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Bone Development and Regeneration 2.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (31 August 2022) | Viewed by 38145

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Prof. Dr. Kazuo Yudoh

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Department of Frontier Medicine, Institute of Medical Science, St. Marianna University School of Medicine, Kawasaki 216-8512, Japan
Interests: articular cartilage; chondrocytes; polychondritis
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Dear Colleagues,

Bone is a fascinating tissue conferring structural body support, mechanical integrity, and organ protection. A more holistic perspective accommodates bone as an integral organ that together with other tissues not only regulates mineral homeostasis and maintains the hematopoietic niche but also acts as an endocrine organ to contribute and regulate numerous metabolic processes that are independent of mineral metabolism.

Bone formation is orchestrated by multiple stimuli and processes and based on their embryological origin, ossification of collagenous tissues is regulated by different paths. Compared to other musculoskeletal tissues, bone has a high regenerative potential, with the skeleton being fully remodeled multiple times throughout the human lifespan. However, with a continuous extension of live expectancy, aging-related bone issues and pathologies become more prominent, which negatively impacts the quality of life of an increasing number of individuals.

While several mechanisms and pathways like the WNT, BMP2 or PTH signaling pathway have been thoroughly studied over the last few decades, new scientific capabilities and perspectives allow for a more integrative and comprehensive view on bone development and bone regeneration. With the revolutionary rise of the -omics field and the latest advances in cell lineage tracing models and single cell analysis, new molecular mechanisms are being elucidated and novel important players are being recognized. For example, our understanding of epigenetic processes or metabolites that control bone integrity is growing at a rapid pace. In concert with the progress made recently in the development and design of new scaffolds and biomaterials, all these advances generate novel and alternative approaches to target bone regeneration and are under investigation with the potential to increase the quality of life for many.

This Special Issue of IJMS provides a platform for high-quality publications elucidating novel insights on bone development and/or presenting new molecular and conceptual approaches for the manipulation of osteogenesis and bone regeneration, as well as bone homeostasis. This will generate a representative picture of the latest advances in bone research and serve as a road map for where the bone field is headed.

Prof. Dr. Kazuo Yudoh
Guest Editor

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Keywords

osteoblast
osteocyte
osteoclast
mesenchymal stem cell
cell differentiation
epigenetics
omics
integrative analysis
biomaterials

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Related Special Issues

Bone Development and Regeneration in International Journal of Molecular Sciences (15 articles)
Bone Development and Regeneration 3.0 in International Journal of Molecular Sciences (9 articles)

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Research

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13 pages, 1855 KiB

Open AccessArticle

Transcription Factor Lmx1b Negatively Regulates Osteoblast Differentiation and Bone Formation

by Kabsun Kim, Jung Ha Kim, Inyoung Kim, Semun Seong, Jeong Eun Han, Keun-Bae Lee, Jeong-Tae Koh and Nacksung Kim

Int. J. Mol. Sci. 2022, 23(9), 5225; https://doi.org/10.3390/ijms23095225 - 7 May 2022

Cited by 4 | Viewed by 2494

Abstract

The LIM-homeodomain transcription factor Lmx1b plays a key role in body pattern formation during development. Although Lmx1b is essential for the normal development of multiple tissues, its regulatory mechanism in bone cells remains unclear. Here, we demonstrated that Lmx1b negatively regulates bone morphogenic protein 2 (BMP2)-induced osteoblast differentiation. Overexpressed Lmx1b in the osteoblast precursor cells inhibited alkaline phosphatase (ALP) activity and nodule formation, as well as the expression of osteoblast maker genes, including runt-related transcription factor 2 (Runx2), alkaline phosphatase (Alpl), bone sialoprotein (Ibsp), and osteocalcin (Bglap). Conversely, the knockdown of Lmx1b in the osteoblast precursors enhanced the osteoblast differentiation and function. Lmx1b physically interacted with and repressed the transcriptional activity of Runx2 by reducing the recruitment of Runx2 to the promoter region of its target genes. In vivo analysis of BMP2-induced ectopic bone formation revealed that the knockdown of Lmx1b promoted osteogenic differentiation and bone regeneration. Our data demonstrate that Lmx1b negatively regulates osteoblast differentiation and function through regulation of Runx2 and provides a molecular basis for therapeutic targets for bone diseases. Full article

(This article belongs to the Special Issue Bone Development and Regeneration 2.0)

