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Rodríguez-Ortiz ME, Díaz-Tocados JM, Torralbo AI, Valdés-Díaz K, Rivas-Domínguez A, Guerrero F, Reina-Alfonso I, Naves-Díaz M, Alonso-Montes C, Rodelo-Haad C, Rodríguez M, Muñoz-Castañeda JR, IMIBIC Nephrology Group. Impact of elevated sclerostin levels on bone resorption : unravelling structural changes and mineral metabolism disruption. Bone Joint Res 2025; 14:448-462. [PMID: 40355125 PMCID: PMC12068932 DOI: 10.1302/2046-3758.145.bjr-2024-0227.r1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/14/2025] Open
Abstract
Aims The physiological function of sclerostin remains unknown. Sclerostin is synthesized by osteocytes and operates by inhibiting the Wnt/β-catenin pathway. Similarly, it is well established that low levels of sclerostin lead to enhanced bone formation and reduced calciuria, and that high levels of sclerostin are associated with osteoporosis. Methods The impact of high levels of recombinant sclerostin on bone and mineral metabolism parameters was analyzed in this study. In male healthy rats, the effects of three elevated doses of sclerostin over a 14-day period were studied, involving bone histomorphometry, micro-CT (μCT), immunohistochemistry, and analysis of mineral metabolism parameters. Results Although there was increased bone formation, high doses of sclerostin led to a higher reduction in trabecular bone volume due to a significant increase in bone resorption through the direct activation of osteoclastogenesis. In vitro, sclerostin promoted the differentiation of bone marrow stem cells into osteoclasts. Bone resorption, as measured by tartrate-resistant acid phosphatase (TRAP) activity, was excessive in trabecular, cortical, and subchondral bone. Similarly, high doses of sclerostin increased the number of hypertrophic chondrocytes, consequently expanding the growth plate area. At the cortical level, positive TRAP staining could be observed, suggestive of osteocytic osteolysis and trabecularization of cortical bone. The increased bone resorption resulted in a substantial rise in the urinary excretion of phosphorus and calcium, accompanied by elevated levels of FGF23 and a significant decrease in parathyroid hormone (PTH). Conclusion These findings suggest that elevated levels of sclerostin promote bone resorption through the activation of osteoclasts and the generation of osteocytic osteolysis, resulting in increased calciuria, phosphaturia, and changes in mineral metabolism.
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Affiliation(s)
- María Encarnacion Rodríguez-Ortiz
- Nephrology Service, Reina Sofia University Hospital, Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC), University of Cordoba, Córdoba, Spain
- Health Results-Oriented Cooperative Research Network RICORS2040 (Kidney Disease), Institute of Health Carlos III, Madrid, Spain
| | - Juan Miguel Díaz-Tocados
- Health Results-Oriented Cooperative Research Network RICORS2040 (Kidney Disease), Institute of Health Carlos III, Madrid, Spain
- Vascular and Renal Translational Research Group, Biomedical Research Institute of Lleida, Dr. Pifarré Foundation (IRBLleida), Lleida, Spain
| | - Ana Isabel Torralbo
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), University Hospital Reina Sofia, University of Cordoba, Córdoba, Spain
| | - Karen Valdés-Díaz
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), University Hospital Reina Sofia, University of Cordoba, Córdoba, Spain
| | - Antonio Rivas-Domínguez
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), University Hospital Reina Sofia, University of Cordoba, Córdoba, Spain
| | - Fátima Guerrero
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), University Hospital Reina Sofia, University of Cordoba, Córdoba, Spain
| | - Irene Reina-Alfonso
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), University Hospital Reina Sofia, University of Cordoba, Córdoba, Spain
| | - Manuel Naves-Díaz
- Health Results-Oriented Cooperative Research Network RICORS2040 (Kidney Disease), Institute of Health Carlos III, Madrid, Spain
- Bone and Mineral Research Unit, Hospital Universitario Central de Asturias, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain
| | - Cristina Alonso-Montes
- Health Results-Oriented Cooperative Research Network RICORS2040 (Kidney Disease), Institute of Health Carlos III, Madrid, Spain
- Bone and Mineral Research Unit, Hospital Universitario Central de Asturias, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain
| | - Cristian Rodelo-Haad
- Nephrology Service, Reina Sofia University Hospital, Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC), University of Cordoba, Córdoba, Spain
