disorder that is usually caused by mutations affecting collagen type I. We compared the calvaria bone tissue transcriptome of male 10-week-old heterozygous Jrt (Col1a1 mutation) and homozygous oim mice (Col1a2 mutation) to their respective littermate results. We found that Jrt and oim mice shared 185 differentially expressed genes (upregulated: 106 genes; downregulated: 79 genes). A total of seven genes were upregulated by a factor of two or more in both mouse models (Cyp2e1, Slc13a5, Cgref1, Smpd3, Ifitm5, Cthrc1 and Rerg). One gene (Gypa, coding for a blood group antigen) was downregulated by a factor of two or more in both OI mouse models. Overrepresentation analyses revealed that genes involved in ‘ossification’ were significantly overrepresented among upregulated genes in both Jrt and oim mice, whereas hematopoietic genes were downregulated. Several genes involved in Wnt signaling and transforming growth factor beta signaling were upregulated in oim mice, but less so in Jrt mice. Thus, this study identified a set of genes that are dysregulated across various OI mouse models and are likely to play an important role in the pathophysiology of this disorder. Full article

(This article belongs to the Special Issue Osteoblast Differentiation and Activity in Skeletal Diseases)

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21 pages, 3837 KiB

Open AccessArticle

Increased Osteocyte Lacunae Density in the Hypermineralized Bone Matrix of Children with Osteogenesis Imperfecta Type I

by Matthias Mähr, Stéphane Blouin, Martina Behanova, Barbara M. Misof, Francis H. Glorieux, Jochen Zwerina, Frank Rauch, Markus A. Hartmann and Nadja Fratzl-Zelman

Int. J. Mol. Sci. 2021, 22(9), 4508; https://doi.org/10.3390/ijms22094508 - 26 Apr 2021

Cited by 14 | Viewed by 2825

Abstract

Osteocytes are terminally differentiated osteoblasts embedded within the bone matrix and key orchestrators of bone metabolism. However, they are generally not characterized by conventional bone histomorphometry because of their location and the limited resolution of light microscopy. OI is characterized by disturbed bone [...] Read more.

Osteocytes are terminally differentiated osteoblasts embedded within the bone matrix and key orchestrators of bone metabolism. However, they are generally not characterized by conventional bone histomorphometry because of their location and the limited resolution of light microscopy. OI is characterized by disturbed bone homeostasis, matrix abnormalities and elevated bone matrix mineralization density. To gain further insights into osteocyte characteristics and bone metabolism in OI, we evaluated 2D osteocyte lacunae sections (OLS) based on quantitative backscattered electron imaging in transiliac bone biopsy samples from children with OI type I (n = 19) and age-matched controls (n = 24). The OLS characteristics were related to previously obtained, re-visited histomorphometric parameters. Moreover, we present pediatric bone mineralization density distribution reference data in OI type I (n = 19) and controls (n = 50) obtained with a field emission scanning electron microscope. Compared to controls, OI has highly increased OLS density in cortical and trabecular bone (+50.66%, +61.73%; both p < 0.001), whereas OLS area is slightly decreased in trabecular bone (−10.28%; p = 0.015). Correlation analyses show a low to moderate, positive association of OLS density with surface-based bone formation parameters and negative association with indices of osteoblast function. In conclusion, hyperosteocytosis of the hypermineralized OI bone matrix associates with abnormal bone cell metabolism and might further impact the mechanical competence of the bone tissue. Full article

(This article belongs to the Special Issue Osteoblast Differentiation and Activity in Skeletal Diseases)

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13 pages, 2430 KiB

Open AccessArticle

Hesperidin Promotes Osteogenesis and Modulates Collagen Matrix Organization and Mineralization In Vitro and In Vivo

by Patricia A. Miguez, Stephen A. Tuin, Adam G. Robinson, Joyce Belcher, Prapaporn Jongwattanapisan, Kimberly Perley, Vinicius de Paiva Gonҫalves, Arash Hanifi, Nancy Pleshko and Elisabeth R. Barton

Int. J. Mol. Sci. 2021, 22(6), 3223; https://doi.org/10.3390/ijms22063223 - 22 Mar 2021

Cited by 15 | Viewed by 2727

Abstract

This study evaluated the direct effect of a phytochemical, hesperidin, on pre-osteoblast cell function as well as osteogenesis and collagen matrix quality, as there is little known about hesperidin’s influence in mineralized tissue formation and regeneration. Hesperidin was added to a culture of [...] Read more.

