|
1
|
Wu Y, Song P, Wang M, Liu H, Jing Y, Su J. Extracellular derivatives for bone metabolism. J Adv Res 2024; 66:329-347. [PMID: 38218580 PMCID: PMC11674789 DOI: 10.1016/j.jare.2024.01.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 12/13/2023] [Accepted: 01/09/2024] [Indexed: 01/15/2024] Open
Abstract
BACKGROUND Bone metabolism can maintain the normal homeostasis and function of bone tissue. Once the bone metabolism balance is broken, it will cause osteoporosis, osteoarthritis, bone defects, bone tumors, or other bone diseases. However, such orthopedic diseases still have many limitations in clinical treatment, such as drug restrictions, drug tolerance, drug side effects, and implant rejection. AIM OF REVIEW In complex bone therapy and bone regeneration, extracellular derivatives have become a promising research focus to solve the problems of bone metabolic diseases. These derivatives, which include components such as extracellular matrix, growth factors, and extracellular vesicles, have significant therapeutic potential. It has the advantages of good biocompatibility, low immune response, and dynamic demand for bone tissue. The purpose of this review is to provide a comprehensive perspective on extracellular derivatives for bone metabolism and elucidate the intrinsic properties and versatility of extracellular derivatives. Further discussion of them as innovative advanced orthopedic materials for improving the effectiveness of bone therapy and regeneration processes. KEY SCIENTIFIC CONCEPTS OF REVIEW In this review, we first listed the types and functions of three extracellular derivatives. Then, we discussed the effects of extracellular derivatives of different cell sources on bone metabolism. Subsequently, we collected applications of extracellular derivatives in the treatment of bone metabolic diseases and summarized the advantages and challenges of extracellular derivatives in clinical applications. Finally, we prospected the extracellular derivatives in novel orthopedic materials and clinical applications. We hope that the comprehensive understanding of extracellular derivatives in bone metabolism will provide new solutions to bone diseases.
Collapse
Affiliation(s)
- Yan Wu
- Institute of Translational Medicine, Shanghai University, Shanghai 200444, China; Organoid Research Center, Shanghai University, Shanghai 200444, China; National Center for Translational Medicine (Shanghai) SHU Branch, Shanghai University, Shanghai 200444, China
| | - Peiran Song
- Institute of Translational Medicine, Shanghai University, Shanghai 200444, China; Organoid Research Center, Shanghai University, Shanghai 200444, China; National Center for Translational Medicine (Shanghai) SHU Branch, Shanghai University, Shanghai 200444, China
| | - Miaomiao Wang
- Institute of Translational Medicine, Shanghai University, Shanghai 200444, China; Department of Rehabilitation Medicine, Shanghai Zhongye Hospital, Shanghai 200941, China
| | - Han Liu
- Institute of Translational Medicine, Shanghai University, Shanghai 200444, China; Organoid Research Center, Shanghai University, Shanghai 200444, China; National Center for Translational Medicine (Shanghai) SHU Branch, Shanghai University, Shanghai 200444, China.
| | - Yingying Jing
- Institute of Translational Medicine, Shanghai University, Shanghai 200444, China; Organoid Research Center, Shanghai University, Shanghai 200444, China; National Center for Translational Medicine (Shanghai) SHU Branch, Shanghai University, Shanghai 200444, China.
| | - Jiacan Su
- Institute of Translational Medicine, Shanghai University, Shanghai 200444, China; Organoid Research Center, Shanghai University, Shanghai 200444, China; National Center for Translational Medicine (Shanghai) SHU Branch, Shanghai University, Shanghai 200444, China; Department of Orthopedics, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China.
| |
Collapse
|
|
2
|
Schwartzman JD, McCall M, Ghattas Y, Pugazhendhi AS, Wei F, Ngo C, Ruiz J, Seal S, Coathup MJ. Multifunctional scaffolds for bone repair following age-related biological decline: Promising prospects for smart biomaterial-driven technologies. Biomaterials 2024; 311:122683. [PMID: 38954959 DOI: 10.1016/j.biomaterials.2024.122683] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Revised: 06/09/2024] [Accepted: 06/23/2024] [Indexed: 07/04/2024]
Abstract
The repair of large bone defects due to trauma, disease, and infection can be exceptionally challenging in the elderly. Despite best clinical practice, bone regeneration within contemporary, surgically implanted synthetic scaffolds is often problematic, inconsistent, and insufficient where additional osteobiological support is required to restore bone. Emergent smart multifunctional biomaterials may drive important and dynamic cellular crosstalk that directly targets, signals, stimulates, and promotes an innate bone repair response following age-related biological decline and when in the presence of disease or infection. However, their role remains largely undetermined. By highlighting their mechanism/s and mode/s of action, this review spotlights smart technologies that favorably align in their conceivable ability to directly target and enhance bone repair and thus are highly promising for future discovery for use in the elderly. The four degrees of interactive scaffold smartness are presented, with a focus on bioactive, bioresponsive, and the yet-to-be-developed autonomous scaffold activity. Further, cell- and biomolecular-assisted approaches were excluded, allowing for contemporary examination of the capabilities, demands, vision, and future requisites of next-generation biomaterial-induced technologies only. Data strongly supports that smart scaffolds hold significant promise in the promotion of bone repair in patients with a reduced osteobiological response. Importantly, many techniques have yet to be tested in preclinical models of aging. Thus, greater clarity on their proficiency to counteract the many unresolved challenges within the scope of aging bone is highly warranted and is arguably the next frontier in the field. This review demonstrates that the use of multifunctional smart synthetic scaffolds with an engineered strategy to circumvent the biological insufficiencies associated with aging bone is a viable route for achieving next-generation therapeutic success in the elderly population.
Collapse
Affiliation(s)
| | - Max McCall
- College of Medicine, University of Central Florida, Orlando, FL, USA
| | - Yasmine Ghattas
- College of Medicine, University of Central Florida, Orlando, FL, USA
| | - Abinaya Sindu Pugazhendhi
- College of Medicine, University of Central Florida, Orlando, FL, USA; Biionix Cluster, University of Central Florida, Orlando, FL, USA
| | - Fei Wei
- College of Medicine, University of Central Florida, Orlando, FL, USA; Biionix Cluster, University of Central Florida, Orlando, FL, USA
| | - Christopher Ngo
- College of Medicine, University of Central Florida, Orlando, FL, USA; Biionix Cluster, University of Central Florida, Orlando, FL, USA
| | - Jonathan Ruiz
- College of Medicine, University of Central Florida, Orlando, FL, USA
| | - Sudipta Seal
- College of Medicine, University of Central Florida, Orlando, FL, USA; Biionix Cluster, University of Central Florida, Orlando, FL, USA; Advanced Materials Processing and Analysis Centre, Nanoscience Technology Center (NSTC), Materials Science and Engineering, College of Medicine, University of Central Florida, USA, Orlando, FL
| | - Melanie J Coathup
- College of Medicine, University of Central Florida, Orlando, FL, USA; Biionix Cluster, University of Central Florida, Orlando, FL, USA.
| |
Collapse
|
|
3
|
Li X, Deng Z, Lu W. Mechanistic study of the effect of flexible fixation and load-bearing stress environment on fracture healing and shaping. Animal Model Exp Med 2024; 7:816-823. [PMID: 38978345 PMCID: PMC11680484 DOI: 10.1002/ame2.12448] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 04/27/2024] [Accepted: 05/22/2024] [Indexed: 07/10/2024] Open
Abstract
BACKGROUND The biomechanical environment created by suture-button fixation Latarjet is conducive to the healing and shaping of the transplanted coracoid, but its mechanism remains unclear. The latest research has found that the absence of stem cell chemokine (CXCL12) impeded bone regeneration in Sonic Hedgehog (SHH)-deficient animals. However, whether the biomechanical environment affects SHH and CXCL12 function has not been studied. METHODS Rat fracture models were constructed to simulate stress environments under non-load-bearing and load-bearing conditions. The fracture healing and shaping, as well as the expression levels of SHH and CXCL12, were assessed through gross viewing, micro-computed tomography (micro-CT), and histochemical staining. RESULTS Under flexible fixation, the relative bone volume (BV/TV) of rats exposed to the load-bearing stress environment was significantly higher than that of rats under a non-load-bearing stress environment (p ≤ 0.05). Adverse bone shaping was not observed in rats subjected to flexible fixation. The levels of SHH and CXCL12 in load-bearing rats exhibited significant elevation (p ≤ 0.05). Under a load-bearing stress environment, no significant difference was observed in the BV/TV between the flexible fixation group and the rigid fixation group (p ≥ 0.05), but there was excessive hyperplasia of the fracture callus in the rigid fixation group. The levels of SHH and CXCL12 in rats subjected to rigid fixation were significantly elevated (p ≤ 0.05). CONCLUSIONS Flexible fixation and load-bearing stress environment may contribute to bone healing and shaping by influencing the levels of SHH and CXCL12, suggested that this mechanism may be relevant to the healing and shaping of the transplanted coracoid after suture-button fixation Latarjet.
Collapse
Affiliation(s)
- Xingfu Li
- Department of Sports MedicineShenzhen Second People's Hospital (The First Affiliated Hospital of Shenzhen University)ShenzhenGuangdongChina
- Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, National‐Regional Key Technology Engineering Laboratory for Medical Ultrasound, School of Biomedical EngineeringShenzhen University Medical SchoolShenzhenGuangdongChina
| | - Zhenhan Deng
- Department of Sports MedicineShenzhen Second People's Hospital (The First Affiliated Hospital of Shenzhen University)ShenzhenGuangdongChina
- Department of Orthopedics SurgeryThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouZhejiangChina
| | - Wei Lu
- Department of Sports MedicineShenzhen Second People's Hospital (The First Affiliated Hospital of Shenzhen University)ShenzhenGuangdongChina
| |
Collapse
|
|
4
|
Zhou W, Li Y, Hou Y, Dan W, Chen L, Shi F, Zhao F, Fang L. Simulated microgravity increases CD226 + Lin - CD117 - Sca1 + mesenchymal stem cells in mice. Physiol Rep 2024; 12:e15971. [PMID: 38467556 DOI: 10.14814/phy2.15971] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Revised: 02/29/2024] [Accepted: 02/29/2024] [Indexed: 03/13/2024] Open
Abstract
Microgravity is one of the most common causes counting for the bone loss. Mesenchymal stem cells (MSCs) contribute greatly to the differentiation and function of bone related cells. The development of novel MSCs biomarkers is critical for implementing effective therapies for microgravity induced bone loss. We aimed to find the new molecules involved in the differentiation and function of MSCs in mouse simulated microgravity model. We found CD226 was preferentially expressed on a subset of MSCs. Simulation of microgravity treatment significantly increased the proportion of CD226+ Lin- CD117- Sca1+ MSCs. The CD226+ MSCs produced higher IL-6, M-CSF, RANKL and lower CD200 expression, and promoted osteoclast differentiation. This study provides pivotal information to understand the role of CD226 in MSCs, and inspires new ideas for prevention of bone loss related diseases.