- Health Results-Oriented Cooperative Research Network RICORS2040 (Kidney Disease), Institute of Health Carlos III, Madrid, Spain
| | - Mariano Rodríguez
- Nephrology Service, Reina Sofia University Hospital, Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC), University of Cordoba, Córdoba, Spain
- Health Results-Oriented Cooperative Research Network RICORS2040 (Kidney Disease), Institute of Health Carlos III, Madrid, Spain
| | - Juan Rafael Muñoz-Castañeda
- Nephrology Service, Reina Sofia University Hospital, Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC), University of Cordoba, Córdoba, Spain
- Health Results-Oriented Cooperative Research Network RICORS2040 (Kidney Disease), Institute of Health Carlos III, Madrid, Spain
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Mizoguchi T. In vivo dynamics of hard tissue-forming cell origins: Insights from Cre/loxP-based cell lineage tracing studies. JAPANESE DENTAL SCIENCE REVIEW 2024; 60:109-119. [PMID: 38406212 PMCID: PMC10885318 DOI: 10.1016/j.jdsr.2024.01.003] [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: 11/20/2023] [Revised: 01/25/2024] [Accepted: 01/30/2024] [Indexed: 02/27/2024] Open
Abstract
Bone tissue provides structural support for our bodies, with the inner bone marrow (BM) acting as a hematopoietic organ. Within the BM tissue, two types of stem cells play crucial roles: mesenchymal stem cells (MSCs) (or skeletal stem cells) and hematopoietic stem cells (HSCs). These stem cells are intricately connected, where BM-MSCs give rise to bone-forming osteoblasts and serve as essential components in the BM microenvironment for sustaining HSCs. Despite the mid-20th century proposal of BM-MSCs, their in vivo identification remained elusive owing to a lack of tools for analyzing stemness, specifically self-renewal and multipotency. To address this challenge, Cre/loxP-based cell lineage tracing analyses are being employed. This technology facilitated the in vivo labeling of specific cells, enabling the tracking of their lineage, determining their stemness, and providing a deeper understanding of the in vivo dynamics governing stem cell populations responsible for maintaining hard tissues. This review delves into cell lineage tracing studies conducted using commonly employed genetically modified mice expressing Cre under the influence of LepR, Gli1, and Axin2 genes. These studies focus on research fields spanning long bones and oral/maxillofacial hard tissues, offering insights into the in vivo dynamics of stem cell populations crucial for hard tissue homeostasis.
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Zhang Y, Li Z, Chen X. The role of galectin-3 in bone homeostasis: A review. Int J Biol Macromol 2024; 278:134882. [PMID: 39168209 DOI: 10.1016/j.ijbiomac.2024.134882] [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: 06/13/2024] [Revised: 08/05/2024] [Accepted: 08/17/2024] [Indexed: 08/23/2024]
Abstract
The skeletal system maintains a delicate balance known as bone homeostasis, which is essential for the lifelong preservation of bone mass, shape, and integrity. This equilibrium relies on a complex interplay between bone marrow mesenchymal stem cells (BMSCs), osteoblasts, osteocytes, and osteoclasts. Galectin-3 (Gal-3), a chimeric galectin with a unique N-terminal tail and a conserved carbohydrate recognition domain (CRD) at its C-terminus, has emerged as a critical regulator in bone homeostasis. The CRD of Gal-3 mediates carbohydrate binding, while its N-terminal tail is implicated in oligomerization and phase separation, which are vital for its functionality. Gal-3's multivalency is central to its role in a range of cellular activities, including inflammation, immune response, apoptosis, cell adhesion, and migration. Imbalances in bone homeostasis often arise from disruptions in osteoblast differentiation and activity, increased osteoclast differentiation and activity. Gal-3's influence on these processes suggests its significant role in the regulation of bone remodeling. This review will examine the molecular mechanisms through which Gal-3 contributes to bone remodeling and discuss its potential as a therapeutic target for the treatment of bone-related disorders.
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Affiliation(s)
- Yanchao Zhang
- Department of Orthopedics, Tianjin Baodi Hospital/Baodi Clinical College of Tianjin Medical University, Tianjin 301800, China
| | - Zhiyong Li
- Department of Orthopedics, Tianjin Baodi Hospital/Baodi Clinical College of Tianjin Medical University, Tianjin 301800, China
| | - Xueqing Chen
- Department of Orthopedics, Tianjin Baodi Hospital/Baodi Clinical College of Tianjin Medical University, Tianjin 301800, China.