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17 pages, 1875 KiB

Open AccessArticle

TBP, PPIA, YWHAZ and EF1A1 Are the Most Stably Expressed Genes during Osteogenic Differentiation

by Nina Franko, Lucija Ana Vrščaj, Taja Zore, Barbara Ostanek, Janja Marc and Jasna Lojk

Int. J. Mol. Sci. 2022, 23(8), 4257; https://doi.org/10.3390/ijms23084257 - 12 Apr 2022

Cited by 7 | Viewed by 2955

Abstract

RT-qPCR is the gold standard and the most commonly used method for measuring gene expression. Selection of appropriate reference gene(s) for normalization is a crucial part of RT-qPCR experimental design, which allows accurate quantification and reliability of the results. Because there is no universal reference gene and even commonly used housekeeping genes’ expression can vary under certain conditions, careful selection of an appropriate internal control must be performed for each cell type or tissue and experimental design. The aim of this study was to identify the most stable reference genes during osteogenic differentiation of the human osteosarcoma cell lines MG-63, HOS, and SaOS-2 using the geNorm, NormFinder, and BestKeeper statistical algorithms. Our results show that TBP, PPIA, YWHAZ, and EF1A1 are the most stably expressed genes, while ACTB, and 18S rRNA expressions are most variable. These data provide a basis for future RT-qPCR normalizations when studying gene expression during osteogenic differentiation, for example, in studies of osteoporosis and other bone diseases. Full article

(This article belongs to the Special Issue Bone Development and Regeneration 2.0)

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18 pages, 57669 KiB

Open AccessArticle

Bone Reconstruction Using Two-Layer Porcine-Derived Bone Scaffold Composed of Cortical and Cancellous Bones in a Rabbit Calvarial Defect Model

by Yong-Ho Seo, Su-Hyun Hwang, Yu-Na Kim, Hyung-Joon Kim, Eun-Bin Bae and Jung-Bo Huh

Int. J. Mol. Sci. 2022, 23(5), 2647; https://doi.org/10.3390/ijms23052647 - 28 Feb 2022

Cited by 9 | Viewed by 2573

Abstract

In this study, we aimed to investigate the bone regeneration efficiency of two-layer porcine-derived bone scaffolds composed of cancellous and cortical bones in a rabbit calvarial defect model. Four circular calvaria defects were formed on cranium of rabbit and were filled with block bone scaffolds of each group: cortical bone block (Cortical group), cancellous bone block (Cancellous group), and two-layer bone block (2layer group). After 8 weeks, new bones were primarily observed in cancellous parts of the Cancellous and 2layer groups, while the Cortical group exhibited few new bones. In the results of new bone volume and area analyses, the Cancellous group showed the highest value, followed by the 2layer group, and were significantly higher than the Cortical group. Within the limitations of this study, the cancellous and two-layer porcine-derived bone scaffolds showed satisfactory bone regeneration efficiency; further studies on regulating the ratio of cortical and cancellous bones in two-layer bones are needed. Full article

(This article belongs to the Special Issue Bone Development and Regeneration 2.0)

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15 pages, 2699 KiB

Open AccessArticle

Cytoskeletal Protein 4.1G Is Essential for the Primary Ciliogenesis and Osteoblast Differentiation in Bone Formation

by Masaki Saito, Marina Hirano, Tomohiro Izumi, Yu Mori, Kentaro Ito, Yurika Saitoh, Nobuo Terada, Takeya Sato and Jun Sukegawa

Int. J. Mol. Sci. 2022, 23(4), 2094; https://doi.org/10.3390/ijms23042094 - 14 Feb 2022

Cited by 8 | Viewed by 2522

Abstract

The primary cilium is a hair-like immotile organelle with specific membrane receptors, including the receptor of Hedgehog signaling, smoothened. The cilium organized in preosteoblasts promotes differentiation of the cells into osteoblasts (osteoblast differentiation) by mediating Hedgehog signaling to achieve bone formation. Notably, 4.1G is a plasma membrane-associated cytoskeletal protein that plays essential roles in various tissues, including the peripheral nervous system, testis, and retina. However, its function in the bone remains unexplored. In this study, we identified 4.1G expression in the bone. We found that, in the 4.1G-knockout mice, calcium deposits and primary cilium formation were suppressed in the trabecular bone, which is preosteoblast-rich region of the newborn tibia, indicating that 4.1G is a prerequisite for osteoblast differentiation by organizing the primary cilia in preosteoblasts. Next, we found that the primary cilium was elongated in the differentiating mouse preosteoblast cell line MC3T3-E1, whereas the knockdown of 4.1G suppressed its elongation. Moreover, 4.1G-knockdown suppressed the induction of the cilia-mediated Hedgehog signaling and subsequent osteoblast differentiation. These results demonstrate a new regulatory mechanism of 4.1G in bone formation that promotes the primary ciliogenesis in the differentiating preosteoblasts and induction of cilia-mediated osteoblast differentiation, resulting in bone formation at the newborn stage. Full article

