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Novel Osteogenic Molecules and Delivery Methods for Bone Regeneration

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

Deadline for manuscript submissions: closed (28 February 2023) | Viewed by 9782

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Dr. Oliver B. Betz

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Guest Editor

Anderson and Langer Lab, David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02142, USA
Interests: biotechnology; biomaterials; bone regeneration; bone; molecular biology; cell biology; tissue engineering; cell culture; regenerative medicine; stem cell differentiation

Dr. Volker M. Betz

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Guest Editor

Musculoskeletal University Center Munich, University Hospital LMU Munich, Munich, Germany
Interests: bone regeneration; tissue engineering; molecular orthopedics; cell therapy; gene therapy; growth factors; delivery systems; biomaterials; nanomedicine
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Dear Colleagues,

A growing aging population at an increased risk of fall-induced bone fractures, often combined with impaired bone healing and higher fracture risk due to osteoporosis and diabetes, in addition to the currently inevitable loosening of prosthetic implants over time, necessitates adequate bone regeneration strategies. This situation is exacerbated by a rising number of devastating traumatic war injuries for which treatment options other than amputation are scant due to the extensive loss of bone and soft tissue. Current treatment options are associated with high morbidity or deficient efficacy. Osteogenic molecules, especially bone morphogenetic proteins, have been shown to promote bone regeneration, but rapid protein degradation impedes their efficacy and safety due to the high-dosage requirement. Therefore, there is an urgent need for improved molecules with stronger osteogenic properties and/or enhanced delivery of such molecules.

New therapy options, such as viral and non-viral gene transfer including nano technology, mRNA technology and gene-enhanced cell therapy, might offer much needed improvement of the current treatment options by enhancing the efficiency of current and novel osteogenic molecules.

Dr. Oliver B. Betz
Dr. Volker M. Betz
Guest Editors

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Keywords

osteogenic molecules
drug delivery
viral / non-viral gene transfer
mRNA
nano-technology

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Published Papers (4 papers)

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Research

20 pages, 7330 KiB

Open AccessArticle

CHIR99021-Treated Osteocytes with Wnt Activation in 3D-Printed Module Form an Osteogenic Microenvironment for Enhanced Osteogenesis and Vasculogenesis

by Yisheng Luo, Yangxi Liu, Bo Wang and Xiaolin Tu

Int. J. Mol. Sci. 2023, 24(6), 6008; https://doi.org/10.3390/ijms24066008 - 22 Mar 2023

Cited by 4 | Viewed by 2463

Abstract

Finding a bone implant that has high bioactivity that can safely drive stem cell differentiation and simulate a real in vivo microenvironment is a challenge for bone tissue engineering. Osteocytes significantly regulate bone cell fate, and Wnt-activated osteocytes can reversely regulate bone formation by regulating bone anabolism, which may improve the biological activity of bone implants. To achieve a safe application, we used the Wnt agonist CHIR99021 (C91) to treat MLO-Y4 for 24 h, in a co-culture with ST2 for 3 days after withdrawal. We found that the expression of Runx2 and Osx increased, promoted osteogenic differentiation, and inhibited adipogenic differentiation in the ST2 cells, and these effects were eliminated by the triptonide. Therefore, we hypothesized that C91-treated osteocytes form an osteogenic microenvironment (COOME). Subsequently, we constructed a bio-instructive 3D printing system to verify the function of COOME in 3D modules that mimic the in vivo environment. Within PCI3D, COOME increased the survival and proliferation rates to as high as 92% after 7 days and promoted ST2 cell differentiation and mineralization. Simultaneously, we found that the COOME-conditioned medium also had the same effects. Therefore, COOME promotes ST2 cell osteogenic differentiation both directly and indirectly. It also promotes HUVEC migration and tube formation, which can be explained by the high expression of Vegf. Altogether, these results indicate that COOME, combined with our independently developed 3D printing system, can overcome the poor cell survival and bioactivity of orthopedic implants and provide a new method for clinical bone defect repair. Full article

(This article belongs to the Special Issue Novel Osteogenic Molecules and Delivery Methods for Bone Regeneration)

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17 pages, 2721 KiB

Open AccessArticle

Inhibition of Sphingosine-1-Phosphate Receptor 2 by JTE013 Enhanced Alveolar Bone Regeneration by Promoting Angiogenesis

by William Lory, Bridgette Wellslager, Chao Sun, Özlem Yilmaz and Hong Yu

Int. J. Mol. Sci. 2023, 24(4), 3401; https://doi.org/10.3390/ijms24043401 - 8 Feb 2023

Cited by 5 | Viewed by 2139

Abstract

Sphingosine-1-phosphate receptor 2 (S1PR2) is a G protein-coupled receptor that regulates various immune responses. Herein, we report the effects of a S1PR2 antagonist (JTE013) on bone regeneration. Murine bone marrow stromal cells (BMSCs) were treated with dimethylsulfoxide (DMSO) or JTE013 with or without infection by an oral bacterial pathogen Aggregatibacter actinomycetemcomitans. Treatment with JTE013 enhanced vascular endothelial growth factor A (VEGFA), platelet derived growth factor subunit A (PDGFA), and growth differentiation factor 15 (GDF15) gene expression and increased transforming growth factor beta (TGFβ)/Smad and Akt signaling. Eight-week-old male C57BL/6J mice were challenged with ligatures around the left maxillary 2nd molar for 15 days to induce inflammatory bone loss. After ligature removal, mice were treated with diluted DMSO or JTE013 in the periodontal tissues 3 times per week for 3 weeks. Calcein was also injected twice to measure bone regeneration. Micro-CT scanning of maxillary bone tissues and calcein imaging revealed that treatment with JTE013 enhanced alveolar bone regeneration. JTE013 also increased VEGFA, PDGFA, osteocalcin, and osterix gene expressions in the periodontal tissues compared to control. Histological examination of periodontal tissues revealed that JTE013 promoted angiogenesis in the periodontal tissues compared to control. Our findings support that inhibition of S1PR2 by JTE013 increased TGFβ/Smad and Akt signaling; enhanced VEGFA, PDGFA, and GDF15 gene expression; and subsequently promoted angiogenesis and alveolar bone regeneration. Full article