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Hu L, Chen W, Qian A, Li YP. Wnt/β-catenin signaling components and mechanisms in bone formation, homeostasis, and disease. Bone Res 2024; 12:39. [PMID: 38987555 PMCID: PMC11237130 DOI: 10.1038/s41413-024-00342-8] [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: 12/10/2023] [Revised: 04/27/2024] [Accepted: 05/12/2024] [Indexed: 07/12/2024] Open
Abstract
Wnts are secreted, lipid-modified proteins that bind to different receptors on the cell surface to activate canonical or non-canonical Wnt signaling pathways, which control various biological processes throughout embryonic development and adult life. Aberrant Wnt signaling pathway underlies a wide range of human disease pathogeneses. In this review, we provide an update of Wnt/β-catenin signaling components and mechanisms in bone formation, homeostasis, and diseases. The Wnt proteins, receptors, activators, inhibitors, and the crosstalk of Wnt signaling pathways with other signaling pathways are summarized and discussed. We mainly review Wnt signaling functions in bone formation, homeostasis, and related diseases, and summarize mouse models carrying genetic modifications of Wnt signaling components. Moreover, the therapeutic strategies for treating bone diseases by targeting Wnt signaling, including the extracellular molecules, cytosol components, and nuclear components of Wnt signaling are reviewed. In summary, this paper reviews our current understanding of the mechanisms by which Wnt signaling regulates bone formation, homeostasis, and the efforts targeting Wnt signaling for treating bone diseases. Finally, the paper evaluates the important questions in Wnt signaling to be further explored based on the progress of new biological analytical technologies.
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Affiliation(s)
- Lifang Hu
- Laboratory for Bone Metabolism, Xi'an Key Laboratory of Special Medicine and Health Engineering, Key Laboratory for Space Biosciences and Biotechnology, Research Center for Special Medicine and Health Systems Engineering, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi, 710072, China
| | - Wei Chen
- Division in Cellular and Molecular Medicine, Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, Tulane University, New Orleans, LA, 70112, USA
| | - Airong Qian
- Laboratory for Bone Metabolism, Xi'an Key Laboratory of Special Medicine and Health Engineering, Key Laboratory for Space Biosciences and Biotechnology, Research Center for Special Medicine and Health Systems Engineering, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi, 710072, China.
| | - Yi-Ping Li
- Division in Cellular and Molecular Medicine, Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, Tulane University, New Orleans, LA, 70112, USA.
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Yu L, Huang L, Zhao Y, Liu S, Zhou R, Yue Y, Sun H, Su X, Liu Q, Li S, Ying J, Zhao F, Qu Y. Atorvastatin Promotes Pro/anti-inflammatory Phenotypic Transformation of Microglia via Wnt/β-catenin Pathway in Hypoxic-Ischemic Neonatal Rats. Mol Neurobiol 2024; 61:3559-3577. [PMID: 37996729 PMCID: PMC11087325 DOI: 10.1007/s12035-023-03777-y] [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: 02/01/2023] [Accepted: 11/06/2023] [Indexed: 11/25/2023]
Abstract
Inflammatory reaction plays a key role in the pathogenesis of hypoxic-ischemic encephalopathy (HIE) in neonates. Microglia are resident innate immune cells in the central nervous system and are profoundly involved in neuroinflammation. Studies have revealed that atorvastatin exerts a neuroprotective effect by regulating neuroinflammation in adult animal models of brain stroke and traumatic brain injury, but its role regarding damage to the developing brain remains unclear. This study aimed to clarify the effect and mechanism of atorvastatin on the regulation of microglia function in neonatal hypoxic-ischemic brain damage (HIBD). The oxygen glucose deprivation (OGD) of microglia and neonatal rat HIBD model was established. Atorvastatin, recombinant sclerostin protein (SOST), and XAV939 (degradation of β-catenin) were administered to OGD microglia and HIBD rats. The pathological changes of brain tissue, cerebral infarction volume, learning and memory ability of rats, pro-inflammatory (CD16+/Iba1+) and anti-inflammatory (CD206+/Iba1+) microglia markers, inflammation-related indicators (Inos, Tnfα, Il6, Arg1, Tgfb, and Mrc1), and Wnt/β-catenin signaling molecules were examined. Atorvastatin reduced OGD-induced pro-inflammatory microglia and pro-inflammatory factors, while increasing anti-inflammatory microglia and anti-inflammatory factors. In vivo, atorvastatin attenuated hypoxia-ischemia (HI)-induced neuroinflammation and brain damage. Mechanistically, atorvastatin decreased SOST expression and activated the Wnt/β-catenin signaling pathway, and the administration of recombinant SOST protein or XAV939 inhibited Wnt/β-catenin signaling and attenuated the anti-inflammatory effect of atorvastatin. Atorvastatin promotes the pro/anti-inflammatory phenotypic transformation of microglia via the Wnt/β-catenin pathway in HI neonatal rats. Atorvastatin may be developed as a potent agent for the treatment of HIE in neonates.