Collapse
Affiliation(s)
- Wenjing Zhou
- College of Life Sciences, Northwest University, Xi' an, China
- Department of Immunology, Fourth Military Medical University, Xi'an, China
| | - Yi Li
- Department of Immunology, Fourth Military Medical University, Xi'an, China
- Medical School of Yan'an University, Yan'an, China
| | - Yongli Hou
- Department of Immunology, Fourth Military Medical University, Xi'an, China
| | - Wenli Dan
- Department of Immunology, Fourth Military Medical University, Xi'an, China
| | - Lihua Chen
- Department of Immunology, Fourth Military Medical University, Xi'an, China
| | - Fei Shi
- The Key Laboratory of Aerospace Medicine, Ministry of Education, Fourth Military Medical University, Xi'an, China
| | - Fang Zhao
- Department of Occupational and Environmental Health, The Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an, China
| | - Liang Fang
- Department of Immunology, Fourth Military Medical University, Xi'an, China
| |
Collapse
|
|
5
|
Dai Z, Chen Y, He E, Wang H, Guo W, Wu Z, Huang K, Zhao Q. Interleukin-19 promotes bone resorption by suppressing osteoprotegerin expression in BMSCs in a lipopolysaccharide-induced bone loss mouse model. Bone Joint Res 2023; 12:691-701. [PMID: 37918438 PMCID: PMC10622185 DOI: 10.1302/2046-3758.1211.bjr-2023-0101.r1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/04/2023] Open
Abstract
Aims Osteoporosis is characterized by decreased trabecular bone volume, and microarchitectural deterioration in the medullary cavity. Interleukin-19 (IL-19), a member of the IL-10 family, is an anti-inflammatory cytokine produced primarily by macrophages. The aim of our study was to investigate the effect of IL-19 on osteoporosis. Methods Blood and femoral bone marrow suspension IL-19 levels were first measured in the lipopolysaccharide (LPS)-induced bone loss model. Small interfering RNA (siRNA) was applied to knock down IL-19 for further validation. Thereafter, osteoclast production was stimulated with IL-19 in combination with mouse macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor-κB ligand (RANKL). The effect of IL-19 was subsequently evaluated using tartrate-resistant acid phosphatase (TRAP) staining and quantitative real-time polymerase chain reaction (RT-qPCR). The effect of IL-19 on osteoprotegerin (OPG) was then assessed using in vitro recombinant IL-19 treatment of primary osteoblasts and MLO-Y4 osteoblast cell line. Finally, transient transfection experiments and chromatin immunoprecipitation (ChIP) experiments were used to examine the exact mechanism of action. Results In the LPS-induced bone loss mouse model, the levels of IL-19 in peripheral blood serum and femoral bone marrow suspension were significantly increased. The in vivo results indicated that global IL-19 deletion had no significant effect on RANKL content in the serum and bone marrow, but could increase the content of OPG in serum and femoral bone marrow, suggesting that IL-19 inhibits OPG expression in bone marrow mesenchymal stem cells (BMSCs) and thus increases bone resorption. Conclusion IL-19 promotes bone resorption by suppressing OPG expression in BMSCs in a LPS-induced bone loss mouse model, which highlights the potential benefits and side effects of IL-19 for future clinical applications.
Collapse
Affiliation(s)
- Zhicheng Dai
- Department of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yanan Chen
- Department of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Enjun He
- Department of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hongjie Wang
- Department of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Weihong Guo
- Department of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhenkai Wu
- Department of Pediatric Orthopaedics, Shanghai Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Kai Huang
- Department of Orthopedics, Zhabei Central Hospital of Jing’an District, Shanghai, China
| | - Qinghua Zhao
- Department of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| |
Collapse
|
|
6
|
Skubica P, Husakova M, Dankova P. In vitro osteoclastogenesis in autoimmune diseases - Strengths and pitfalls of a tool for studying pathological bone resorption and other disease characteristics. Heliyon 2023; 9:e21925. [PMID: 38034780 PMCID: PMC10682642 DOI: 10.1016/j.heliyon.2023.e21925] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Revised: 10/31/2023] [Accepted: 10/31/2023] [Indexed: 12/02/2023] Open
Abstract
Osteoclasts play a critical role in bone pathology frequently associated with autoimmune diseases. Studying the etiopathogenesis of these diseases and their clinical manifestations can involve in vitro osteoclastogenesis, an experimental technique that utilizes osteoclast precursors that are relatively easily accessible from peripheral blood or synovial fluid. However, the increasing number of methodical options to study osteoclastogenesis in vitro poses challenges in translating findings to clinical research and practice. This review compares and critically evaluates previous research work based on in vitro differentiation of human osteoclast precursors originating from patients, which aimed to explain autoimmune pathology in rheumatic and enteropathic diseases. The discussion focuses primarily on methodical differences between the studies, including the origin of osteoclast precursors, culture conditions, and methods for identifying osteoclasts and assessing their activity. Additionally, the review examines the clinical significance of the three most commonly used in vitro approaches: induced osteoclastogenesis, spontaneous osteoclastogenesis, and cell co-culture. By analyzing and integrating the gathered information, this review proposes general connections between different studies, even in cases where their results are seemingly contradictory. The derived conclusions and future directions aim to enhance our understanding of a potential and limitations of in vitro osteoclastogenesis and provide a foundation for discussing novel methods (such as osteoclastogenesis dynamic) and standardized approaches (such as spontaneous osteoclastogenesis) for future use in autoimmune disease research.
Collapse
Affiliation(s)
- Patrik Skubica
- Faculty of Science, Charles University, Prague, Czech Republic
| | - Marketa Husakova
- First Faculty of Medicine, Charles University, Prague and Institute of Rheumatology, Prague, Czech Republic
| | - Pavlina Dankova
- Faculty of Science, Charles University, Prague, Czech Republic
| |
Collapse
|
|
7
|
Nugraha AP, Ernawati DS, Narmada IB, Bramantoro T, Riawan W, Situmorang PC, Nam HY. RANK-RANKL-OPG expression after gingival mesenchymal stem cell hypoxia preconditioned application in an orthodontic tooth movement animal model. J Oral Biol Craniofac Res 2023; 13:781-790. [PMID: 38028229 PMCID: PMC10661597 DOI: 10.1016/j.jobcr.2023.10.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Revised: 09/17/2023] [Accepted: 10/26/2023] [Indexed: 12/01/2023] Open
Abstract
Background The expression of receptor activator of Nuclear Factor Kappa Beta (RANK) and its ligand (RANKL), as well as osteoprotegrin (OPG), in the alveolar bone (AB), may improve bone remodeling during orthodontic tooth movement (OTM). It is hypothesized that hypoxia-preconditioned gingival mesenchymal stem cells (GMSC) may be more effective than normoxia-preconditioned GMSC in this regard. This study aims to investigate the expression of RANK, RANKL, and OPG in the compression and tension sides of AB after allogeneic administration of GMSC that were normoxia or hypoxia-preconditioned in rabbits (Oryctolagus cuniculus) undergoing OTM. Methods Twenty-four healthy young male rabbits were divided into two groups: T1, which underwent OTM and received normoxia-preconditioned GMSC, and T2, which underwent OTM and received hypoxia-preconditioned GMSC. A ligature wire was attached to the mandibular first molar and connected to a 50 g/mm2 closed coil spring, exerting force on the central incisor and left mandibular molar of the experimental animals. After 24 h of OTM, either normoxia- or hypoxia-preconditioned GMSC were injected into the gingiva of the samples in a single dose of 20 μl of phosphate-buffered saline (PBS). All samples were sacrificed on days 7, 14, and 28, and immunohistochemistry was performed to analyze the expression of RANK, RANKL, and OPG on the tension and compression sides. Results The expressions of RANK-RANKL-OPG in the alveolar bone of the compression and tension sides were significantly different during the 14-day period of OTM following allogeneic administration of GMSC that were normoxia or hypoxia-preconditioned (p < 0.05). Conclusion The expression of RANK-RANKL was significantly increased on the compression side of the alveolar bone during OTM after the administration of hypoxia-preconditioned allogeneic GMSC but not on the tension side. Conversely, RANKL-OPG expression was enhanced on the tension side but not on the compression side, as observed through immunohistochemical analysis in vivo.
Collapse
Affiliation(s)
- Alexander Patera Nugraha
- Department of Orthodontics, Faculty of Dental Medicine, Universitas Airlangga, Surabaya, Indonesia
| | - Diah Savitri Ernawati
- Department of Oral Medicine, Faculty of Dental Medicine, Universitas Airlangga, Surabaya, Indonesia
| | - Ida Bagus Narmada
- Department of Orthodontics, Faculty of Dental Medicine, Universitas Airlangga, Surabaya, Indonesia
| | - Taufan Bramantoro
- Department of Dental Public Health, Faculty of Dental Medicine, Universitas Airlangga, Surabaya, Indonesia
| | - Wibi Riawan
- Department of Biomolecular Biochemistry, Faculty of Medicine, Universitas Brawijaya, Malang, Indonesia
| | - Putri Cahaya Situmorang
- Department of Biology, Faculty of Mathematics and Natural Science, Universitas Sumatera Utara, Medan, Indonesia
| | - Hui Yin Nam
- Nanotechnology and Catalysis Research Center (NANOCAT), Universiti Malaya, Kuala Lumpur, Malaysia
- Tissue Engineering Group, Department of Orthopaedic Surgery (NOCERAL), Faculty of Medicine, Universiti Malaya, Kuala Lumpur, Malaysia
| |
Collapse
|
|
8
|
Osteoclastogenesis of human peripheral blood, bone marrow, and cord blood monocytes. Sci Rep 2023; 13:3763. [PMID: 36882450 PMCID: PMC9992388 DOI: 10.1038/s41598-023-30701-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2022] [Accepted: 02/28/2023] [Indexed: 03/09/2023] Open
Abstract
Osteoclasts are multinucleated bone resorbing cells that can be differentiated from human monocytes in vitro. There are few studies comparing osteoclastogenesis of different monocyte sources. We compared monocytes from human bone marrow (BM), peripheral blood (PB), and umbilical cord blood (CB) and their osteoclastogenic potential by culturing them with RANKL (20 and 80 ng/ml) and M-CSF (10 ng/ml) for 14 days. We also cultured cells without growth factors, as umbilical cord blood monocytes have been reported to be able to fuse spontaneously into osteoclasts. The data was analysed on d4, d8, d11, and d14. After culture with RANKL and M-CSF, all types of cell cultures developed TRACP -positive multinuclear cells that were able to form resorption pits on human bone slices. Only occasional multinuclear cells and small infrequent resorbed areas could be found in PB and CB-derived cultures without growth factors. BM-derived cells formed greater resorption areas than PB- and CB-derived monocytes. The greatest monocyte population in BM samples were intermediate (CD14++CD16+) and in PB and CB classical monocytes (76.3% and 54.4%, respectively). In conclusion, our data demonstrates that bone resorbing osteoclasts can be differentiated from BM, PB and CB. However, the osteoclast precursor origin can affect the osteoclast properties and function.
Collapse
|
|
9
|
Xu J, Lin Y, Tian M, Li X, Yin Y, Li Q, Li Z, Zhou J, Jiang X, Li Y, Chen S. Periodontal Ligament Stem Cell-Derived Extracellular Vesicles Enhance Tension-Induced Osteogenesis. ACS Biomater Sci Eng 2023; 9:388-398. [PMID: 36538768 DOI: 10.1021/acsbiomaterials.2c00717] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Tension-induced osteogenesis has great significance in maintaining bone homeostasis and ensuring the efficiency and stability of orthodontic treatment. Recently, extracellular vesicles (EVs) have shown great potential in regulating bone remodeling. Here, we aimed to explore the effects of periodontal ligament stem cell (PDLSC)-derived EVs on tension-induced osteogenesis and the potential mechanism. PDLSC-derived EVs were extracted by ultracentrifugation. In vitro, PDLSC-derived EVs of 10 μg/mL significantly improved the proliferation of MC3T3-E1 cells and enhanced the osteogenic differentiation of osteoblasts under a tensile strain of 2000 uε. Next, a mouse model of orthodontic tooth movement (OTM) was established and treated with subperiosteal injection of PDLSC-derived EVs (1 mg/kg) on the tension side. The results showed that treatment with PDLSC-derived EVs effectively enhanced OTM and promoted osteogenesis on the tension side, including increasing trabecular bone parameters and promoting the expression of osteogenic-related biomarkers (OCN and OPN). More interestingly, we identified several mechano-sensitive miRNAs enriched in PDLSC-derived EVs by high-throughput miRNA sequencing. Bioinformatics analysis indicated that they were related to various osteogenesis-related signaling pathways. Therefore, PDLSC-derived EVs could improve the efficiency of OTM by enhancing tension-induced osteogenesis of osteoblasts. Our study may provide potential evidence for the promoting effects of PDLSC-derived EVs on osteogenesis and offer new insights into the development of treatment strategies for enhancing osteogenesis in orthodontic treatment and other metabolic bone diseases.