(This article belongs to the Special Issue Bone Development and Regeneration 2.0)

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11 pages, 2201 KiB

Open AccessArticle

NACA and LRP6 Are Part of a Common Genetic Pathway Necessary for Full Anabolic Response to Intermittent PTH

by René St-Arnaud, Martin Pellicelli, Mahmoud Ismail, Alice Arabian, Toghrul Jafarov and Chengji J. Zhou

Int. J. Mol. Sci. 2022, 23(2), 940; https://doi.org/10.3390/ijms23020940 - 15 Jan 2022

Viewed by 1856

Abstract

PTH induces phosphorylation of the transcriptional coregulator NACA on serine 99 through Gαs and PKA. This leads to nuclear translocation of NACA and expression of the target gene Lrp6, encoding a coreceptor of the PTH receptor (PTH1R) necessary for full anabolic response to intermittent PTH (iPTH) treatment. We hypothesized that maintaining enough functional PTH1R/LRP6 coreceptor complexes at the plasma membrane through NACA-dependent Lrp6 transcription is important to ensure maximal response to iPTH. To test this model, we generated compound heterozygous mice in which one allele each of Naca and Lrp6 is inactivated in osteoblasts and osteocytes, using a knock-in strain with a Naca⁹⁹ Ser-to-Ala mutation and an Lrp6 floxed strain (test genotype: Naca^99S/A; Lrp6^+/fl;OCN-Cre). Four-month-old females were injected with vehicle or 100 μg/kg PTH(1-34) once daily, 5 days a week for 4 weeks. Control mice showed significant increases in vertebral trabecular bone mass and biomechanical properties that were abolished in compound heterozygotes. Lrp6 expression was reduced in compound heterozygotes vs. controls. The iPTH treatment increased Alpl and Col1a1 mRNA levels in the control but not in the test group. These results confirm that NACA and LRP6 form part of a common genetic pathway that is necessary for the full anabolic effect of iPTH. Full article

(This article belongs to the Special Issue Bone Development and Regeneration 2.0)

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16 pages, 8522 KiB

Open AccessArticle

BMP3 Affects Cortical and Trabecular Long Bone Development in Mice

by Ivan Banovac, Lovorka Grgurevic, Viktorija Rumenovic, Slobodan Vukicevic and Igor Erjavec

Int. J. Mol. Sci. 2022, 23(2), 785; https://doi.org/10.3390/ijms23020785 - 12 Jan 2022

Cited by 8 | Viewed by 2995

Abstract

Bone morphogenetic proteins (BMPs) have a major role in tissue development. BMP3 is synthesized in osteocytes and mature osteoblasts and has an antagonistic effect on other BMPs in bone tissue. The main aim of this study was to fully characterize cortical bone and trabecular bone of long bones in both male and female Bmp3^−/− mice. To investigate the effect of Bmp3 from birth to maturity, we compared Bmp3^−/− mice with wild-type littermates at the following stages of postnatal development: 1 day (P0), 2 weeks (P14), 8 weeks and 16 weeks of age. Bmp3 deletion was confirmed using X-gal staining in P0 animals. Cartilage and bone tissue were examined in P14 animals using Alcian Blue/Alizarin Red staining. Detailed long bone analysis was performed in 8-week-old and 16-week-old animals using micro-CT. The Bmp3 reporter signal was localized in bone tissue, hair follicles, and lungs. Bone mineralization at 2 weeks of age was increased in long bones of Bmp3^−/− mice. Bmp3 deletion was shown to affect the skeleton until adulthood, where increased cortical and trabecular bone parameters were found in young and adult mice of both sexes, while delayed mineralization of the epiphyseal growth plate was found in adult Bmp3^−/− mice. Full article

(This article belongs to the Special Issue Bone Development and Regeneration 2.0)