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Affiliation(s)
- Luting Yu
- Department of Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), NHC Key Laboratory of Chronobiology, West China Second University Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Lingyi Huang
- Department of Orthodontics, State Key Laboratory of Oral Diseases, West China College of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Yuanyuan Zhao
- Department of Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), NHC Key Laboratory of Chronobiology, West China Second University Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Shixi Liu
- Department of Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), NHC Key Laboratory of Chronobiology, West China Second University Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Ruixi Zhou
- Department of Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), NHC Key Laboratory of Chronobiology, West China Second University Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Yan Yue
- Department of Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), NHC Key Laboratory of Chronobiology, West China Second University Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Hao Sun
- Department of Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), NHC Key Laboratory of Chronobiology, West China Second University Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Xiaojuan Su
- Department of Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), NHC Key Laboratory of Chronobiology, West China Second University Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Qian Liu
- Department of Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), NHC Key Laboratory of Chronobiology, West China Second University Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Shiping Li
- Department of Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), NHC Key Laboratory of Chronobiology, West China Second University Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Junjie Ying
- Department of Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), NHC Key Laboratory of Chronobiology, West China Second University Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Fengyan Zhao
- Department of Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), NHC Key Laboratory of Chronobiology, West China Second University Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Yi Qu
- Department of Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), NHC Key Laboratory of Chronobiology, West China Second University Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.
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Meyer C, Brockmueller A, Buhrmann C, Shakibaei M. Prevention and Co-Management of Breast Cancer-Related Osteoporosis Using Resveratrol. Nutrients 2024; 16:708. [PMID: 38474838 DOI: 10.3390/nu16050708] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2024] [Revised: 02/21/2024] [Accepted: 02/26/2024] [Indexed: 03/14/2024] Open
Abstract
Breast cancer (BC) is currently one of the most common cancers in women worldwide with a rising tendency. Epigenetics, generally inherited variations in gene expression that occur independently of changes in DNA sequence, and their disruption could be one of the main causes of BC due to inflammatory processes often associated with different lifestyle habits. In particular, hormone therapies are often indicated for hormone-positive BC, which accounts for more than 50-80% of all BC subtypes. Although the cure rate in the early stage is more than 70%, serious negative side effects such as secondary osteoporosis (OP) due to induced estrogen deficiency and chemotherapy are increasingly reported. Approaches to the management of secondary OP in BC patients comprise adjunctive therapy with bisphosphonates, non-steroidal anti-inflammatory drugs (NSAIDs), and cortisone, which partially reduce bone resorption and musculoskeletal pain but which are not capable of stimulating the necessary intrinsic bone regeneration. Therefore, there is a great therapeutic need for novel multitarget treatment strategies for BC which hold back the risk of secondary OP. In this review, resveratrol, a multitargeting polyphenol that has been discussed as a phytoestrogen with anti-inflammatory and anti-tumor effects at the epigenetic level, is presented as a potential adjunct to both support BC therapy and prevent osteoporotic risks by positively promoting intrinsic regeneration. In this context, resveratrol is also known for its unique role as an epigenetic modifier in the regulation of essential signaling processes-both due to its catabolic effect on BC and its anabolic effect on bone tissue.