This study evaluated the direct effect of a phytochemical, hesperidin, on pre-osteoblast cell function as well as osteogenesis and collagen matrix quality, as there is little known about hesperidin’s influence in mineralized tissue formation and regeneration. Hesperidin was added to a culture of MC3T3-E1 cells at various concentrations. Cell proliferation, viability, osteogenic gene expression and deposited collagen matrix analyses were performed. Treatment with hesperidin showed significant upregulation of osteogenic markers, particularly with lower doses. Mature and compact collagen fibrils in hesperidin-treated cultures were observed by picrosirius red staining (PSR), although a thinner matrix layer was present for the higher dose of hesperidin compared to osteogenic media alone. Fourier-transform infrared spectroscopy indicated a better mineral-to-matrix ratio and matrix distribution in cultures exposed to hesperidin and confirmed less collagen deposited with the 100-µM dose of hesperidin. In vivo, hesperidin combined with a suboptimal dose of bone morphogenetic protein 2 (BMP2) (dose unable to promote healing of a rat mandible critical-sized bone defect) in a collagenous scaffold promoted a well-controlled (not ectopic) pattern of bone formation as compared to a large dose of BMP2 (previously defined as optimal in healing the critical-sized defect, although of ectopic nature). PSR staining of newly formed bone demonstrated that hesperidin can promote maturation of bone organic matrix. Our findings show, for the first time, that hesperidin has a modulatory role in mineralized tissue formation via not only osteoblast cell differentiation but also matrix organization and matrix-to-mineral ratio and could be a potential adjunct in regenerative bone therapies. Full article

(This article belongs to the Special Issue Osteoblast Differentiation and Activity in Skeletal Diseases)

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16 pages, 2508 KiB

Open AccessArticle

The Formation of the Epiphyseal Bone Plate Occurs via Combined Endochondral and Intramembranous-Like Ossification

by Ángela Fernández-Iglesias, Rocío Fuente, Helena Gil-Peña, Laura Alonso-Durán, Fernando Santos and José Manuel López

Int. J. Mol. Sci. 2021, 22(2), 900; https://doi.org/10.3390/ijms22020900 - 18 Jan 2021

Cited by 8 | Viewed by 2730

Abstract

The formation of the epiphyseal bone plate, the flat bony structure that provides strength and firmness to the growth plate cartilage, was studied in the present study by using light, confocal, and scanning electron microscopy. Results obtained evidenced that this bone tissue is [...] Read more.

The formation of the epiphyseal bone plate, the flat bony structure that provides strength and firmness to the growth plate cartilage, was studied in the present study by using light, confocal, and scanning electron microscopy. Results obtained evidenced that this bone tissue is generated by the replacement of the lower portion of the epiphyseal cartilage. However, this process differs considerably from the usual bone tissue formation through endochondral ossification. Osteoblasts deposit bone matrix on remnants of mineralized cartilage matrix that serve as a scaffold, but also on non-mineralized cartilage surfaces and as well as within the perivascular space. These processes occur simultaneously at sites located close to each other, so that, a core of the sheet of bone is established very quickly. Subsequently, thickening and reshaping occurs by appositional growth to generate a dense parallel-fibered bone structurally intermediate between woven and lamellar bone. All these processes occur in close relationship with a cartilage but most of the bone tissue is generated in a manner that may be considered as intramembranous-like. Overall, the findings here reported provide for the first time an accurate description of the tissues and events involved in the formation of the epiphyseal bone plate and gives insight into the complex cellular events underlying bone formation at different sites on the skeleton. Full article