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19 pages, 6004 KiB

Open AccessArticle

Metformin-Incorporated Gelatin/Nano-Hydroxyapatite Scaffolds Promotes Bone Regeneration in Critical Size Rat Alveolar Bone Defect Model

by Chih-Hsiang Fang, Chung-Kai Sun, Yi-Wen Lin, Min-Chih Hung, Hung-Ying Lin, Ching-Hung Li, I-Ping Lin, Hung-Chen Chang, Jui-Sheng Sun and Jenny Zwei-Chieng Chang

Int. J. Mol. Sci. 2022, 23(1), 558; https://doi.org/10.3390/ijms23010558 - 5 Jan 2022

Cited by 16 | Viewed by 4560

Abstract

In this study, we fabricated gelatin/nano-hydroxyapatite/metformin scaffold (GHMS) and compared its effectiveness in bone regeneration with extraction-only, Sinbone, and Bio-Oss Collagen^® groups in a critical size rat alveolar bone defect model. GHMS was synthesized by co-precipitating calcium hydroxide and orthophosphoric acid within gelatin solution, incorporating metformin, and cross-linked by microbial transglutaminase. The morphology, characterization, and biocompatibility of scaffold were examined. The in vitro effects of GHMS on osteogenic gene and protein expressions were evaluated. In vivo bone formation was assessed in a critical size rat alveolar bone defect model with micro-computed tomography and histological examination by comparing GHMS with extraction-only, Sinbone, and Bio-Oss Collagen^®. The synthesized GHMS had a highly interconnected porous structure with a mean pore size of 81.85 ± 13.8 µm. GHMS exhibited good biocompatibility; promoted ALPL, RUNX2, SP7, BGLAP, SPARC and Col1a1 gene expressions; and upregulated the synthesis of osteogenic proteins, including osteonectin, osteocalcin, and collagen type I. In critical size rat alveolar bone defects, GHMS showed superior bone regeneration compared to extraction-only, Sinbone, and Bio-Oss Collagen^® groups as manifested by greater alveolar ridge preservation, while more bone formation with a lower percentage of connective tissue and residual scaffold at the defect sites grafted with GHMS in histological staining. The GHMS presented in this study may be used as a potential bone substitute to regenerate alveolar bone. The good biocompatibility, relatively fast degradation, interconnected pores allowing vascularization, and higher bioactivity properties of the components of the GHMS (gelatin, nHA, and metformin) may contribute to direct osteogenesis. Full article

(This article belongs to the Special Issue Bone Development and Regeneration 2.0)

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14 pages, 4267 KiB

Open AccessArticle

In Vivo Efficacy of Neutrophil-Mediated Bone Regeneration Using a Rabbit Calvarial Defect Model

by Thanuja D. K. Herath, Leonardo Saigo, Benoit Schaller, Anis Larbi, Swee Hin Teoh, Charles James Kirkpatrick and Bee Tin Goh

Int. J. Mol. Sci. 2021, 22(23), 13016; https://doi.org/10.3390/ijms222313016 - 1 Dec 2021

Cited by 13 | Viewed by 2847

Abstract

Reconstruction of bone due to surgical removal or disease-related bony defects is a clinical challenge. It is known that the immune system exerts positive immunomodulatory effects on tissue repair and regeneration. In this study, we evaluated the in vivo efficacy of autologous neutrophils on bone regeneration using a rabbit calvarial defect model. Methods: Twelve rabbits, each with two surgically created calvarial bone defects (10 mm diameter), were randomly divided into two groups; (i) single application of neutrophils (SA-NP) vs. SA-NP control, and (ii) repetitive application of neutrophils (RA-NP) vs. RA-NP control. The animals were euthanized at 4 and 8 weeks post-operatively and the treatment outcomes were evaluated by micro-computed tomography, histology, and histomorphometric analyses. Results: The micro-CT analysis showed a significantly higher bone volume fraction (bone volume/total volume) in the neutrophil-treated groups, i.e., median interquartile range (IQR) SA-NP (18) and RA-NP (24), compared with the untreated controls, i.e., SA-NP (7) and RA-NP (14) at 4 weeks (p < 0.05). Similarly, new bone area fraction (bone area/total area) was significantly higher in neutrophil-treated groups at 4 weeks (p < 0.05). Both SA-NP and RA-NP had a considerably higher bone volume and bone area at 8 weeks, although the difference was not statistically significant. In addition, immunohistochemical analysis at 8 weeks revealed a higher expression of osteocalcin in both SA-NP and RA-NP groups. Conclusions: The present study provides first hand evidence that autologous neutrophils may have a positive effect on promoting new bone formation. Future studies should be performed with a larger sample size in non-human primate models. If proven feasible, this new promising strategy could bring clinical benefits for bone defects to the field of oral and maxillofacial surgery. Full article