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Affiliation(s)
- Christine Meyer
- Chair of Vegetative Anatomy, Institute of Anatomy, Faculty of Medicine, LMU Munich, Pettenkoferstr. 11, 80336 Munich, Germany
| | - Aranka Brockmueller
- Chair of Vegetative Anatomy, Institute of Anatomy, Faculty of Medicine, LMU Munich, Pettenkoferstr. 11, 80336 Munich, Germany
| | - Constanze Buhrmann
- Institute of Anatomy and Cell Biology, Faculty of Medicine, University of Augsburg, 86159 Augsburg, Germany
| | - Mehdi Shakibaei
- Chair of Vegetative Anatomy, Institute of Anatomy, Faculty of Medicine, LMU Munich, Pettenkoferstr. 11, 80336 Munich, Germany
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Furtado GS, Martin V, Araújo R, Gomes PS, Lago ADN. Osteoinductive activity of photobiomodulation in an organotypic bone model. Photodiagnosis Photodyn Ther 2024; 45:103936. [PMID: 38104705 DOI: 10.1016/j.pdpdt.2023.103936] [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: 12/08/2023] [Accepted: 12/12/2023] [Indexed: 12/19/2023]
Abstract
Photobiomodulation (PBM) is a technique that harnesses non-ionizing light at specific wavelengths, triggering the modulation of metabolic pathways, engendering favourable biological outcomes that reduce inflammation and foster enhanced tissue healing and regeneration. PBM holds significant promise for bone tissue applications due to its non-invasive nature and ability to stimulate cellular activity and vascularization within the healing framework. Notwithstanding, the impact of PBM on bone functionality remains largely undisclosed, particularly in the absence of influencing factors such as pathologies or regenerative therapies. This study aims to investigate the potential effects of PBM using red (660 nm) (RED) and near-infrared (808 nm) (NIR) wavelengths within an ex vivo bone culture system - the organotypic embryonic chicken femur model. A continuous irradiation mode was used, administering a total energy dose of 1.0 J, at an intensity of 100 mW for 10 s, which was repeated four times over the course of the 11-day culture period. The primary focus is on characterizing the expression of pivotal osteoblastic genes, the maturation and deposition of collagen, and the formation of bone mineral. Exposing femora to both RED and NIR wavelengths led to a notable increase in the expression of osteochondrogenic transcription factors (i.e., SOX9 and RUNX2), correlating with enhanced mineralization. Notably, NIR irradiation further elevated the expression of bone matrix-related genes and fostered enhanced deposition and maturation of fibrillar collagen. This study demonstrates that PBM has the potential to enhance osteogenic functionality within a translational organotypic bone culture system, with the NIR wavelength showing remarkable capabilities in augmenting the formation and maturation of the collagenous matrix.
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Affiliation(s)
- Guilherme Silva Furtado
- Graduate Student in the Postgraduate Program in Dentistry at the Federal University of Maranhão, Av. dos Portugueses, 1966, Bacanga, São Luís 65080-805, Brazil
| | - Victor Martin
- DDS, MSc and Graduate student at Laboratory for Bone Metabolism and Regeneration, Faculty of Dental Medicine, University of Porto, Rua Dr. Manuel Pereira da Silva, Porto 4200-393, Portugal; REQUIMTE/LAQV, University of Porto, Praça Coronel Pacheco, 15, Porto 4050-453, Portugal
| | - Rita Araújo
- DDS, MSc and Graduate student at Laboratory for Bone Metabolism and Regeneration, Faculty of Dental Medicine, University of Porto, Rua Dr. Manuel Pereira da Silva, Porto 4200-393, Portugal; REQUIMTE/LAQV, University of Porto, Praça Coronel Pacheco, 15, Porto 4050-453, Portugal
| | - Pedro Sousa Gomes
- REQUIMTE/LAQV, University of Porto, Praça Coronel Pacheco, 15, Porto 4050-453, Portugal; DDS, MSc, PhD Full Professor at Laboratory for Bone Metabolism and Regeneration, Faculty of Dental Medicine, University of Porto, Porto, Portugal.