Collapse
Affiliation(s)
- Jingchen Xu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, #14, 3rd Section, Ren Min S Rd, Chengdu, Sichuan 610041, China
| | - Yao Lin
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, #14, 3rd Section, Ren Min S Rd, Chengdu, Sichuan 610041, China
| | - Mi Tian
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, #14, 3rd Section, Ren Min S Rd, Chengdu, Sichuan 610041, China
| | - Xinyi Li
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, #14, 3rd Section, Ren Min S Rd, Chengdu, Sichuan 610041, China
| | - Yuanyuan Yin
- Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Stomatological Hospital of Chongqing Medical University, Chongqing 401147, China
| | - Qiming Li
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, #14, 3rd Section, Ren Min S Rd, Chengdu, Sichuan 610041, China
| | - Ziyu Li
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, #14, 3rd Section, Ren Min S Rd, Chengdu, Sichuan 610041, China
| | - Jialiang Zhou
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, #14, 3rd Section, Ren Min S Rd, Chengdu, Sichuan 610041, China
| | - Xiaoge Jiang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, #14, 3rd Section, Ren Min S Rd, Chengdu, Sichuan 610041, China
| | - Yulin Li
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, #14, 3rd Section, Ren Min S Rd, Chengdu, Sichuan 610041, China
| | - Song Chen
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, #14, 3rd Section, Ren Min S Rd, Chengdu, Sichuan 610041, China
| |
Collapse
|
|
10
|
Kumar K, Datta K, Fornace AJ, Suman S. Total body proton and heavy-ion irradiation causes cellular senescence and promotes pro-osteoclastogenic activity in mouse bone marrow. Heliyon 2022; 8:e08691. [PMID: 35028468 PMCID: PMC8741516 DOI: 10.1016/j.heliyon.2021.e08691] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 12/01/2021] [Accepted: 12/27/2021] [Indexed: 12/12/2022] Open
Abstract
Low-LET photon radiation-induced persistent alterations in bone marrow (BM) cells are well documented in total-body irradiated (TBI) rodents and also among radiotherapy patients. However, the late effects of protons and high-LET heavy-ion radiation on BM cells and its implications in osteoclastogenesis are not fully understood. Therefore, C57BL6/J female mice (8 weeks; n = 10/group) were irradiated to sham, and 1 Gy of the proton (0.22 keV/μm), or high-LET 56Fe-ions (148 keV/μm) and at 60 d post-exposure, mice were sacrificed and femur sections were obtained for histological, cellular and molecular analysis. Cell proliferation (PCNA), cell death (active caspase-3), senescence (p16), osteoclast (RANK), osteoblast (OPG), osteoblast progenitor (c-Kit), and osteoclastogenesis-associated secretory factors (like RANKL) were assessed using immunostaining. While no change in cell proliferation and apoptosis between control and irradiated groups was noted, the number of BM megakaryocytes was significantly reduced in irradiated mice at 60 d post-exposure. A remarkable increase in p16 positive cells indicated a persistent increase in cell senescence, whereas increased RANKL/OPG ratio, reductions in the number of osteoblast progenitor cells, and osteocalcin provided clear evidence that exposure to both proton and 56Fe-ions promotes pro-osteoclastogenic activity in BM. Among irradiated groups, 56Fe-induced alterations in the BM cellularity and osteoclastogenesis were significantly greater than the protons that demonstrated a radiation quality-dependent effect. This study has implications in understanding the role of IR-induced late changes in the BM cells and its involvement in bone degeneration among deep-space astronauts, and also in patients undergoing proton or heavy-ion radiotherapy.
Collapse
Affiliation(s)
- Kamendra Kumar
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA
| | - Kamal Datta
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA
| | - Albert J. Fornace
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA
- Department of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center, Washington, DC 20057, USA
| | - Shubhankar Suman
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA
- Corresponding author.
| |
Collapse
|
|
11
|
Abu-Shahba N, Mahmoud M, El-Erian AM, Husseiny MI, Nour-Eldeen G, Helwa I, Amr K, ElHefnawi M, Othman AI, Ibrahim SA, Azmy O. Impact of type 2 diabetes mellitus on the immunoregulatory characteristics of adipose tissue-derived mesenchymal stem cells. Int J Biochem Cell Biol 2021; 140:106072. [PMID: 34455058 DOI: 10.1016/j.biocel.2021.106072] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 08/02/2021] [Accepted: 08/24/2021] [Indexed: 12/15/2022]
Abstract
BACKGROUND Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder associated with several complications. Adipose tissue-derived mesenchymal stem cells (AT-MSCs) represent an emerging type of MSCs with high plasticity and immunoregulatory capabilities and are useful for treating inflammation-related disorders such as T2DM. However, the pathogenic microenvironment of T2DM may affect their therapeutic potential. We aimed to examine the impact of the diabetic milieu on the immunomodulatory/anti-inflammatory potential of AT-MSCs. METHODS We assessed the proliferation potential, cell surface expression of MSC-characteristic markers and immunomodulatory markers, along with the gene expression and protein secretion of pro-inflammatory and anti-inflammatory cytokines and adipokines in AT-MSCs derived from T2DM patients (dAT-MSCs) vs. those derived from non-diabetic volunteers (ndAT-MSCs). Furthermore, we evaluated the IFN-γ priming effect on both groups. RESULTS Our data revealed comparable proliferative activities in both groups. Flow cytometric analysis results showed a lower expression of CD200 and CD276 on dAT-MSCs vs. ndAT-MSCs. qPCR demonstrated upregulation of IL-1β associated with a downregulation of IL-1RN in dAT-MSCs vs. ndAT-MSCs. IFN-γ priming induced an elevation in CD274 expression associated with IDO1 and ILRN overexpression and IL-1β downregulation in both groups. ELISA analysis uncovered elevated levels of secreted IL-1β, TNF, and visfatin/NAMPT in dAT-MSCs, whereas IL-1RA and IDO levels were reduced. ELISA results were also evident in the secretome of dAT-MSCs upon IFN-γ priming. CONCLUSIONS This study suggests that the T2DM milieu alters the immunomodulatory characteristics of AT-MSCs with a shift towards a proinflammatory phenotype which may restrain their autologous therapeutic use. Furthermore, our findings indicate that IFN-γ priming could be a useful strategy for enhancing dAT-MSC anti-inflammatory potential.
Collapse
Affiliation(s)
- Nourhan Abu-Shahba
- Stem Cell Research Group, Medical Research Centre of Excellence, National Research Centre, Cairo, Egypt; Department of Medical Molecular Genetics, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt.
| | - Marwa Mahmoud
- Stem Cell Research Group, Medical Research Centre of Excellence, National Research Centre, Cairo, Egypt; Department of Medical Molecular Genetics, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt
| | - Alaa Mohammed El-Erian
- Department of Endocrine Surgery, National Institute of Diabetes and Endocrinology, Cairo, Egypt
| | - Mohamed Ibrahim Husseiny
- Department of Translational Research and Cellular Therapeutics, Arthur Riggs DMRI, Beckman Research Institute, City of Hope, National Medical Center, Durate, CA, USA; Faculty of Pharmacy, Zagazig University, Zagazig, Egypt
| | - Ghada Nour-Eldeen
- Stem Cell Research Group, Medical Research Centre of Excellence, National Research Centre, Cairo, Egypt; Department of Molecular Genetics and Enzymology, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt
| | - Iman Helwa
- Department of Immunogenetics, Human Genetics and Genome Research Division, National Resrearch Centre, Egypt
| | - Khalda Amr
- Department of Medical Molecular Genetics, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt
| | - Mahmoud ElHefnawi
- Biomedical Informatics and Chemoinformatics Group, Informatics and Systems Department, National Research Centre, Cairo, Egypt
| | - Amel Ibrahim Othman
- Department of Zoology, Faculty of Science, Cairo University, 12613, Giza, Egypt
| | | | - Osama Azmy
- Stem Cell Research Group, Medical Research Centre of Excellence, National Research Centre, Cairo, Egypt; Department of Reproductive Health Research, Medical Research Division, National Research Centre, Cairo, Egypt; Egypt Center for Research and Regenerative Medicine, Cairo, Egypt
| |
Collapse
|
|
12
|
Brennan MÁ, Monahan DS, Brulin B, Gallinetti S, Humbert P, Tringides C, Canal C, Ginebra MP, Layrolle P. Biomimetic versus sintered macroporous calcium phosphate scaffolds enhanced bone regeneration and human mesenchymal stromal cell engraftment in calvarial defects. Acta Biomater 2021; 135:689-704. [PMID: 34520883 DOI: 10.1016/j.actbio.2021.09.007] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Revised: 09/01/2021] [Accepted: 09/06/2021] [Indexed: 01/08/2023]
Abstract
In contrast to sintered calcium phosphates (CaPs) commonly employed as scaffolds to deliver mesenchymal stromal cells (MSCs) targeting bone repair, low temperature setting conditions of calcium deficient hydroxyapatite (CDHA) yield biomimetic topology with high specific surface area. In this study, the healing capacity of CDHA administering MSCs to bone defects is evaluated for the first time and compared with sintered beta-tricalcium phosphate (β-TCP) constructs sharing the same interconnected macroporosity. Xeno-free expanded human bone marrow MSCs attached to the surface of the hydrophobic β-TCP constructs, while infiltrating the pores of the hydrophilic CDHA. Implantation of MSCs on CaPs for 8 weeks in calvaria defects of nude mice exhibited complete healing, with bone formation aligned along the periphery of β-TCP, and conversely distributed within the pores of CDHA. Human monocyte-osteoclast differentiation was inhibited in vitro by direct culture on CDHA compared to β-TCP biomaterials and indirectly by administration of MSC-conditioned media generated on CDHA, while MSCs increased osteoclastogenesis in both CaPs in vivo. MSC engraftment was significantly higher in CDHA constructs, and also correlated positively with bone in-growth in scaffolds. These findings demonstrate that biomimetic CDHA are favorable carriers for MSC therapies and should be explored further towards clinical bone regeneration strategies. STATEMENT OF SIGNIFICANCE: Delivery of mesenchymal stromal cells (MSCs) on calcium phosphate (CaP) biomaterials enhances reconstruction of bone defects. Traditional CaPs are produced at high temperature, but calcium deficient hydroxyapatite (CDHA) prepared at room temperature yields a surface structure more similar to native bone mineral. The objective of this study was to compare the capacity of biomimetic CDHA scaffolds with sintered β-TCP scaffolds for bone repair mediated by MSCs for the first time. In vitro, greater cell infiltration occurred in CDHA scaffolds and following 8 weeks in vivo, MSC engraftment was higher in CDHA compared to β-TCP, as was bone in-growth. These findings demonstrate the impact of material features such as surface structure, and highlight that CDHA should be explored towards clinical bone regeneration strategies.
Collapse
Affiliation(s)
- Meadhbh Á Brennan
- INSERM, UMR 1238, PHY-OS, Faculty of Medicine, University of Nantes, 1 Rue Gaston Veil, Nantes 44035, France; Harvard John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138, USA; Biomedical Engineering, School of Engineering; and Regenerative Medicine Institute (REMEDI), School of Medicine, National University of Ireland (NUIG), Galway, Ireland
| | - David S Monahan
- Biomedical Engineering, School of Engineering; and Regenerative Medicine Institute (REMEDI), School of Medicine, National University of Ireland (NUIG), Galway, Ireland
| | - Bénédicte Brulin
- INSERM, UMR 1238, PHY-OS, Faculty of Medicine, University of Nantes, 1 Rue Gaston Veil, Nantes 44035, France; INSERM, UMR 1214, ToNIC, CHU Purpan, Université Paul Sabatier, Toulouse 31024, France
| | - Sara Gallinetti
- Biomaterials, Biomechanics and Tissue Engineering Group, Dpt. Materials Science and Engineering, Universitat Politècnica de Catalunya (UPC), Av. Eduard Maristany 10-14, Barcelona 08019, Spain; Research Centre in Multiscale Science and Engineering, Universitat Politècnica de Catalunya, Barcelona, Spain
| | - Paul Humbert
- INSERM, UMR 1238, PHY-OS, Faculty of Medicine, University of Nantes, 1 Rue Gaston Veil, Nantes 44035, France
| | - Christina Tringides
- Harvard John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138, USA; Harvard Program in Biophysics, Harvard University, Cambridge, MA 02138, USA
| | - Cristina Canal
- Biomaterials, Biomechanics and Tissue Engineering Group, Dpt. Materials Science and Engineering, Universitat Politècnica de Catalunya (UPC), Av. Eduard Maristany 10-14, Barcelona 08019, Spain; Research Centre in Multiscale Science and Engineering, Universitat Politècnica de Catalunya, Barcelona, Spain
| | - Maria Pau Ginebra
- Biomaterials, Biomechanics and Tissue Engineering Group, Dpt. Materials Science and Engineering, Universitat Politècnica de Catalunya (UPC), Av. Eduard Maristany 10-14, Barcelona 08019, Spain; Research Centre in Multiscale Science and Engineering, Universitat Politècnica de Catalunya, Barcelona, Spain; Institute of Bioengineering of Catalonia (IBEC), Barcelona Institute of Science and Technology, Baldiri i Reixach 10-12, Barcelona 08028, Spain
| | - Pierre Layrolle
- INSERM, UMR 1238, PHY-OS, Faculty of Medicine, University of Nantes, 1 Rue Gaston Veil, Nantes 44035, France; INSERM, UMR 1214, ToNIC, CHU Purpan, Université Paul Sabatier, Toulouse 31024, France.
| |
Collapse
|
|
13
|
Agas D, Sabbieti MG. Autophagic Mediators in Bone Marrow Niche Homeostasis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1376:61-75. [PMID: 34480334 DOI: 10.1007/5584_2021_666] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
The bone marrow serves as a reservoir for a multifunctional assortment of stem, progenitor, and mature cells, located in functional anatomical micro-areas termed niches. Within the niche, hematopoietic and mesenchymal progenies establish a symbiotic relationship characterized by interdependency and interconnectedness. The fine-tuned physical and molecular interactions that occur in the niches guarantee physiological bone turnover, blood cell maturation and egression, and moderation of inflammatory and oxidative intramural stressful conditions. The disruption of bone marrow niche integrity causes severe local and systemic pathological settings, and thus bone marrow inhabitants have been the object of extensive study. In this context, research has revealed the importance of the autophagic apparatus for niche homeostatic maintenance. Archetypal autophagic players such as the p62 and the Atg family proteins have been found to exert a variety of actions, some autophagy-related and others not; they moderate the essential features of mesenchymal and hematopoietic stem cells and switch their operational schedules. This chapter focuses on our current understanding of bone marrow functionality and the role of the executive autophagic apparatus in the niche framework. Autophagic mediators such as p62 and Atg7 are currently considered the most important orchestrators of stem and mature cell dynamics in the bone marrow.