(This article belongs to the Special Issue Bone Development and Regeneration 2.0)

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17 pages, 7338 KiB

Open AccessArticle

Aromatic Bis[aminomethylidenebis(phosphonic)] Acids Prevent Ovariectomy-Induced Bone Loss and Suppress Osteoclastogenesis in Mice

by Anna Nasulewicz-Goldeman, Waldemar Goldeman, Anna Nikodem, Marcin Nowak, Diana Papiernik, Tomasz M. Goszczyński and Joanna Wietrzyk

Int. J. Mol. Sci. 2021, 22(17), 9590; https://doi.org/10.3390/ijms22179590 - 3 Sep 2021

Cited by 1 | Viewed by 2504

Abstract

Osteoporosis is a skeletal disease associated with excessive bone turnover. Among the compounds with antiresorptive activity, nitrogen-containing bisphosphonates play the most important role in antiosteoporotic treatment. In previous studies, we obtained two aminomethylidenebisphosphonates—benzene-1,4-bis[aminomethylidene(bisphosphonic)] (WG12399C) acid and naphthalene-1,5-bis[aminomethylidene(bisphosphonic)] (WG12592A) acid—which showed a significant antiproliferative activity toward J774E macrophages, a model of osteoclast precursors. The aim of these studies was to evaluate the antiresorptive activity of these aminobisphosphonates in ovariectomized (OVX) Balb/c mice. The influence of WG12399C and WG12592A administration on bone microstructure and bone strength was studied. Intravenous injections of WG12399C and WG12592A bisphosphonates remarkably prevented OVX-induced bone loss; for example, they sustained bone mineral density at control levels and restored other bone parameters such as trabecular separation. This was accompanied by a remarkable reduction in the number of TRAP-positive cells in bone tissue. However, a significant improvement in the quality of bone structure did not correlate with a parallel increase in bone strength. In ex vivo studies, WG12399C and WG12592A remarkably bisphosphonates reduced osteoclastogenesis and partially inhibited the resorptive activity of mature osteoclasts. Our results show interesting biological activity of two aminobisphosphonates, which may be of interest in the context of antiresorptive therapy. Full article

(This article belongs to the Special Issue Bone Development and Regeneration 2.0)

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17 pages, 15345 KiB

Open AccessArticle

Physiologic Mechanical Stress Directly Induces Bone Formation by Activating Glucose Transporter 1 (Glut 1) in Osteoblasts, Inducing Signaling via NAD+-Dependent Deacetylase (Sirtuin 1) and Runt-Related Transcription Factor 2 (Runx2)

by Shu Somemura, Takanori Kumai, Kanaka Yatabe, Chizuko Sasaki, Hiroto Fujiya, Hisateru Niki and Kazuo Yudoh

Int. J. Mol. Sci. 2021, 22(16), 9070; https://doi.org/10.3390/ijms22169070 - 23 Aug 2021

Cited by 12 | Viewed by 3183

Abstract

Mechanical stress is an important factor affecting bone tissue homeostasis. We focused on the interactions among mechanical stress, glucose uptake via glucose transporter 1 (Glut1), and the cellular energy sensor sirtuin 1 (SIRT1) in osteoblast energy metabolism, since it has been recognized that SIRT1, an NAD+-dependent deacetylase, may function as a master regulator of the mechanical stress response as well as of cellular energy metabolism (glucose metabolism). In addition, it has already been demonstrated that SIRT1 regulates the activity of the osteogenic transcription factor runt-related transcription factor 2 (Runx2). The effects of mechanical loading on cellular activities and the expressions of Glut1, SIRT1, and Runx2 were evaluated in osteoblasts and chondrocytes in a 3D cell–collagen sponge construct. Compressive mechanical loading increased osteoblast activity. Mechanical loading also significantly increased the expression of Glut1, significantly decreased the expression of SIRT1, and significantly increased the expression of Runx2 in osteoblasts in comparison with non-loaded osteoblasts. Incubation with a Glut1 inhibitor blocked mechanical stress-induced changes in SIRT1 and Runx2 in osteoblasts. In contrast with osteoblasts, the expressions of Glut1, SIRT1, and Runx2 in chondrocytes were not affected by loading. Our present study indicated that mechanical stress induced the upregulation of Glut1 following the downregulation of SIRT1 and the upregulation of Runx2 in osteoblasts but not in chondrocytes. Since SIRT1 is known to negatively regulate Runx2 activity, a mechanical stress-induced downregulation of SIRT1 may lead to the upregulation of Runx2, resulting in osteoblast differentiation. Incubation with a Glut1 inhibitor the blocked mechanical stress-induced downregulation of SIRT1 following the upregulation of Runx2, suggesting that Glut1 is necessary to mediate the responses of SIRT1 and Runx2 to mechanical loading in osteoblasts. Full article