| | - Andréa Dias Neves Lago
- DDS, MSc, PhD, Associate Professor of the Postgraduate Program in Dentistry at the Federal University of Maranhão, São Luís, Maranhão, Av. dos Portugueses, 1966, Bacanga, São Luís 65080-805, Brazil
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Bao DY, Yang Y, Tong X, Qin HY. Activation of wnt/β-catenin signaling pathway down regulated osteogenic differentiation of bone marrow-derived stem cells in an anhidrotic ectodermal dysplasia patient with EDA/EDAR/EDARADD mutation. Heliyon 2024; 10:e23057. [PMID: 38169761 PMCID: PMC10758735 DOI: 10.1016/j.heliyon.2023.e23057] [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: 12/30/2022] [Revised: 10/29/2023] [Accepted: 11/24/2023] [Indexed: 01/05/2024] Open
Abstract
Objective To explore the mechanism by which the Wnt/β-catenin pathway induces osteogenic differentiation of bone marrow-derived stem cells (BMSCs) in anhidrotic ectodermal dysplasia (AED) with an Ectodysplasin A (EDA)/EDA receptor (EDAR)/EDARADD mutation. Methods An AED patient served as the AED group, whereas the other patients without AED were included in the normal group. Peripheral venous blood collected from the AED patient was subjected to whole-genome resequencing. BMSCs from the mandible of patients with AED and normal individuals were isolated and cultured in vitro. Cell proliferation assay was performed to compare the growth speed of BMSCs between the AED and normal groups. CHIR-99021, an activator of the Wnt/β-catenin pathway and XAV-939, an inhibitor, was used to manage BMSCs in an osteogenic environment in both groups. The expression of β-catenin was detected by quantitative polymerase chain reaction, while that of RUNX2 was detected by western blotting. Alizarin red was used for staining. Results A novel mutation (c.152T > A in EDA) and two known mutations (c.1109T > C in EDAR and c.27G > A in EDARADD) were identified. The growth rate in the normal group was higher than that in the AED group. In the normal group, the number and size of calcified nodes and the expression of RUNX-2 increased with CHIR-99021 treatment, which could be inhibited by XAV-939. In contrast, CHIR-99021 inhibited osteogenesis in the AED group and this effect was promoted by XAV-939. Conclusion Activation of the Wnt/β-catenin pathway downregulates osteogenesis of BMSCs in AED patients with EDA/EDAR/EDARADD gene mutations. Further investigation in more AED patients is required, given the wide range of mutations involved in AED.
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Affiliation(s)
- Dong-yu Bao
- Department of Stomatology, the Affiliated Drum Tower Hospital of Nanjing University Medical School. 321 Zhongshan Road, Nanjing, 210008, China
- Department of Dental Implantology, Nanjing Stomatological Hospital, Medical School of Nanjing University, No.30 Zhongyang Road, Nanjing, 210008, China
| | - Yun Yang
- Department of Stomatology, the Affiliated Drum Tower Hospital of Nanjing University Medical School. 321 Zhongshan Road, Nanjing, 210008, China
| | - Xin Tong
- Department of Dental Implantology, Nanjing Stomatological Hospital, Medical School of Nanjing University, No.30 Zhongyang Road, Nanjing, 210008, China
| | - Hai-yan Qin
- Department of Stomatology, the Affiliated Drum Tower Hospital of Nanjing University Medical School. 321 Zhongshan Road, Nanjing, 210008, China
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Lipreri MV, Di Pompo G, Boanini E, Graziani G, Sassoni E, Baldini N, Avnet S. Bone on-a-chip: a 3D dendritic network in a screening platform for osteocyte-targeted drugs. Biofabrication 2023; 15:045019. [PMID: 37552982 DOI: 10.1088/1758-5090/acee23] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Accepted: 08/08/2023] [Indexed: 08/10/2023]
Abstract
Age-related musculoskeletal disorders, including osteoporosis, are frequent and associated with long lasting morbidity, in turn significantly impacting on healthcare system sustainability. There is therefore a compelling need to develop reliable preclinical models of disease and drug screening to validate novel drugs possibly on a personalized basis, without the need ofin vivoassay. In the context of bone tissue, although the osteocyte (Oc) network is a well-recognized therapeutic target, currentin vitropreclinical models are unable to mimic its physiologically relevant and highly complex structure. To this purpose, several features are needed, including an osteomimetic extracellular matrix, dynamic perfusion, and mechanical cues (e.g. shear stress) combined with a three-dimensional (3D) culture of Oc. Here we describe, for the first time, a high throughput microfluidic platform based on 96-miniaturized chips for large-scale preclinical evaluation to predict drug efficacy. We bioengineered a commercial microfluidic device that allows real-time visualization and equipped with multi-chips by the development and injection of a highly stiff bone-like 3D matrix, made of a blend of collagen-enriched natural hydrogels loaded with hydroxyapatite nanocrystals. The microchannel, filled with the ostemimetic matrix and Oc, is subjected to passive perfusion and shear stress. We used scanning electron microscopy for preliminary material characterization. Confocal microscopy and fluorescent microbeads were used after material injection into the microchannels to detect volume changes and the distribution of cell-sized objects within the hydrogel. The formation of a 3D dendritic network of Oc was monitored by measuring cell viability, evaluating phenotyping markers (connexin43, integrin alpha V/CD51, sclerostin), quantification of dendrites, and responsiveness to an anabolic drug. The platform is expected to accelerate the development of new drug aimed at modulating the survival and function of osteocytes.