Collapse
Affiliation(s)
- Dimitrios Agas
- School of Biosciences and Veterinary Medicine, University of Camerino, Camerino, MC, Italy.
| | | |
Collapse
|
|
14
|
Lim KT, Patel DK, Dutta SD, Ganguly K. Fluid Flow Mechanical Stimulation-Assisted Cartridge Device for the Osteogenic Differentiation of Human Mesenchymal Stem Cells. MICROMACHINES 2021; 12:927. [PMID: 34442549 PMCID: PMC8398302 DOI: 10.3390/mi12080927] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 07/28/2021] [Accepted: 08/02/2021] [Indexed: 12/30/2022]
Abstract
Human mesenchymal stem cells (hMSCs) have the potential to differentiate into different types of mesodermal tissues. In vitro proliferation and differentiation of hMSCs are necessary for bone regeneration in tissue engineering. The present study aimed to design and develop a fluid flow mechanically-assisted cartridge device to enhance the osteogenic differentiation of hMSCs. We used the fluorescence-activated cell-sorting method to analyze the multipotent properties of hMSCs and found that the cultured cells retained their stemness potential. We also evaluated the cell viabilities of the cultured cells via water-soluble tetrazolium salt 1 (WST-1) assay under different rates of flow (0.035, 0.21, and 0.35 mL/min) and static conditions and found that the cell growth rate was approximately 12% higher in the 0.035 mL/min flow condition than the other conditions. Moreover, the cultured cells were healthy and adhered properly to the culture substrate. Enhanced mineralization and alkaline phosphatase activity were also observed under different perfusion conditions compared to the static conditions, indicating that the applied conditions play important roles in the proliferation and differentiation of hMSCs. Furthermore, we determined the expression levels of osteogenesis-related genes, including the runt-related protein 2 (Runx2), collagen type I (Col1), osteopontin (OPN), and osteocalcin (OCN), under various perfusion vis-à-vis static conditions and found that they were significantly affected by the applied conditions. Furthermore, the fluorescence intensities of OCN and OPN osteogenic gene markers were found to be enhanced in the 0.035 mL/min flow condition compared to the control, indicating that it was a suitable condition for osteogenic differentiation. Taken together, the findings of this study reveal that the developed cartridge device promotes the proliferation and differentiation of hMSCs and can potentially be used in the field of tissue engineering.
Collapse
Affiliation(s)
- Ki-Taek Lim
- Department of Biosystems Engineering, Institute of Forest Science, Kangwon National University, Chuncheon 24341, Korea; (D.-K.P.); (S.-D.D.); (K.G.)
- Biomechagen Co., Ltd., Chuncheon 24341, Korea
| | - Dinesh-K. Patel
- Department of Biosystems Engineering, Institute of Forest Science, Kangwon National University, Chuncheon 24341, Korea; (D.-K.P.); (S.-D.D.); (K.G.)
| | - Sayan-Deb Dutta
- Department of Biosystems Engineering, Institute of Forest Science, Kangwon National University, Chuncheon 24341, Korea; (D.-K.P.); (S.-D.D.); (K.G.)
| | - Keya Ganguly
- Department of Biosystems Engineering, Institute of Forest Science, Kangwon National University, Chuncheon 24341, Korea; (D.-K.P.); (S.-D.D.); (K.G.)
| |
Collapse
|
|
15
|
Nifosì G, Nifosì L, Nifosì AF. Mesenchymal stem cells in the treatment of osteonecrosis of the jaw. J Korean Assoc Oral Maxillofac Surg 2021; 47:65-75. [PMID: 33911038 PMCID: PMC8084742 DOI: 10.5125/jkaoms.2021.47.2.65] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2020] [Revised: 11/08/2020] [Accepted: 11/10/2020] [Indexed: 12/22/2022] Open
Abstract
Medication-related osteonecrosis of the jaw (MRONJ) has recently associated to the increase in antiresorptive and anti-angiogenic drugs prescriptions in the treatment of oncologic and osteoporotic patients. The physiopathogenesis of MRONJ remains unclear and available treatments are unsatisfactory. Newer pharmacological treatments have shown good results, but are not curative and could have major side effects. At the same time as pharmacological treatments, mesenchymal stem cells (MSCs) have emerged as a promising therapeutic modality for tissue regeneration and repair. MSCs are multipotential non-hematopoietic progenitor cells capable to differentiating into multiple lineages of the mesenchyme. Bone marrow MSCs can differentiate into osteogenic cells and display immunological properties and secrete paracrine anti-inflammatory factors in damaged tissues. The immunomodulatory, reparative, and anti-inflammatory properties of bone marrow MSCs have been tested in a variety of animal models of MRONJ and applied in specific clinical settings. The aim of this review is to discuss critically the immunogenicity and immunomodulatory properties of MSCs, both in vitro and in vivo, the possible underlying mechanisms of their effects, and their potential clinical use as modulators of immune responses in MRONJ, and to identify clinical safety and recommendations for future research.
Collapse
|
|
16
|
Surface Modified β-Tricalcium phosphate enhanced stem cell osteogenic differentiation in vitro and bone regeneration in vivo. Sci Rep 2021; 11:9234. [PMID: 33927241 PMCID: PMC8084957 DOI: 10.1038/s41598-021-88402-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Accepted: 04/12/2021] [Indexed: 02/08/2023] Open
Abstract
A major number of studies have demonstrated Beta-tricalcium phosphate (β-TCP) biocompatibility, bioactivity, and osteoconductivity characteristics in bone regeneration. The aim of this research was to enhance β-TCP's biocompatibility, and evaluate its physicochemical properties by argon glow discharge plasma (GDP) plasma surface treatment without modifying its surface. Treated β-TCP was analyzed by scanning electron microscopy (SEM), energy-dispersive spectrometry, X-ray photoelectron spectroscopy (XPS), X-ray diffraction analysis, and Fourier transform infrared spectroscopy characterization. To evaluate treated β-TCP biocompatibility and osteoblastic differentiation, water-soluble tetrazolium salts-1 (WST-1), immunofluorescence, alkaline phosphatase (ALP) assay, and quantitative real-time polymerase chain reaction (QPCR) were done using human mesenchymal stem cells (hMSCs). The results indicated a slight enhancement of the β-TCP by GDP sputtering, which resulted in a higher Ca/P ratio (2.05) than the control. Furthermore, when compared with control β-TCP, we observed an improvement of WST-1 on all days (p < 0.05) as well as of ALP activity (day 7, p < 0.05), with up-regulation of ALP, osteocalcin, and Osteoprotegerin osteogenic genes in cells cultured with the treated β-TCP. XPS and SEM results indicated that treated β-TCP’s surface was not modified. In vivo, micro-computed tomography and histomorphometric analysis indicated that the β-TCP test managed to regenerate more new bone than the untreated β-TCP and control defects at 8 weeks (p < 0.05). Argon GDP treatment is a viable method for removing macro and micro particles of < 7 μm in size from β-TCP bigger particles surfaces and therefore improving its biocompatibility with slight surface roughness modification, enhancing hMSCs proliferation, osteoblastic differentiation, and stimulating more new bone formation.
Collapse
|
|
17
|
Wang J, Jiao D, Huang X, Bai Y. Osteoclastic effects of mBMMSCs under compressive pressure during orthodontic tooth movement. Stem Cell Res Ther 2021; 12:148. [PMID: 33632323 PMCID: PMC7905894 DOI: 10.1186/s13287-021-02220-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Accepted: 02/09/2021] [Indexed: 01/10/2023] Open
Abstract
Background During orthodontic tooth movement (OTM), alveolar bone remodelling is closely related to mechanical force. It is unclear whether stem cells can affect osteoclastogenesis to promote OTM. This study aimed to investigate the role of mouse bone marrow mesenchymal stem cells (mBMMSCs) under compression load in OTM. Methods A mouse OTM model was established, and GFP-labelled mBMMSCs and normal saline were injected into different groups of mice by tail vein injection. OTM distance was measured using tissue specimens and micro-computed tomography (micro-CT). The locations of mBMMSCs were traced using GFP immunohistochemistry. Haematoxylin-eosin staining, tartrate-resistant acid phosphate (TRAP) staining and immunohistochemistry of Runx2 and lipoprotein lipase were used to assess changes in the periodontal ligament during OTM. mBMMSCs under compression were co-cultured with mouse bone marrow-derived macrophages (mBMMs), and the gene expression levels of Rankl, Mmp-9, TRAP, Ctsk, Alp, Runx2, Ocn and Osterix were determined by RT-PCR. Results Ten days after mBMMSCs were injected into the tail vein of mice, the OTM distance increased from 176 (normal saline) to 298.4 μm, as determined by tissue specimen observation, and 174.2 to 302.6 μm, as determined by micro-CT metrological analysis. GFP-labelled mBMMSCs were mostly located on the compressed side of the periodontal ligament. Compared to the saline group, the number of osteoclasts in the alveolar bone increased significantly (P < 0.01) on the compressed side in the mBMMSC group. Three days after mBMMSC injection, the number of Runx2-GFP double-positive cells on the tension side was significantly higher than that on the compression side. After applying compressive force on the mBMMSCs in vitro for 2 days, RANKL expression was significantly higher than in the non-compression cells, but expression of Alp, Runx2, Ocn and Osterix was significantly decreased (P < 0.05). The numbers of osteoclasts differentiated in response to mBMMs co-cultured with mBMMSCs under pressure load and expression of osteoclast differentiation marker genes (Mmp-9, TRAP and Ctsk) were significantly higher than those in mBMMs stimulated by M-CSF alone (P < 0.05). Conclusions mBMMSCs are not only recruited to the compressed side of the periodontal ligament but can also promote osteoclastogenesis by expressing Rankl, improving the efficiency of OTM.