(This article belongs to the Special Issue Osteoblast Differentiation and Activity in Skeletal Diseases)

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15 pages, 3033 KiB

Open AccessArticle

TGFβ1 Suppressed Matrix Mineralization of Osteoblasts Differentiation by Regulating SMURF1–C/EBPβ–DKK1 Axis

by Bora Nam, Hyosun Park, Young Lim Lee, Younseo Oh, Jinsung Park, So Yeon Kim, Subin Weon, Sung Hoon Choi, Jae-Hyuk Yang, Sungsin Jo and Tae-Hwan Kim

Int. J. Mol. Sci. 2020, 21(24), 9771; https://doi.org/10.3390/ijms21249771 - 21 Dec 2020

Cited by 22 | Viewed by 2543

Abstract

Transforming growth factor β1 (TGFβ1) is a major mediator in the modulation of osteoblast differentiation. However, the underlying molecular mechanism is still not fully understood. Here, we show that TGFβ1 has a dual stage-dependent role in osteoblast differentiation; TGFβ1 induced matrix maturation but [...] Read more.

Transforming growth factor β1 (TGFβ1) is a major mediator in the modulation of osteoblast differentiation. However, the underlying molecular mechanism is still not fully understood. Here, we show that TGFβ1 has a dual stage-dependent role in osteoblast differentiation; TGFβ1 induced matrix maturation but inhibited matrix mineralization. We discovered the underlying mechanism of the TGFβ1 inhibitory role in mineralization using human osteoprogenitors. In particular, the matrix mineralization-related genes of osteoblasts such as osteocalcin (OCN), Dickkopf 1 (DKK1), and CCAAT/enhancer-binding protein beta (C/EBPβ) were dramatically suppressed by TGFβ1 treatment. The suppressive effects of TGFβ1 were reversed with anti-TGFβ1 treatment. Mechanically, TGFβ1 decreased protein levels of C/EBPβ without changing mRNA levels and reduced both mRNA and protein levels of DKK1. The degradation of the C/EBPβ protein by TGFβ1 was dependent on the ubiquitin–proteasome pathway. TGFβ1 degraded the C/EBPβ protein by inducing the expression of the E3 ubiquitin ligase Smad ubiquitin regulatory factor 1 (SMURF1) at the transcript level, thereby reducing the C/EBPβ-DKK1 regulatory mechanism. Collectively, our findings suggest that TGFβ1 suppressed the matrix mineralization of osteoblast differentiation by regulating the SMURF1-C/EBPβ-DKK1 axis. Full article

(This article belongs to the Special Issue Osteoblast Differentiation and Activity in Skeletal Diseases)

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Review

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12 pages, 654 KiB

Open AccessReview

Osteoblast Dysfunction in Non-Hereditary Sclerosing Bone Diseases

by Liberato Giardullo, Alberto Altomare, Cinzia Rotondo, Addolorata Corrado and Francesco Paolo Cantatore

Int. J. Mol. Sci. 2021, 22(15), 7980; https://doi.org/10.3390/ijms22157980 - 26 Jul 2021

Cited by 1 | Viewed by 3058

Abstract

A review of the available literature was performed in order to summarize the existing evidence between osteoblast dysfunction and clinical features in non-hereditary sclerosing bone diseases. It has been known that proliferation and migration of osteoblasts are concerted by soluble factors such as [...] Read more.