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Affiliation(s)
| | - Gemma Di Pompo
- Biomedical Science, Technologies, and Nanobiotecnologiy Lab, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
| | - Elisa Boanini
- Department of Chemistry 'Giacomo Ciamician', University of Bologna, Bologna, Italy
| | - Gabriela Graziani
- Biomedical Science, Technologies, and Nanobiotecnologiy Lab, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
| | - Enrico Sassoni
- Department of Civil, Chemical, Environmental and Materials Engineering, University of Bologna, Bologna, Italy
| | - Nicola Baldini
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
- Biomedical Science, Technologies, and Nanobiotecnologiy Lab, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
| | - Sofia Avnet
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
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10
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Jiang H, Li D, Han Y, Li N, Tao X, Liu J, Zhang Z, Yu Y, Wang L, Yu S, Zhang N, Xiao H, Yang X, Zhang Y, Zhang G, Zhang BT. The role of sclerostin in lipid and glucose metabolism disorders. Biochem Pharmacol 2023; 215:115694. [PMID: 37481136 DOI: 10.1016/j.bcp.2023.115694] [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: 05/05/2023] [Revised: 07/01/2023] [Accepted: 07/11/2023] [Indexed: 07/24/2023]
Abstract
Lipid and glucose metabolism are critical for human activities, and their disorders can cause diabetes and obesity, two prevalent metabolic diseases. Studies suggest that the bone involved in lipid and glucose metabolism is emerging as an endocrine organ that regulates systemic metabolism through bone-derived molecules. Sclerostin, a protein mainly produced by osteocytes, has been therapeutically targeted by antibodies for treating osteoporosis owing to its ability to inhibit bone formation. Moreover, recent evidence indicates that sclerostin plays a role in lipid and glucose metabolism disorders. Although the effects of sclerostin on bone have been extensively examined and reviewed, its effects on systemic metabolism have not yet been well summarized. In this paper, we provide a systemic review of the effects of sclerostin on lipid and glucose metabolism based on in vitro and in vivo evidence, summarize the research progress on sclerostin, and prospect its potential manipulation for obesity and diabetes treatment.
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Affiliation(s)
- Hewen Jiang
- School of Chinese Medicine, Chinese University of Hong Kong, Hong Kong, China; Guangdong-Hong Kong Macao Greater Bay Area International Research Platform for Aptamer-Based Translational Medicine and Drug Discovery, Hong Kong, China
| | - Dijie Li
- Guangdong-Hong Kong Macao Greater Bay Area International Research Platform for Aptamer-Based Translational Medicine and Drug Discovery, Hong Kong, China; Law Sau Fai Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China; Institute of Integrated Bioinformedicine and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
| | - Ying Han
- Guangdong-Hong Kong Macao Greater Bay Area International Research Platform for Aptamer-Based Translational Medicine and Drug Discovery, Hong Kong, China; Law Sau Fai Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China; Institute of Integrated Bioinformedicine and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
| | - Nanxi Li
- Guangdong-Hong Kong Macao Greater Bay Area International Research Platform for Aptamer-Based Translational Medicine and Drug Discovery, Hong Kong, China; Law Sau Fai Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China; Institute of Integrated Bioinformedicine and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
| | - Xiaohui Tao
- Guangdong-Hong Kong Macao Greater Bay Area International Research Platform for Aptamer-Based Translational Medicine and Drug Discovery, Hong Kong, China; Law Sau Fai Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China; Institute of Integrated Bioinformedicine and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
| | - Jin Liu
- Guangdong-Hong Kong Macao Greater Bay Area International Research Platform for Aptamer-Based Translational Medicine and Drug Discovery, Hong Kong, China; Law Sau Fai Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China; Institute of Integrated Bioinformedicine and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
| | - Zongkang Zhang
- School of Chinese Medicine, Chinese University of Hong Kong, Hong Kong, China; Guangdong-Hong Kong Macao Greater Bay Area International Research Platform for Aptamer-Based Translational Medicine and Drug Discovery, Hong Kong, China
| | - Yuanyuan Yu
- Guangdong-Hong Kong Macao Greater Bay Area International Research Platform for Aptamer-Based Translational Medicine and Drug Discovery, Hong Kong, China; Law Sau Fai Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China; Institute of Integrated Bioinformedicine and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
| | - Luyao Wang