Collapse
Affiliation(s)
- Jing Wang
- Department of Orthodontics, School of Stomatology, Beijing Stomatological Hospital, Capital Medical University, Beijing, 100050, China
| | - Delong Jiao
- Department of Orthodontics, School of Stomatology, Beijing Stomatological Hospital, Capital Medical University, Beijing, 100050, China
| | - Xiaofeng Huang
- Department of Stomatology, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China.
| | - Yuxing Bai
- Department of Orthodontics, School of Stomatology, Beijing Stomatological Hospital, Capital Medical University, Beijing, 100050, China.
| |
Collapse
|
|
18
|
Negri S, Wang Y, Sono T, Lee S, Hsu GC, Xu J, Meyers CA, Qin Q, Broderick K, Witwer KW, Peault B, James AW. Human perivascular stem cells prevent bone graft resorption in osteoporotic contexts by inhibiting osteoclast formation. Stem Cells Transl Med 2020; 9:1617-1630. [PMID: 32697440 PMCID: PMC7695633 DOI: 10.1002/sctm.20-0152] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Revised: 05/24/2020] [Accepted: 06/15/2020] [Indexed: 12/15/2022] Open
Abstract
The vascular wall stores mesenchymal progenitor cells which are able to induce bone regeneration, via direct and paracrine mechanisms. Although much is known regarding perivascular cell regulation of osteoblasts, their regulation of osteoclasts, and by extension utility in states of high bone resorption, is not known. Here, human perivascular stem cells (PSCs) were used as a means to prevent autograft resorption in a gonadectomy-induced osteoporotic spine fusion model. Furthermore, the paracrine regulation by PSCs of osteoclast formation was evaluated, using coculture, conditioned medium, and purified extracellular vesicles. Results showed that PSCs when mixed with autograft bone induce an increase in osteoblast:osteoclast ratio, promote bone matrix formation, and prevent bone graft resorption. The confluence of these factors resulted in high rates of fusion in an ovariectomized rat lumbar spine fusion model. Application of PSCs was superior across metrics to either the use of unpurified, culture-defined adipose-derived stromal cells or autograft bone alone. Under coculture conditions, PSCs negatively regulated osteoclast formation and did so via secreted, nonvesicular paracrine factors. Total RNA sequencing identified secreted factors overexpressed by PSCs which may explain their negative regulation of graft resorption. In summary, PSCs reduce osteoclast formation and prevent bone graft resorption in high turnover states such as gonadectomy-induced osteoporosis.
Collapse
Affiliation(s)
- Stefano Negri
- Department of PathologyJohns Hopkins UniversityBaltimoreMarylandUSA
- Orthopaedic and Trauma Surgery Unit, Department of Surgery, DentistryPaediatrics and Gynaecology of the University of VeronaVeronaItaly
| | - Yiyun Wang
- Department of PathologyJohns Hopkins UniversityBaltimoreMarylandUSA
| | - Takashi Sono
- Department of PathologyJohns Hopkins UniversityBaltimoreMarylandUSA
| | - Seungyong Lee
- Department of PathologyJohns Hopkins UniversityBaltimoreMarylandUSA
| | | | - Jiajia Xu
- Department of PathologyJohns Hopkins UniversityBaltimoreMarylandUSA
| | | | - Qizhi Qin
- Department of PathologyJohns Hopkins UniversityBaltimoreMarylandUSA
| | - Kristen Broderick
- Department of Plastic SurgeryJohns Hopkins UniversityBaltimoreMarylandUSA
| | - Kenneth W. Witwer
- Departments of Molecular and Comparative Pathobiology and NeurologyJohns Hopkins UniversityBaltimoreMarylandUSA
| | - Bruno Peault
- UCLA and Orthopaedic Hospital Department of Orthopaedic Surgery and the Orthopaedic Hospital Research CenterLos AngelesCaliforniaUSA
- Center for Cardiovascular Science and MRC Center for Regenerative MedicineUniversity of EdinburghEdinburghUK
| | - Aaron W. James
- Department of PathologyJohns Hopkins UniversityBaltimoreMarylandUSA
| |
Collapse
|
|
19
|
Almasoud N, Binhamdan S, Younis G, Alaskar H, Alotaibi A, Manikandan M, Alfayez M, Kassem M, AlMuraikhi N. Tankyrase inhibitor XAV-939 enhances osteoblastogenesis and mineralization of human skeletal (mesenchymal) stem cells. Sci Rep 2020; 10:16746. [PMID: 33028869 PMCID: PMC7541626 DOI: 10.1038/s41598-020-73439-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Accepted: 08/31/2020] [Indexed: 02/07/2023] Open
Abstract
Tankyrase is part of poly (ADP-ribose) polymerase superfamily required for numerous cellular and molecular processes. Tankyrase inhibition negatively regulates Wnt pathway. Thus, Tankyrase inhibitors have been extensively investigated for the treatment of clinical conditions associated with activated Wnt signaling such as cancer and fibrotic diseases. Moreover, Tankyrase inhibition has been recently reported to upregulate osteogenesis through the accumulation of SH3 domain-binding protein 2, an adaptor protein required for bone metabolism. In this study, we investigated the effect of Tankyrase inhibition in osteoblast differentiation of human skeletal (mesenchymal) stem cells (hMSCs). A Tankyrase inhibitor, XAV-939, identified during a functional library screening of small molecules. Alkaline phosphatase activity and Alizarin red staining were employed as markers for osteoblastic differentiation and in vitro mineralized matrix formation, respectively. Global gene expression profiling was performed using the Agilent microarray platform. XAV-939, a Tankyrase inhibitor, enhanced osteoblast differentiation of hBMSCs as evidenced by increased ALP activity, in vitro mineralized matrix formation, and upregulation of osteoblast-related gene expression. Global gene expression profiling of XAV-939-treated cells identified 847 upregulated and 614 downregulated mRNA transcripts, compared to vehicle-treated control cells. It also points towards possible changes in multiple signaling pathways, including TGFβ, insulin signaling, focal adhesion, estrogen metabolism, oxidative stress, RANK-RANKL (receptor activator of nuclear factor κB ligand) signaling, Vitamin D synthesis, IL6, and cytokines and inflammatory responses. Further bioinformatic analysis, employing Ingenuity Pathway Analysis identified significant enrichment in XAV-939-treated cells of functional categories and networks involved in TNF, NFκB, and STAT signaling. We identified a Tankyrase inhibitor (XAV-939) as a powerful enhancer of osteoblastic differentiation of hBMSC that may be useful as a therapeutic option for treating conditions associated with low bone formation.
Collapse
Affiliation(s)
- Nuha Almasoud
- Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University, Riyadh, 11461, Kingdom of Saudi Arabia
| | - Sarah Binhamdan
- Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University, Riyadh, 11461, Kingdom of Saudi Arabia.,College of Medicine, Alfaisal University, Riyadh, 11533, Kingdom of Saudi Arabia
| | - Ghaydaa Younis
- Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University, Riyadh, 11461, Kingdom of Saudi Arabia
| | - Hanouf Alaskar
- Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University, Riyadh, 11461, Kingdom of Saudi Arabia.,Science Department, College of Science, King Saud University, Riyadh, 11461, Kingdom of Saudi Arabia
| | - Amal Alotaibi
- Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University, Riyadh, 11461, Kingdom of Saudi Arabia
| | - Muthurangan Manikandan
- Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University, Riyadh, 11461, Kingdom of Saudi Arabia
| | - Musaad Alfayez
- Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University, Riyadh, 11461, Kingdom of Saudi Arabia
| | - Moustapha Kassem
- Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University, Riyadh, 11461, Kingdom of Saudi Arabia.,Molecular Endocrinology Unit (KMEB), Department of Endocrinology, University Hospital of Odense and University of Southern Denmark, Odense, Denmark.,Department of Cellular and Molecular Medicine, Danish Stem Cell Center (DanStem), University of Copenhagen, 2200, Copenhagen, Denmark
| | - Nihal AlMuraikhi
- Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University, Riyadh, 11461, Kingdom of Saudi Arabia.
| |
Collapse
|
|
20
|
Corrado A, Cici D, Rotondo C, Maruotti N, Cantatore FP. Molecular Basis of Bone Aging. Int J Mol Sci 2020; 21:ijms21103679. [PMID: 32456199 PMCID: PMC7279376 DOI: 10.3390/ijms21103679] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 05/18/2020] [Accepted: 05/21/2020] [Indexed: 12/16/2022] Open
Abstract
A decline in bone mass leading to an increased fracture risk is a common feature of age-related bone changes. The mechanisms underlying bone senescence are very complex and implicate systemic and local factors and are the result of the combination of several changes occurring at the cellular, tissue and structural levels; they include alterations of bone cell differentiation and activity, oxidative stress, genetic damage and the altered responses of bone cells to various biological signals and to mechanical loading. The molecular mechanisms responsible for these changes remain greatly unclear and many data derived from in vitro or animal studies appear to be conflicting and heterogeneous, probably due to the different experimental approaches; nevertheless, understanding the main physio-pathological processes that cause bone senescence is essential for the development of new potential therapeutic options for treating age-related bone loss. This article reviews the current knowledge concerning the molecular mechanisms underlying the pathogenesis of age-related bone changes.
Collapse
|
|
21
|
Bone Defect Repair Using a Bone Substitute Supported by Mesenchymal Stem Cells Derived from the Umbilical Cord. Stem Cells Int 2020; 2020:1321283. [PMID: 32300364 PMCID: PMC7142388 DOI: 10.1155/2020/1321283] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Revised: 01/10/2020] [Accepted: 02/13/2020] [Indexed: 12/15/2022] Open
Abstract
Objective Bone defects or atrophy may arise as a consequence of injury, inflammation of various etiologies, and neoplastic or traumatic processes or as a result of surgical procedures. Sometimes the regeneration process of bone loss is impaired, significantly slowed down, or does not occur, e.g., in congenital defects. For the bone defect reconstruction, a piece of the removed bone from ala of ilium or bone transplantation from a decedent is used. Replacement of the autologous or allogenic source of the bone-by-bone substitute could reduce the number of surgeries and time in the pharmacological coma during the reconstruction of the bone defect. Application of mesenchymal stem cells in the reconstruction surgery may have positive influence on tissue regeneration by secretion of angiogenic factors, recruitment of other MSCs, or differentiation into osteoblasts. Materials and Methods. Mesenchymal stem cells derived from the umbilical cord (Wharton's jelly (WJ-MSC)) were cultured in GMP-grade DMEM low glucose supplemented with heparin, 10% platelet lysate, glucose, and antibiotics. In vitro WJ-MSCs were seeded on the bone substitute Bio-Oss Collagen® and cultured in the StemPro® Osteogenesis Differentiation Kit. During the culture on the 1st, 7th, 14th, and 21st day (day in vitro (DIV)), we analyzed viability (confocal microscopy) and adhesion capability (electron microscopy) of WJ-MSC on Bio-Oss scaffolds, gene expression (qPCR), and secretion of proteins (Luminex). In vivo Bio-Oss® scaffolds with WJ-MSC were transplanted to trepanation holes in the cranium to obtain their overgrowth. The computed tomography was performed 7, 14, and 21 days after surgery to assess the regeneration. Results The Bio-Oss® scaffold provides a favourable environment for WJ-MSC survival. WJ-MSCs in osteodifferentiation medium are able to attach and proliferate on Bio-Oss® scaffolds. Results obtained from qPCR and Luminex® indicate that WJ-MSCs possess the ability to differentiate into osteoblast-like cells and may induce osteoclastogenesis, angiogenesis, and mobilization of host MSCs. In animal studies, WJ-MSCs seeded on Bio-Oss® increased the scaffold integration with host bone and changed their morphology to osteoblast-like cells. Conclusions The presented construct consisted of Bio-Oss®, the scaffold with high flexibility and plasticity, approved for clinical use with seeded immunologically privileged WJ-MSC which may be considered reconstructive therapy in bone defects.