(This article belongs to the Special Issue Novel Osteogenic Molecules and Delivery Methods for Bone Regeneration)

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15 pages, 4202 KiB

Open AccessArticle

Lactoferrin Mediates Enhanced Osteogenesis of Adipose-Derived Stem Cells: Innovative Molecular and Cellular Therapy for Bone Repair

by Yiqiang Chang, Ansong Ping, Chunyu Chang, Volker M. Betz, Lin Cai and Bin Ren

Int. J. Mol. Sci. 2023, 24(2), 1749; https://doi.org/10.3390/ijms24021749 - 16 Jan 2023

Cited by 5 | Viewed by 2533

Abstract

A prospective source of stem cells for bone tissue engineering is adipose-derived stem cells (ADSCs), and BMP-2 has been proven to be highly effective in promoting the osteogenic differentiation of stem cells. Rarely has research been conducted on the impact of lactoferrin (LF) on ADSCs’ osteogenic differentiation. As such, in this study, we examined the effects of LF and BMP-2 to assess the ability of LF to stimulate ADSCs’ osteogenic differentiation. The osteogenic medium was supplemented with the LF at the following concentrations to culture ADSCs: 0, 10, 20, 50, 100, and 500 μg/mL. The Cell Counting Kit-8 (CCK-8) assay was used to measure the proliferation of ADSCs. Calcium deposition, alkaline phosphatase (ALP) staining, real-time polymerase chain reaction (RT-PCR), and an ALP activity assay were used to establish osteogenic differentiation. RNA sequencing analysis was carried out to investigate the mechanism of LF boosting the osteogenic development of ADSCs. In the concentration range of 0–100 μg/mL, LF concentration-dependently increased the proliferative vitality and osteogenic differentiation of ADSCs. At a dose of 500 μg/mL, LF sped up and enhanced differentiation, but inhibited ADSCs from proliferating. LF (100 and 500 μg/mL) produced more substantial osteoinductive effects than BMP-2. The PI3 kinase/AKT (PI3K/AKT) and IGF-R1 signaling pathways were significantly activated in LF-treated ADSCs. The in vitro study results showed that LF could effectively promote osteogenic differentiation of ADSCs by activating the PI3K/AKT and IGF-R1 pathways. In our in vitro investigation, an LF concentration of 100 μg/mL was optimal for osteoinduction and proliferation. Our study suggests that LF is an attractive alternative to BMP-2 in bone tissue engineering. As a bioactive molecule capable of inducing adipose stem cells to form osteoblasts, LF is expected to be clinically used in combination with biomaterials as an innovative molecular and cellular therapy to promote bone repair. Full article

(This article belongs to the Special Issue Novel Osteogenic Molecules and Delivery Methods for Bone Regeneration)

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15 pages, 2674 KiB

Open AccessArticle

Impact of Sulfated Hyaluronan on Bone Metabolism in Diabetic Charcot Neuroarthropathy and Degenerative Arthritis

by Sabine Schulze, Christin Neuber, Stephanie Möller, Ute Hempel, Lorenz C. Hofbauer, Klaus-Dieter Schaser, Jens Pietzsch and Stefan Rammelt

Int. J. Mol. Sci. 2022, 23(23), 15146; https://doi.org/10.3390/ijms232315146 - 2 Dec 2022

Cited by 3 | Viewed by 1855

Abstract

Bone in diabetes mellitus is characterized by an altered microarchitecture caused by abnormal metabolism of bone cells. Together with diabetic neuropathy, this is associated with serious complications including impaired bone healing culminating in complicated fractures and dislocations, especially in the lower extremities, so-called Charcot neuroarthropathy (CN). The underlying mechanisms are not yet fully understood, and treatment of CN is challenging. Several in vitro and in vivo investigations have suggested positive effects on bone regeneration by modifying biomaterials with sulfated glycosaminoglycans (sGAG). Recent findings described a beneficial effect of sGAG for bone healing in diabetic animal models compared to healthy animals. We therefore aimed at studying the effects of low- and high-sulfated hyaluronan derivatives on osteoclast markers as well as gene expression patterns of osteoclasts and osteoblasts from patients with diabetic CN compared to non-diabetic patients with arthritis at the foot and ankle. Exposure to sulfated hyaluronan (sHA) derivatives reduced the exaggerated calcium phosphate resorption as well as the expression of genes associated with bone resorption in both groups, but more pronounced in patients with CN. Moreover, sHA derivatives reduced the release of pro-inflammatory cytokines in osteoclasts of patients with CN. The effects of sHA on osteoblasts differed only marginally between patients with CN and non-diabetic patients with arthritis. These results suggest balancing effects of sHA on osteoclastic bone resorption parameters in diabetes. Full article

(This article belongs to the Special Issue Novel Osteogenic Molecules and Delivery Methods for Bone Regeneration)

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