A review of the available literature was performed in order to summarize the existing evidence between osteoblast dysfunction and clinical features in non-hereditary sclerosing bone diseases. It has been known that proliferation and migration of osteoblasts are concerted by soluble factors such as fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), transforming growth factor (TGF), bone morphogenetic protein (BMP) but also by signal transduction cascades such as Wnt signaling pathway. Protein kinases play also a leading role in triggering the activation of osteoblasts in this group of diseases. Post-zygotic changes in mitogen-activated protein kinase (MAPK) have been shown to be associated with sporadic cases of Melorheostosis. Serum levels of FGF and PDGF have been shown to be increased in myelofibrosis, although studies focusing on Sphingosine-1-phosphate receptor was shown to be strongly expressed in Paget disease of the bone, which may partially explain the osteoblastic hyperactivity during this condition. Pathophysiological mechanisms of osteoblasts in osteoblastic metastases have been studied much more thoroughly than in rare sclerosing syndromes: striking cellular mechanisms such as osteomimicry or complex intercellular signaling alterations have been described. Further research is needed to describe pathological mechanisms by which rare sclerosing non hereditary diseases lead to osteoblast dysfunction. Full article

(This article belongs to the Special Issue Osteoblast Differentiation and Activity in Skeletal Diseases)

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12 pages, 932 KiB

Open AccessReview

Expression and Role of Ubiquitin-Specific Peptidases in Osteoblasts

by Hadla Hariri and René St-Arnaud

Int. J. Mol. Sci. 2021, 22(14), 7746; https://doi.org/10.3390/ijms22147746 - 20 Jul 2021

Cited by 9 | Viewed by 2321

Abstract

The ubiquitin-proteasome system regulates biological processes in normal and diseased states. Recent investigations have focused on ubiquitin-dependent modifications and their impacts on cellular function, commitment, and differentiation. Ubiquitination is reversed by deubiquitinases, including ubiquitin-specific peptidases (USPs), whose roles have been widely investigated. In [...] Read more.

The ubiquitin-proteasome system regulates biological processes in normal and diseased states. Recent investigations have focused on ubiquitin-dependent modifications and their impacts on cellular function, commitment, and differentiation. Ubiquitination is reversed by deubiquitinases, including ubiquitin-specific peptidases (USPs), whose roles have been widely investigated. In this review, we explore recent findings highlighting the regulatory functions of USPs in osteoblasts and providing insight into the molecular mechanisms governing their actions during bone formation. We also give a brief overview of our work on USP53, a target of PTH in osteoblasts and a regulator of mesenchymal cell lineage fate decisions. Emerging evidence addresses questions pertaining to the complex layers of regulation exerted by USPs on osteoblast signaling. We provide a short overview of our and others’ understanding of how USPs modulate osteoblastogenesis. However, further studies using knockout mouse models are needed to fully understand the mechanisms underpinning USPs actions. Full article

(This article belongs to the Special Issue Osteoblast Differentiation and Activity in Skeletal Diseases)

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13 pages, 19847 KiB

Open AccessReview

Osteoblast Differentiation and Signaling: Established Concepts and Emerging Topics

by Marco Ponzetti and Nadia Rucci

Int. J. Mol. Sci. 2021, 22(13), 6651; https://doi.org/10.3390/ijms22136651 - 22 Jun 2021

Cited by 68 | Viewed by 7913

Abstract

Osteoblasts, the cells that build up our skeleton, are remarkably versatile and important cells that need tight regulation in all the phases of their differentiation to guarantee proper skeletal development and homeostasis. Although we know many of the key pathways involved in osteoblast [...] Read more.

Osteoblasts, the cells that build up our skeleton, are remarkably versatile and important cells that need tight regulation in all the phases of their differentiation to guarantee proper skeletal development and homeostasis. Although we know many of the key pathways involved in osteoblast differentiation and signaling, it is becoming clearer and clearer that this is just the tip of the iceberg, and we are constantly discovering novel concepts in osteoblast physiology. In this review, we discuss well-established pathways of osteoblastic differentiation, i.e., the classical ones committing mesenchymal stromal cells to osteoblast, and then osteocytes as well as recently emerged players. In particular, we discuss micro (mi)RNAs, long non-coding (lnc)RNAs, circular (circ)RNAs, and extracellular vesicles, focusing on the mechanisms through which osteoblasts are regulated by these factors, and conversely, how they use extracellular vesicles to communicate with the surrounding microenvironment. Full article