Collapse
|
|
22
|
Xiang LX, Ran Q, Chen L, Xiang Y, Li FJ, Zhang XM, Xiao YN, Zou LY, Zhong JF, Li SC, Li ZJ. CR6-interacting factor-1 contributes to osteoclastogenesis by inducing receptor activator of nuclear factor κB ligand after radiation. World J Stem Cells 2020; 12:222-240. [PMID: 32266053 PMCID: PMC7118287 DOI: 10.4252/wjsc.v12.i3.222] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2020] [Revised: 03/09/2020] [Accepted: 03/15/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Radiation induces rapid bone loss and enhances bone resorption and adipogenesis, leading to an increased risk of bone fracture. There is still a lack of effective preventive or therapeutic method for irradiation-induced bone injury. Receptor activator of nuclear factor κB ligand (RANKL) provides the crucial signal to induce osteoclast differentiation and plays an important role in bone resorption. However, the mechanisms of radiation-induced osteoporosis are not fully understood. AIM To investigate the role of CR6-interacting factor-1 (Crif1) in osteoclastogenesis after radiation and its possible mechanism. METHODS C57BL/6 mice were exposed to Co-60 gamma rays and received 5 Gy of whole-body sublethal irradiation at a rate of 0.69 Gy/min. For in vitro study, mouse bone marrow mesenchymal stem/stromal cells (BM-MSCs) were irradiated with Co-60 at a single dose of 9 Gy. For osteoclast induction, monocyte-macrophage RAW264.7 cells were cocultured with mouse BM-MSCs for 7 d. ClusPro and InterProSurf were used to investigate the interaction interface in Crif1 and protein kinase cyclic adenosine monophosphate (cAMP)-activited catalytic subunit alpha complex. Virtual screening using 462608 compounds from the Life Chemicals database around His120 of Crif1 was carried out using the program Autodock_vina. A tetrazolium salt (WST-8) assay was carried out to study the toxicity of compounds to different cells, including human BM-MSCs, mouse BM-MSCs, and Vero cells. RESULTS Crif1 expression increased in bone marrow cells after radiation in mice. Overexpression of Crif1 in mouse BM-MSCs and radiation exposure could increase RANKL secretion and promote osteoclastogenesis in vitro. Deletion of Crif1 in BM-MSCs could reduce both adipogenesis and RANKL expression, resulting in the inhibition of osteoclastogenesis. Deletion of Crif1 in RAW264.7 cells did not affect the receptor activator of nuclear factor κB expression or osteoclast differentiation. Following treatment with protein kinase A (PKA) agonist (forskolin) and inhibitor (H-89) in mouse BM-MSCs, Crif1 induced RANKL secretion via the cAMP/PKA pathway. Moreover, we identified the Crif1-protein kinase cyclic adenosine monophosphate-activited catalytic subunit alpha interaction interface by in silico studies and shortlisted interface inhibitors through virtual screening on Crif1. Five compounds dramatically suppressed RANKL secretion and adipogenesis by inhibiting the cAMP/PKA pathway. CONCLUSION Crif1 promotes RANKL expression via the cAMP/PKA pathway, which induces osteoclastogenesis by binding to receptor activator of nuclear factor κB on monocytes-macrophages in the mouse model. These results suggest a role for Crif1 in modulating osteoclastogenesis and provide insights into potential therapeutic strategies targeting the balance between osteogenesis and adipogenesis for radiation-induced bone injury.
Collapse
Affiliation(s)
- Li-Xin Xiang
- Laboratory Medicine Center, Department of Blood Transfusion, Lab of Radiation Biology, The Second Affiliated Hospital, Third Military Medical University, Chongqing, 400037, China
| | - Qian Ran
- Laboratory Medicine Center, Department of Blood Transfusion, Lab of Radiation Biology, The Second Affiliated Hospital, Third Military Medical University, Chongqing, 400037, China
| | - Li Chen
- Laboratory Medicine Center, Department of Blood Transfusion, Lab of Radiation Biology, The Second Affiliated Hospital, Third Military Medical University, Chongqing, 400037, China
| | - Yang Xiang
- Laboratory Medicine Center, Department of Blood Transfusion, Lab of Radiation Biology, The Second Affiliated Hospital, Third Military Medical University, Chongqing, 400037, China
| | - Feng-Jie Li
- Laboratory Medicine Center, Department of Blood Transfusion, Lab of Radiation Biology, The Second Affiliated Hospital, Third Military Medical University, Chongqing, 400037, China
| | - Xiao-Mei Zhang
- Laboratory Medicine Center, Department of Blood Transfusion, Lab of Radiation Biology, The Second Affiliated Hospital, Third Military Medical University, Chongqing, 400037, China
| | - Yan-Ni Xiao
- Laboratory Medicine Center, Department of Blood Transfusion, Lab of Radiation Biology, The Second Affiliated Hospital, Third Military Medical University, Chongqing, 400037, China
| | - Ling-Yun Zou
- Bioinformatics Center, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, China
| | - Jiang F Zhong
- Department of Otolaryngology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, United States
| | - Shengwen Calvin Li
- CHOC Children's Research Institute, Children's Hospital of Orange County, University of California, Irvine, CA 92868, United States
| | - Zhong-Jun Li
- Laboratory Medicine Center, Department of Blood Transfusion, Lab of Radiation Biology, The Second Affiliated Hospital, Third Military Medical University, Chongqing, 400037, China.
| |
Collapse
|
|
23
|
Mazzoni E, D'Agostino A, Iaquinta MR, Bononi I, Trevisiol L, Rotondo JC, Patergnani S, Giorgi C, Gunson MJ, Arnett GW, Nocini PF, Tognon M, Martini F. Hydroxylapatite-collagen hybrid scaffold induces human adipose-derived mesenchymal stem cells to osteogenic differentiation in vitro and bone regrowth in patients. Stem Cells Transl Med 2020; 9:377-388. [PMID: 31834992 PMCID: PMC7031637 DOI: 10.1002/sctm.19-0170] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2019] [Accepted: 10/10/2019] [Indexed: 12/17/2022] Open
Abstract
Tissue engineering-based bone graft is an emerging viable treatment modality to repair and regenerate tissues damaged as a result of diseases or injuries. The structure and composition of scaffolds should modulate the classical osteogenic pathways in human stem cells. The osteoinductivity properties of the hydroxylapatite-collagen hybrid scaffold named Coll/Pro Osteon 200 were investigated in an in vitro model of human adipose mesenchymal stem cells (hASCs), whereas the clinical evaluation was carried out in maxillofacial patients. Differentially expressed genes (DEGs) induced by the scaffold were analyzed using the Osteogenesis RT2 PCR Array. The osteoinductivity potential of the scaffold was also investigated by studying the alkaline phosphatase (ALP) activity, matrix mineralization, osteocalcin (OCN), and CLEC3B expression protein. Fifty patients who underwent zygomatic augmentation and bimaxillary osteotomy were evaluated clinically, radiologically, and histologically during a 3-year follow-up. Among DEGs, osteogenesis-related genes, including BMP1/2, ALP, BGLAP, SP7, RUNX2, SPP1, and EGFR, which play important roles in osteogenesis, were found to be upregulated. The genes to cartilage condensation SOX9, BMPR1B, and osteoclast cells TNFSF11 were detected upregulated at every time point of the investigation. This scaffold has a high osteoinductivity revealed by the matrix mineralization, ALP activity, OCN, and CLEC3B expression proteins. Clinical evaluation evidences that the biomaterial promotes bone regrowth. Histological results of biopsy specimens from patients showed prominent ossification. Experimental data using the Coll/Pro Osteon 200 indicate that clinical evaluation of bone regrowth in patients, after scaffold implantation, was supported by DEGs implicated in skeletal development as shown in "in vitro" experiments with hASCs.
Collapse
Affiliation(s)
- Elisa Mazzoni
- Department of MorphologySurgery and Experimental Medicine, University of FerraraFerraraItaly
| | | | - Maria Rosa Iaquinta
- Department of MorphologySurgery and Experimental Medicine, University of FerraraFerraraItaly
| | - Ilaria Bononi
- Department of MorphologySurgery and Experimental Medicine, University of FerraraFerraraItaly
| | | | - John Charles Rotondo
- Department of MorphologySurgery and Experimental Medicine, University of FerraraFerraraItaly
| | - Simone Patergnani
- Department of MorphologySurgery and Experimental Medicine, University of FerraraFerraraItaly
- Maria Cecilia Hospital, GVM Care & ResearchCotignolaItaly
| | - Carlotta Giorgi
- Department of MorphologySurgery and Experimental Medicine, University of FerraraFerraraItaly
| | - Michael J. Gunson
- Private Practice, Arnett and Gunson Facial ReconstructionSanta BarbaraCalifornia
| | - G. William Arnett
- Private Practice, Arnett and Gunson Facial ReconstructionSanta BarbaraCalifornia
- Department of Oral and Maxillofacial SurgeryLoma Linda UniversityLoma LindaCalifornia
| | | | - Mauro Tognon
- Department of MorphologySurgery and Experimental Medicine, University of FerraraFerraraItaly
| | - Fernanda Martini
- Department of MorphologySurgery and Experimental Medicine, University of FerraraFerraraItaly
| |
Collapse
|
|
24
|
Zhou LL, Liu W, Wu YM, Sun WL, Dörfer CE, Fawzy El-Sayed KM. Oral Mesenchymal Stem/Progenitor Cells: The Immunomodulatory Masters. Stem Cells Int 2020; 2020:1327405. [PMID: 32184830 PMCID: PMC7060886 DOI: 10.1155/2020/1327405] [Citation(s) in RCA: 64] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Revised: 01/08/2020] [Accepted: 01/13/2020] [Indexed: 02/08/2023] Open
Abstract
Oral mesenchymal stem/progenitor cells (MSCs) are renowned in the field of tissue engineering/regeneration for their multilineage differentiation potential and easy acquisition. These cells encompass the periodontal ligament stem/progenitor cells (PDLSCs), the dental pulp stem/progenitor cells (DPSCs), the stem/progenitor cells from human exfoliated deciduous teeth (SHED), the gingival mesenchymal stem/progenitor cells (GMSCs), the stem/progenitor cells from the apical papilla (SCAP), the dental follicle stem/progenitor cells (DFSCs), the bone marrow mesenchymal stem/progenitor cells (BM-MSCs) from the alveolar bone proper, and the human periapical cyst-mesenchymal stem cells (hPCy-MSCs). Apart from their remarkable regenerative potential, oral MSCs possess the capacity to interact with an inflammatory microenvironment. Although inflammation might affect the properties of oral MSCs, they could inversely exert a multitude of immunological actions to the local inflammatory microenvironment. The present review discusses the current understanding about the immunomodulatory role of oral MSCs both in periodontitis and systemic diseases, their "double-edged sword" uniqueness in inflammatory regulation, their affection of the immune system, and the underlying mechanisms, involving oral MSC-derived extracellular vesicles.
Collapse
Affiliation(s)
- Li-li Zhou
- Department of Periodontology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China
- Key Laboratory of Oral Biomedical Research of Zhejiang Province, Zhejiang University School of Stomatology, China
| | - Wei Liu
- Department of Periodontology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China
- Key Laboratory of Oral Biomedical Research of Zhejiang Province, Zhejiang University School of Stomatology, China
| | - Yan-min Wu
- Department of Periodontology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China
| | - Wei-lian Sun
- Department of Periodontology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China
| | - C. E. Dörfer
- Clinic for Conservative Dentistry and Periodontology, School of Dental Medicine, Christian-Albrechts-Universität zu Kiel, Kiel 24105, Germany
| | - K. M. Fawzy El-Sayed
- Oral Medicine and Periodontology Department, Faculty of Oral and Dental Medicine, Cairo University, Cairo 11435, Egypt
| |
Collapse
|
|
25
|
Raimondo D, Remoli C, Astrologo L, Burla R, La Torre M, Vernì F, Tagliafico E, Corsi A, Del Giudice S, Persichetti A, Giannicola G, Robey PG, Riminucci M, Saggio I. Changes in gene expression in human skeletal stem cells transduced with constitutively active Gsα correlates with hallmark histopathological changes seen in fibrous dysplastic bone. PLoS One 2020; 15:e0227279. [PMID: 31999703 PMCID: PMC6991960 DOI: 10.1371/journal.pone.0227279] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Accepted: 12/16/2019] [Indexed: 02/05/2023] Open
Abstract
Fibrous dysplasia (FD) of bone is a complex disease of the skeleton caused by dominant activating mutations of the GNAS locus encoding for the α subunit of the G protein-coupled receptor complex (Gsα). The mutation involves a substitution of arginine at position 201 by histidine or cysteine (GsαR201H or R201C), which leads to overproduction of cAMP. Several signaling pathways are implicated downstream of excess cAMP in the manifestation of disease. However, the pathogenesis of FD remains largely unknown. The overall FD phenotype can be attributed to alterations of skeletal stem/progenitor cells which normally develop into osteogenic or adipogenic cells (in cis), and are also known to provide support to angiogenesis, hematopoiesis, and osteoclastogenesis (in trans). In order to dissect the molecular pathways rooted in skeletal stem/progenitor cells by FD mutations, we engineered human skeletal stem/progenitor cells with the GsαR201C mutation and performed transcriptomic analysis. Our data suggest that this FD mutation profoundly alters the properties of skeletal stem/progenitor cells by pushing them towards formation of disorganized bone with a concomitant alteration of adipogenic differentiation. In addition, the mutation creates an altered in trans environment that induces neovascularization, cytokine/chemokine changes and osteoclastogenesis. In silico comparison of our data with the signature of FD craniofacial samples highlighted common traits, such as the upregulation of ADAM (A Disintegrin and Metalloprotease) proteins and other matrix-related factors, and of PDE7B (Phosphodiesterase 7B), which can be considered as a buffering process, activated to compensate for excess cAMP. We also observed high levels of CEBPs (CCAAT-Enhancer Binding Proteins) in both data sets, factors related to browning of white fat. This is the first analysis of the reaction of human skeletal stem/progenitor cells to the introduction of the FD mutation and we believe it provides a useful background for further studies on the molecular basis of the disease and for the identification of novel potential therapeutic targets.