(This article belongs to the Special Issue Bone Development and Regeneration 2.0)

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Review

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18 pages, 1491 KiB

Open AccessReview

Mechanisms during Osteogenic Differentiation in Human Dental Follicle Cells

by Christian Morsczeck

Int. J. Mol. Sci. 2022, 23(11), 5945; https://doi.org/10.3390/ijms23115945 - 25 May 2022

Cited by 19 | Viewed by 5245

Abstract

Human dental follicle cells (DFCs) as periodontal progenitor cells are used for studies and research in regenerative medicine and not only in dentistry. Even if innovative regenerative therapies in medicine are often considered the main research area for dental stem cells, these cells are also very useful in basic research and here, for example, for the elucidation of molecular processes in the differentiation into mineralizing cells. This article summarizes the molecular mechanisms driving osteogenic differentiation of DFCs. The positive feedback loop of bone morphogenetic protein (BMP) 2 and homeobox protein DLX3 and a signaling pathway associated with protein kinase B (AKT) and protein kinase C (PKC) are presented and further insights related to other signaling pathways such as the WNT signaling pathway are explained. Subsequently, some works are presented that have investigated epigenetic modifications and non-coding ncRNAs and their connection with the osteogenic differentiation of DFCs. In addition, studies are presented that have shown the influence of extracellular matrix molecules or fundamental biological processes such as cellular senescence on osteogenic differentiation. The putative role of factors associated with inflammatory processes, such as interleukin 8, in osteogenic differentiation is also briefly discussed. This article summarizes the most important insights into the mechanisms of osteogenic differentiation in DFCs and is intended to be a small help in the direction of new research projects in this area. Full article

(This article belongs to the Special Issue Bone Development and Regeneration 2.0)

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18 pages, 2388 KiB

Open AccessReview

Educating EVs to Improve Bone Regeneration: Getting Closer to the Clinic

by Arantza Infante, Natividad Alcorta-Sevillano, Iratxe Macías and Clara I. Rodríguez

Int. J. Mol. Sci. 2022, 23(3), 1865; https://doi.org/10.3390/ijms23031865 - 7 Feb 2022

Cited by 6 | Viewed by 2713

Abstract

The incidence of bone-related disorders is continuously growing as the aging of the population in developing countries continues to increase. Although therapeutic interventions for bone regeneration exist, their effectiveness is questioned, especially under certain circumstances, such as critical size defects. This gap of curative options has led to the search for new and more effective therapeutic approaches for bone regeneration; among them, the possibility of using extracellular vesicles (EVs) is gaining ground. EVs are secreted, biocompatible, nano-sized vesicles that play a pivotal role as messengers between donor and target cells, mediated by their specific cargo. Evidence shows that bone-relevant cells secrete osteoanabolic EVs, whose functionality can be further improved by several strategies. This, together with the low immunogenicity of EVs and their storage advantages, make them attractive candidates for clinical prospects in bone regeneration. However, before EVs reach clinical translation, a number of concerns should be addressed. Unraveling the EVs’ mode of action in bone regeneration is one of them; the molecular mediators driving their osteoanabolic effects in acceptor cells are now beginning to be uncovered. Increasing the functional and bone targeting abilities of EVs are also matters of intense research. Here, we summarize the cell sources offering osteoanabolic EVs, and the current knowledge about the molecular cargos that mediate bone regeneration. Moreover, we discuss strategies under development to improve the osteoanabolic and bone-targeting potential of EVs. Full article

(This article belongs to the Special Issue Bone Development and Regeneration 2.0)

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