(This article belongs to the Special Issue Osteoblast Differentiation and Activity in Skeletal Diseases)

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21 pages, 1464 KiB

Open AccessReview

Regulation and Role of Transcription Factors in Osteogenesis

by Wilson Cheuk Wing Chan, Zhijia Tan, Michael Kai Tsun To and Danny Chan

Int. J. Mol. Sci. 2021, 22(11), 5445; https://doi.org/10.3390/ijms22115445 - 21 May 2021

Cited by 100 | Viewed by 8318

Abstract

Bone is a dynamic tissue constantly responding to environmental changes such as nutritional and mechanical stress. Bone homeostasis in adult life is maintained through bone remodeling, a controlled and balanced process between bone-resorbing osteoclasts and bone-forming osteoblasts. Osteoblasts secrete matrix, with some being [...] Read more.

Bone is a dynamic tissue constantly responding to environmental changes such as nutritional and mechanical stress. Bone homeostasis in adult life is maintained through bone remodeling, a controlled and balanced process between bone-resorbing osteoclasts and bone-forming osteoblasts. Osteoblasts secrete matrix, with some being buried within the newly formed bone, and differentiate to osteocytes. During embryogenesis, bones are formed through intramembraneous or endochondral ossification. The former involves a direct differentiation of mesenchymal progenitor to osteoblasts, and the latter is through a cartilage template that is subsequently converted to bone. Advances in lineage tracing, cell sorting, and single-cell transcriptome studies have enabled new discoveries of gene regulation, and new populations of skeletal stem cells in multiple niches, including the cartilage growth plate, chondro-osseous junction, bone, and bone marrow, in embryonic development and postnatal life. Osteoblast differentiation is regulated by a master transcription factor RUNX2 and other factors such as OSX/SP7 and ATF4. Developmental and environmental cues affect the transcriptional activities of osteoblasts from lineage commitment to differentiation at multiple levels, fine-tuned with the involvement of co-factors, microRNAs, epigenetics, systemic factors, circadian rhythm, and the microenvironments. In this review, we will discuss these topics in relation to transcriptional controls in osteogenesis. Full article

(This article belongs to the Special Issue Osteoblast Differentiation and Activity in Skeletal Diseases)

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13 pages, 342 KiB

Open AccessReview

Impact of Intrinsic Muscle Weakness on Muscle–Bone Crosstalk in Osteogenesis Imperfecta

by Victoria L. Gremminger and Charlotte L. Phillips

Int. J. Mol. Sci. 2021, 22(9), 4963; https://doi.org/10.3390/ijms22094963 - 07 May 2021

Cited by 6 | Viewed by 3830

Abstract

Bone and muscle are highly synergistic tissues that communicate extensively via mechanotransduction and biochemical signaling. Osteogenesis imperfecta (OI) is a heritable connective tissue disorder of severe bone fragility and recently recognized skeletal muscle weakness. The presence of impaired bone and muscle in OI [...] Read more.

Bone and muscle are highly synergistic tissues that communicate extensively via mechanotransduction and biochemical signaling. Osteogenesis imperfecta (OI) is a heritable connective tissue disorder of severe bone fragility and recently recognized skeletal muscle weakness. The presence of impaired bone and muscle in OI leads to a continuous cycle of altered muscle–bone crosstalk with weak muscles further compromising bone and vice versa. Currently, there is no cure for OI and understanding the pathogenesis of the skeletal muscle weakness in relation to the bone pathogenesis of OI in light of the critical role of muscle–bone crosstalk is essential to developing and identifying novel therapeutic targets and strategies for OI. This review will highlight how impaired skeletal muscle function contributes to the pathophysiology of OI and how this phenomenon further perpetuates bone fragility. Full article