Collapse
Affiliation(s)
- Domenico Raimondo
- Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Cristina Remoli
- Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Letizia Astrologo
- Department of Biology and Biotechnology, Sapienza University of Rome, Rome, Italy
| | - Romina Burla
- Department of Biology and Biotechnology, Sapienza University of Rome, Rome, Italy
| | - Mattia La Torre
- Department of Biology and Biotechnology, Sapienza University of Rome, Rome, Italy
| | - Fiammetta Vernì
- Department of Biology and Biotechnology, Sapienza University of Rome, Rome, Italy
| | - Enrico Tagliafico
- Department of Biomedical Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Alessandro Corsi
- Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Simona Del Giudice
- Department of Biology and Biotechnology, Sapienza University of Rome, Rome, Italy
| | - Agnese Persichetti
- Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Giuseppe Giannicola
- Department of Anatomical, Histological, Forensic Medicine and Orthopaedics Sciences, Sapienza University of Rome, Rome, Italy
| | - Pamela G. Robey
- National Institute of Dental and Craniofacial Research, NIH, DHHS, Bethesda, MD, United States of America
| | - Mara Riminucci
- Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
- * E-mail: (IS); (MR)
| | - Isabella Saggio
- Department of Biology and Biotechnology, Sapienza University of Rome, Rome, Italy
- School of Biological Sciences, NTU Institute of Structural Biology, Nanyang Technological University, Singapore
- * E-mail: (IS); (MR)
| |
Collapse
|
|
26
|
Li M, Fu X, Gao H, Ji Y, Li J, Wang Y. Regulation of an osteon-like concentric microgrooved surface on osteogenesis and osteoclastogenesis. Biomaterials 2019; 216:119269. [DOI: 10.1016/j.biomaterials.2019.119269] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Revised: 06/04/2019] [Accepted: 06/08/2019] [Indexed: 12/22/2022]
|
|
27
|
Balla B, Sárvári M, Kósa JP, Kocsis-Deák B, Tobiás B, Árvai K, Takács I, Podani J, Liposits Z, Lakatos P. Long-term selective estrogen receptor-beta agonist treatment modulates gene expression in bone and bone marrow of ovariectomized rats. J Steroid Biochem Mol Biol 2019; 188:185-194. [PMID: 30685384 DOI: 10.1016/j.jsbmb.2019.01.012] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2018] [Revised: 01/18/2019] [Accepted: 01/23/2019] [Indexed: 01/20/2023]
Abstract
Gonadal hormones including 17β-estradiol exert important protective functions in skeletal homeostasis. However, numerous details of ovarian hormone deficiency in the common bone marrow microenvironment have not yet been revealed and little information is available on the tissue-specific acts either, especially those via estrogen receptor beta (ERβ). The aim of the present study was therefore to examine the bone-related gene expression changes after ovariectomy (OVX) and long-term ERβ agonist diarylpropionitrile (DPN) administration. We found that OVX produced strong and widespread changes of gene expression in both femoral bone and bone marrow. In the bone out of 22 genes, 20 genes were up- and 2 were downregulated after OVX. It is noteworthy that DPN restored mRNA expression of 10 OVX-induced changes (Aldh2, Col1a1, Daam1, Fgf12, Igf1, Il6r, Nfkb1, Notch1, Notch2 and Psen1) suggesting a modulatory role of ERβ in bone physiology. In bone marrow, out of 37 categorized genes, transcription of 25 genes were up- and 12 were downregulated indicating that the marrow is highly responsive to gonadal hormones. DPN modestly affected transcription, only expression of two genes (Nfatc1 and Tgfb1) was restored by DPN action. The PI3K/Akt signaling pathway was the most affected gene cluster following the interventions in bone and bone marrow, as demonstrated by canonical variates analysis (CVA). We suggested that our results contribute to a deeper understanding of alterations in gene expression of bone and bone marrow niche elicited by ERβ and selective ERβ analogs.
Collapse
Affiliation(s)
- Bernadett Balla
- 1st Department of Internal Medicine, Semmelweis University, Budapest, Hungary.
| | - Miklós Sárvári
- Laboratory of Endocrine Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary
| | - János P Kósa
- 1st Department of Internal Medicine, Semmelweis University, Budapest, Hungary
| | - Barbara Kocsis-Deák
- 1st Department of Internal Medicine, Semmelweis University, Budapest, Hungary
| | - Bálint Tobiás
- 1st Department of Internal Medicine, Semmelweis University, Budapest, Hungary
| | - Kristóf Árvai
- 1st Department of Internal Medicine, Semmelweis University, Budapest, Hungary
| | - István Takács
- 1st Department of Internal Medicine, Semmelweis University, Budapest, Hungary
| | - János Podani
- Biological Institute, Eötvös Loránd University, Budapest, Hungary
| | - Zsolt Liposits
- Laboratory of Endocrine Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary; Department of Neuroscience, Faculty of Information Technology and Bionics, Pázmány Péter Catholic University, Budapest, Hungary
| | - Péter Lakatos
- 1st Department of Internal Medicine, Semmelweis University, Budapest, Hungary
| |
Collapse
|
|
28
|
Rothrauff BB, Smith CA, Ferrer GA, Novaretti JV, Pauyo T, Chao T, Hirsch D, Beaudry MF, Herbst E, Tuan RS, Debski RE, Musahl V. The effect of adipose-derived stem cells on enthesis healing after repair of acute and chronic massive rotator cuff tears in rats. J Shoulder Elbow Surg 2019; 28:654-664. [PMID: 30527883 DOI: 10.1016/j.jse.2018.08.044] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2018] [Revised: 08/26/2018] [Accepted: 08/29/2018] [Indexed: 02/01/2023]
Abstract
BACKGROUND Chronic massive rotator cuff tears heal poorly and often retear. This study investigated the effect of adipose-derived stem cells (ADSCs) and transforming growth factor-β3 (TGF-β3) delivered in 1 of 2 hydrogels (fibrin or gelatin methacrylate [GelMA]) on enthesis healing after repair of acute or chronic massive rotator cuff tears in rats. METHODS Adult male Lewis rats underwent bilateral transection of the supraspinatus and infraspinatus tendons with intramuscular injection of botulinum toxin A (n = 48 rats). After 8 weeks, animals received 1 of 8 interventions (n = 12 shoulders/group): (1) no repair, (2) repair only, or repair augmented with (3) fibrin, (4) GelMA, (5) fibrin + ADSCs, (6) GelMA + ADSCs, (7) fibrin + ADSCs + TGF-β3, or (8) GelMA + ADSCs + TGF-β3. An equal number of animals underwent acute tendon transection and immediate application of 1 of 8 interventions. Enthesis healing was evaluated 4 weeks after the repair by microcomputed tomography, histology, and mechanical testing. RESULTS Increased bone loss and reduced structural properties were seen in chronic compared with acute tears. Bone mineral density of the proximal humerus was higher in repairs of chronic tears augmented with fibrin + ADSCs and GelMA + ADSCs than in unrepaired chronic tears. Similar improvement was not seen in acute tears. No intervention enhanced histologic appearance or structural properties in acute or chronic tears. CONCLUSIONS Surgical repair augmented with ADSCs may provide more benefit in chronic tears compared with acute tears, although there was no added benefit to supplementing ADSCs with TGF-β3.
Collapse
Affiliation(s)
- Benjamin B Rothrauff
- Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA, USA
| | - Catherine A Smith
- Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA
| | - Gerald A Ferrer
- Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA
| | - João V Novaretti
- Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA, USA
| | - Thierry Pauyo
- Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA, USA
| | - Tom Chao
- Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA, USA
| | - David Hirsch
- Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA, USA
| | - Mason F Beaudry
- Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA, USA
| | - Elmar Herbst
- Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA, USA
| | - Rocky S Tuan
- Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA, USA; Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA
| | - Richard E Debski
- Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA, USA; Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA
| | - Volker Musahl
- Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA, USA; Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA.
| |
Collapse
|
|
29
|
Lu LY, Loi F, Nathan K, Lin TH, Pajarinen J, Gibon E, Nabeshima A, Cordova L, Jämsen E, Yao Z, Goodman. SB. Pro-inflammatory M1 macrophages promote Osteogenesis by mesenchymal stem cells via the COX-2-prostaglandin E2 pathway. J Orthop Res 2017; 35:2378-2385. [PMID: 28248001 PMCID: PMC5581298 DOI: 10.1002/jor.23553] [Citation(s) in RCA: 156] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2016] [Accepted: 02/21/2017] [Indexed: 02/04/2023]
Abstract
Bone fractures are among the most common orthopaedic problems that affect individuals of all ages. Immediately after injury, activated macrophages dynamically contribute to and regulate an acute inflammatory response that involves other cells at the injury site, including mesenchymal stem cells (MSCs). These macrophages and MSCs work in concert to modulate bone healing. In this study, we co-cultured undifferentiated M0, pro-inflammatory M1, and anti-inflammatory M2 macrophages with primary murine MSCs in vitro to determine the cross-talk between polarized macrophages and MSCs and their effects on osteogenesis. After 4 weeks of co-culture, MSCs grown with macrophages, especially M1 macrophages, had enhanced bone mineralization compared to MSCs grown alone. The level of bone formation after 4 weeks of culture was closely associated with prostaglandin E2 (PGE2) secretion early in osteogenesis. Treatment with celecoxib, a cyclooxygenase-2 (COX-2) selective inhibitor, significantly reduced bone mineralization in all co-cultures but most dramatically in the M1-MSC co-culture. We also found that the presence of macrophages reduced the secretion of osteoprotegerin (OPG), the decoy RANKL receptor, suggesting that macrophages may indirectly modulate osteoclast activity in addition to enhancing bone formation. Taken together, these findings suggest that an initial pro-inflammatory phase modulated by M1 macrophages promotes osteogenesis in MSCs via the COX-2-PGE2 pathway. Understanding the complex interactions between macrophages and MSCs provide opportunities to optimize bone healing and other regenerative processes via modulation of the inflammatory response. This study provides one possible biological mechanism for the adverse effects of non-steroidal anti-inflammatory drugs on fracture healing and bone regeneration. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:2378-2385, 2017.
Collapse
Affiliation(s)
- Laura Y. Lu
- Department of Orthopaedic Surgery, Stanford University, Stanford, CA
| | - Florence Loi
- Department of Orthopaedic Surgery, Stanford University, Stanford, CA
| | - Karthik Nathan
- Department of Orthopaedic Surgery, Stanford University, Stanford, CA
| | - Tzu-hua Lin
- Department of Orthopaedic Surgery, Stanford University, Stanford, CA
| | - Jukka Pajarinen
- Department of Orthopaedic Surgery, Stanford University, Stanford, CA
| | - Emmanuel Gibon
- Department of Orthopaedic Surgery, Stanford University, Stanford, CA,Laboratoire de Biomécanique et Biomatériaux Ostéo-Articulaires - UMR CNRS 7052, Faculté de Médecine - Université Paris7, Paris, France
| | - Akira Nabeshima
- Department of Orthopaedic Surgery, Stanford University, Stanford, CA
| | - Luis Cordova
- Department of Orthopaedic Surgery, Stanford University, Stanford, CA,Department of Oral and Maxillofacial Surgery, University of Chile, Santiago, Chile
| | - Eemeli Jämsen
- Department of Medicine, Clinicum, University of Helsinki, and Helsinki University Hospital, Helsinki, Finland
| | - Zhenyu Yao
- Department of Orthopaedic Surgery, Stanford University, Stanford, CA
| | - Stuart B. Goodman.
- Department of Orthopaedic Surgery, Stanford University, Stanford, CA,Department of Bioengineering, Stanford University, Stanford, CA
| |
Collapse
|
|
30
|
Kapasa ER, Giannoudis PV, Jia X, Hatton PV, Yang XB. The Effect of RANKL/OPG Balance on Reducing Implant Complications. J Funct Biomater 2017; 8:E42. [PMID: 28937598 PMCID: PMC5748549 DOI: 10.3390/jfb8040042] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2017] [Revised: 09/14/2017] [Accepted: 09/19/2017] [Indexed: 12/27/2022] Open
Abstract
Despite the phenomenal success of implants particularly in the realms of dentistry and orthopaedics, there are still challenges to overcome. The failure of implants resulting from infection, prosthetic loosening, and non-union continue to be the most notorious examples. The cascade of fracture healing and bone repair, especially with the presence of an implant, is complex because it involves a multifaceted immune response alongside the intricate process of bone formation and remodelling. Bone loss is a serious clinical problem that is frequently accompanied by chronic inflammation, illustrating that there is a convoluted relationship between inflammation and bone erosion. The effects of pro-inflammatory factors play a significant role in initiating and maintaining osteoclastogenesis that results in bone resorption by osteoclasts. This is because there is a disruption of the relative ratio between Receptor Activator of Nuclear Factor κB-Ligand (RANKL) and osteoprotegerin (OPG), which is central to modulating bone repair and remodelling. This review aims to provide a background to the bone remodelling process, the bone repair cascade post-implantation, and the associated complications. Furthermore, current clinical solutions that can influence bone formation via either internal or extrinsic mechanisms will be described. These efficacious treatments for osteolysis via targeting the RANKL/OPG ratio may be crucial to reducing the incidence of related implant failures in the future.
Collapse
Affiliation(s)
- Elizabeth R Kapasa
- Doctoral Training Centre-Regenerative Medicine, Institute of Medical and Biological Engineering, School of Mechanical Engineering, University of Leeds, Leeds LS2 9JT, UK.
- Biomaterials and Tissue Engineering Group, School of Dentistry, University of Leeds, Leeds LS2 9JT, UK.
| | - Peter V Giannoudis
- Department of Trauma and Orthopaedic Surgery, School of Medicine, University of Leeds, Leeds LS2 9JT, UK.
| | - Xiaodong Jia
- School of Chemical and Process Engineering, University of Leeds, Leeds LS2 9JT, UK.
| | - Paul V Hatton
- School of Clinical Dentistry, University of Sheffield, Sheffield S10 2TA, UK.
| | - Xuebin B Yang
- Doctoral Training Centre-Regenerative Medicine, Institute of Medical and Biological Engineering, School of Mechanical Engineering, University of Leeds, Leeds LS2 9JT, UK.
- Biomaterials and Tissue Engineering Group, School of Dentistry, University of Leeds, Leeds LS2 9JT, UK.
| |
Collapse
|
|
31
|
Paiva KBS, Granjeiro JM. Matrix Metalloproteinases in Bone Resorption, Remodeling, and Repair. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2017; 148:203-303. [PMID: 28662823 DOI: 10.1016/bs.pmbts.2017.05.001] [Citation(s) in RCA: 143] [Impact Index Per Article: 17.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Matrix metalloproteinases (MMPs) are the major protease family responsible for the cleavage of the matrisome (global composition of the extracellular matrix (ECM) proteome) and proteins unrelated to the ECM, generating bioactive molecules. These proteins drive ECM remodeling, in association with tissue-specific and cell-anchored inhibitors (TIMPs and RECK, respectively). In the bone, the ECM mediates cell adhesion, mechanotransduction, nucleation of mineralization, and the immobilization of growth factors to protect them from damage or degradation. Since the first description of an MMP in bone tissue, many other MMPs have been identified, as well as their inhibitors. Numerous functions have been assigned to these proteins, including osteoblast/osteocyte differentiation, bone formation, solubilization of the osteoid during bone resorption, osteoclast recruitment and migration, and as a coupling factor in bone remodeling under physiological conditions. In turn, a number of pathologies, associated with imbalanced bone remodeling, arise mainly from MMP overexpression and abnormalities of the ECM, leading to bone osteolysis or bone formation. In this review, we will discuss the functions of MMPs and their inhibitors in bone cells, during bone remodeling, pathological bone resorption (osteoporosis and bone metastasis), bone repair/regeneration, and emergent roles in bone bioengineering.
Collapse
Affiliation(s)
- Katiucia B S Paiva
- Laboratory of Extracellular Matrix Biology and Cellular Interaction (LabMec), Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil.
| | - José M Granjeiro
- National Institute of Metrology, Quality and Technology (InMetro), Bioengineering Laboratory, Duque de Caxias, RJ, Brazil; Fluminense Federal University, Dental School, Niterói, RJ, Brazil
| |
Collapse
|
|
32
|
Influence of sinomenine upon mesenchymal stem cells in osteoclastogenesis. Biomed Pharmacother 2017; 90:835-841. [DOI: 10.1016/j.biopha.2017.03.084] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2016] [Revised: 03/23/2017] [Accepted: 03/26/2017] [Indexed: 11/22/2022] Open
|
|
33
|
Sobacchi C, Palagano E, Villa A, Menale C. Soluble Factors on Stage to Direct Mesenchymal Stem Cells Fate. Front Bioeng Biotechnol 2017; 5:32. [PMID: 28567372 PMCID: PMC5434159 DOI: 10.3389/fbioe.2017.00032] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2017] [Accepted: 04/27/2017] [Indexed: 12/17/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are multipotent stromal cells that are identified by in vitro plastic adherence, colony-forming capacity, expression of a panel of surface molecules, and ability to differentiate at least toward osteogenic, adipogenic, and chondrogenic lineages. They also produce trophic factors with immunomodulatory, proangiogenic, and antiapoptotic functions influencing the behavior of neighboring cells. On the other hand, a reciprocal regulation takes place; in fact, MSCs can be isolated from several tissues, and depending on the original microenvironment and the range of stimuli received from there, they can display differences in their essential characteristics. Here, we focus mainly on the bone tissue and how soluble factors, such as growth factors, cytokines, and hormones, present in this microenvironment can orchestrate bone marrow-derived MSCs fate. We also briefly describe the alteration of MSCs behavior in pathological settings such as hematological cancer, bone metastasis, and bone marrow failure syndromes. Overall, the possibility to modulate MSCs plasticity makes them an attractive tool for diverse applications of tissue regeneration in cell therapy. Therefore, the comprehensive understanding of the microenvironment characteristics and components better suited to obtain a specific MSCs response can be extremely useful for clinical use.
Collapse
Affiliation(s)
- Cristina Sobacchi
- Istituto di Ricerca Genetica e Biomedica (IRGB), Consiglio Nazionale delle Ricerche (CNR), Milan Unit, Milan, Italy.,Human Genome Laboratory, Humanitas Clinical and Research Institute, Rozzano, Milan, Italy
| | - Eleonora Palagano
- Human Genome Laboratory, Humanitas Clinical and Research Institute, Rozzano, Milan, Italy.,Department of Medical Biotechnologies and Translational Medicine, University of Milan, Milan, Italy
| | - Anna Villa
- Istituto di Ricerca Genetica e Biomedica (IRGB), Consiglio Nazionale delle Ricerche (CNR), Milan Unit, Milan, Italy.,Human Genome Laboratory, Humanitas Clinical and Research Institute, Rozzano, Milan, Italy
| | - Ciro Menale
- Istituto di Ricerca Genetica e Biomedica (IRGB), Consiglio Nazionale delle Ricerche (CNR), Milan Unit, Milan, Italy.,Human Genome Laboratory, Humanitas Clinical and Research Institute, Rozzano, Milan, Italy
| |
Collapse
|
|
34
|
Rammal H, Dubus M, Aubert L, Reffuveille F, Laurent-Maquin D, Terryn C, Schaaf P, Alem H, Francius G, Quilès F, Gangloff SC, Boulmedais F, Kerdjoudj H. Bioinspired Nanofeatured Substrates: Suitable Environment for Bone Regeneration. ACS APPLIED MATERIALS & INTERFACES 2017; 9:12791-12801. [PMID: 28301131 DOI: 10.1021/acsami.7b01665] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/25/2023]
Abstract
Bone mimicking coatings provide a complex microenvironment in which material, through its inherent properties (such as nanostructure and composition), affects the commitment of stem cells into bone lineage and the production of bone tissue regulating factors required for bone healing and regeneration. Herein, a bioactive mineral/biopolymer composite made of calcium phosphate/chitosan and hyaluronic acid (CaP-CHI-HA) was elaborated using a versatile simultaneous spray coating of interacting species. The resulting CaP-CHI-HA coating was mainly constituted of bioactive, carbonated and crystalline hydroxyapatite with 277 ± 98 nm of roughness, 1 μm of thickness, and 2.3 ± 1 GPa of stiffness. After five days of culture, CaP-CHI-HA suggested a synergistic effect of intrinsic biophysical features and biopolymers on stem cell mechanobiology and nuclear organization, leading to the expression of an early osteoblast-like phenotype and the production of bone tissue regulating factors such as osteoprotegerin and vascular endothelial growth factor. More interestingly, amalgamation with biopolymers conferred to the mineral a bacterial antiadhesive property. These significant data shed light on the potential regenerative application of CaP-CHI-HA bioinspired coating in providing a suitable environment for stem cell bone regeneration and an ideal strategy to prevent implant-associated infections.
Collapse
Affiliation(s)
- H Rammal
- EA 4691, Biomatériaux et Inflammation en Site Osseux (BIOS), SFR-CAP Santé (FED 4231), Université de Reims Champagne Ardenne , 51100 Reims, France
- UFR d'Odontologie, Université de Reims Champagne Ardenne , 51100 Reims, France
| | - M Dubus
- EA 4691, Biomatériaux et Inflammation en Site Osseux (BIOS), SFR-CAP Santé (FED 4231), Université de Reims Champagne Ardenne , 51100 Reims, France
- UFR d'Odontologie, Université de Reims Champagne Ardenne , 51100 Reims, France
| | - L Aubert
- EA 4691, Biomatériaux et Inflammation en Site Osseux (BIOS), SFR-CAP Santé (FED 4231), Université de Reims Champagne Ardenne , 51100 Reims, France
- UFR de Pharmacie, Université de Reims Champagne Ardenne , 51100 Reims, France
| | - F Reffuveille
- EA 4691, Biomatériaux et Inflammation en Site Osseux (BIOS), SFR-CAP Santé (FED 4231), Université de Reims Champagne Ardenne , 51100 Reims, France
- UFR de Pharmacie, Université de Reims Champagne Ardenne , 51100 Reims, France
| | - D Laurent-Maquin
- EA 4691, Biomatériaux et Inflammation en Site Osseux (BIOS), SFR-CAP Santé (FED 4231), Université de Reims Champagne Ardenne , 51100 Reims, France
- UFR d'Odontologie, Université de Reims Champagne Ardenne , 51100 Reims, France
| | - C Terryn
- Plateforme d'Imagerie Cellulaire et Tissulaire (PICT), Université de Reims Champagne Ardenne , 51100 Reims, France
| | - P Schaaf
- INSERM, UMR-S 1121, "Biomatériaux et Bioingénierie", Fédération de médecine translationnelle de Strasbourg, Faculté de Chirurgie Dentaire, Université de Strasbourg , 67000 Strasbourg, France
- CNRS, Institut Charles Sadron UPR 22, Université de Strasbourg , 23 rue du Loess, 67034 Strasbourg Cedex, France
| | - H Alem
- CNRS, UMR 7198, Institut Jean Lamour (IJL), Université de Lorraine , 54500 Vandoeuvre Lès Nancy, France
| | - G Francius
- CNRS, UMR 7564, Laboratoire de Chimie Physique et Microbiologie pour l'Environnement (LCPME), Université de Lorraine , 54500 Vandoeuvre Lès Nancy, France
| | - F Quilès
- CNRS, UMR 7564, Laboratoire de Chimie Physique et Microbiologie pour l'Environnement (LCPME), Université de Lorraine , 54500 Vandoeuvre Lès Nancy, France
| | - S C Gangloff
- EA 4691, Biomatériaux et Inflammation en Site Osseux (BIOS), SFR-CAP Santé (FED 4231), Université de Reims Champagne Ardenne , 51100 Reims, France
- UFR de Pharmacie, Université de Reims Champagne Ardenne , 51100 Reims, France
| | - F Boulmedais
- CNRS, Institut Charles Sadron UPR 22, Université de Strasbourg , 23 rue du Loess, 67034 Strasbourg Cedex, France
| | - H Kerdjoudj
- EA 4691, Biomatériaux et Inflammation en Site Osseux (BIOS), SFR-CAP Santé (FED 4231), Université de Reims Champagne Ardenne , 51100 Reims, France
- UFR d'Odontologie, Université de Reims Champagne Ardenne , 51100 Reims, France
| |
Collapse
|