(This article belongs to the Special Issue Osteoblast Differentiation and Activity in Skeletal Diseases)

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26 pages, 10921 KiB

Open AccessReview

Signaling Pathways in Bone Development and Their Related Skeletal Dysplasia

by Alessandra Guasto and Valérie Cormier-Daire

Int. J. Mol. Sci. 2021, 22(9), 4321; https://doi.org/10.3390/ijms22094321 - 21 Apr 2021

Cited by 24 | Viewed by 4791

Abstract

Bone development is a tightly regulated process. Several integrated signaling pathways including HH, PTHrP, WNT, NOTCH, TGF-β, BMP, FGF and the transcription factors SOX9, RUNX2 and OSX are essential for proper skeletal development. Misregulation of these signaling pathways can cause a large spectrum [...] Read more.

Bone development is a tightly regulated process. Several integrated signaling pathways including HH, PTHrP, WNT, NOTCH, TGF-β, BMP, FGF and the transcription factors SOX9, RUNX2 and OSX are essential for proper skeletal development. Misregulation of these signaling pathways can cause a large spectrum of congenital conditions categorized as skeletal dysplasia. Since the signaling pathways involved in skeletal dysplasia interact at multiple levels and have a different role depending on the time of action (early or late in chondrogenesis and osteoblastogenesis), it is still difficult to precisely explain the physiopathological mechanisms of skeletal disorders. However, in recent years, significant progress has been made in elucidating the mechanisms of these signaling pathways and genotype–phenotype correlations have helped to elucidate their role in skeletogenesis. Here, we review the principal signaling pathways involved in bone development and their associated skeletal dysplasia. Full article

(This article belongs to the Special Issue Osteoblast Differentiation and Activity in Skeletal Diseases)

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16 pages, 1103 KiB

Open AccessReview

Regulation of Osteoblast Differentiation by Cytokine Networks

by Dulshara Sachini Amarasekara, Sumi Kim and Jaerang Rho

Int. J. Mol. Sci. 2021, 22(6), 2851; https://doi.org/10.3390/ijms22062851 - 11 Mar 2021

Cited by 142 | Viewed by 17160

Abstract

Osteoblasts, which are bone-forming cells, play pivotal roles in bone modeling and remodeling. Osteoblast differentiation, also known as osteoblastogenesis, is orchestrated by transcription factors, such as runt-related transcription factor 1/2, osterix, activating transcription factor 4, special AT-rich sequence-binding protein 2 and activator protein-1. [...] Read more.

Osteoblasts, which are bone-forming cells, play pivotal roles in bone modeling and remodeling. Osteoblast differentiation, also known as osteoblastogenesis, is orchestrated by transcription factors, such as runt-related transcription factor 1/2, osterix, activating transcription factor 4, special AT-rich sequence-binding protein 2 and activator protein-1. Osteoblastogenesis is regulated by a network of cytokines under physiological and pathophysiological conditions. Osteoblastogenic cytokines, such as interleukin-10 (IL-10), IL-11, IL-18, interferon-γ (IFN-γ), cardiotrophin-1 and oncostatin M, promote osteoblastogenesis, whereas anti-osteoblastogenic cytokines, such as tumor necrosis factor-α (TNF-α), TNF-β, IL-1α, IL-4, IL-7, IL-12, IL-13, IL-23, IFN-α, IFN-β, leukemia inhibitory factor, cardiotrophin-like cytokine, and ciliary neurotrophic factor, downregulate osteoblastogenesis. Although there are gaps in the body of knowledge regarding the interplay of cytokine networks in osteoblastogenesis, cytokines appear to be potential therapeutic targets in bone-related diseases. Thus, in this study, we review and discuss our osteoblast, osteoblast differentiation, osteoblastogenesis, cytokines, signaling pathway of cytokine networks in osteoblastogenesis. Full article

(This article belongs to the Special Issue Osteoblast Differentiation and Activity in Skeletal Diseases)

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