- Guangdong-Hong Kong Macao Greater Bay Area International Research Platform for Aptamer-Based Translational Medicine and Drug Discovery, Hong Kong, China; Law Sau Fai Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China; Institute of Integrated Bioinformedicine and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
| | - Sifan Yu
- School of Chinese Medicine, Chinese University of Hong Kong, Hong Kong, China; Guangdong-Hong Kong Macao Greater Bay Area International Research Platform for Aptamer-Based Translational Medicine and Drug Discovery, Hong Kong, China
| | - Ning Zhang
- School of Chinese Medicine, Chinese University of Hong Kong, Hong Kong, China; Guangdong-Hong Kong Macao Greater Bay Area International Research Platform for Aptamer-Based Translational Medicine and Drug Discovery, Hong Kong, China
| | - Huan Xiao
- School of Chinese Medicine, Chinese University of Hong Kong, Hong Kong, China; Guangdong-Hong Kong Macao Greater Bay Area International Research Platform for Aptamer-Based Translational Medicine and Drug Discovery, Hong Kong, China
| | - Xin Yang
- School of Chinese Medicine, Chinese University of Hong Kong, Hong Kong, China; Guangdong-Hong Kong Macao Greater Bay Area International Research Platform for Aptamer-Based Translational Medicine and Drug Discovery, Hong Kong, China
| | - Yihao Zhang
- School of Chinese Medicine, Chinese University of Hong Kong, Hong Kong, China; Guangdong-Hong Kong Macao Greater Bay Area International Research Platform for Aptamer-Based Translational Medicine and Drug Discovery, Hong Kong, China
| | - Ge Zhang
- Guangdong-Hong Kong Macao Greater Bay Area International Research Platform for Aptamer-Based Translational Medicine and Drug Discovery, Hong Kong, China; Law Sau Fai Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China; Institute of Integrated Bioinformedicine and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China.
| | - Bao-Ting Zhang
- School of Chinese Medicine, Chinese University of Hong Kong, Hong Kong, China; Guangdong-Hong Kong Macao Greater Bay Area International Research Platform for Aptamer-Based Translational Medicine and Drug Discovery, Hong Kong, China.
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11
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Xie Z, Zhou G, Zhang M, Han J, Wang Y, Li X, Wu Q, Li M, Zhang S. Recent developments on BMPs and their antagonists in inflammatory bowel diseases. Cell Death Discov 2023; 9:210. [PMID: 37391444 DOI: 10.1038/s41420-023-01520-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 06/15/2023] [Accepted: 06/22/2023] [Indexed: 07/02/2023] Open
Abstract
Inflammatory bowel diseases (IBDs), including ulcerative colitis, and Crohn's disease, are intestinal disorders characterized by chronic relapsing inflammation. A large proportion of patients with IBD will progress to develop colitis-associated colorectal cancer due to the chronic intestinal inflammation. Biologic agents that target tumour necrosis factor-α, integrin α4β7, and interleukin (IL)12/23p40 have been more successful than conventional therapies in treating IBD. However, drug intolerance and loss of response are serious drawbacks of current biologics, necessitating the development of novel drugs that target specific pathways in IBD pathogenesis. One promising group of candidate molecules are bone morphogenetic proteins (BMPs), members of the TGF-β family involved in regulating morphogenesis, homeostasis, stemness, and inflammatory responses in the gastrointestinal tract. Also worth examining are BMP antagonists, major regulators of these proteins. Evidence has shown that BMPs (especially BMP4/6/7) and BMP antagonists (especially Gremlin1 and follistatin-like protein 1) play essential roles in IBD pathogenesis. In this review, we provide an updated overview on the involvement of BMPs and BMP antagonists in IBD pathogenesis and in regulating the fate of intestinal stem cells. We also described the expression patterns of BMPs and BMP antagonists along the intestinal crypt-villus axis. Lastly, we synthesized available research on negative regulators of BMP signalling. This review summarizes recent developments on BMPs and BMP antagonists in IBD pathogenesis, which provides novel insights into future therapeutic strategies.
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Affiliation(s)
- Zhuo Xie
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China
| | - Gaoshi Zhou
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China
| | - Mudan Zhang
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China
| | - Jing Han
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China
| | - Ying Wang
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China
| | - Xiaoling Li
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China
| | - Qirui Wu
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China
| | - Manying Li
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China
| | - Shenghong Zhang
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China.
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12
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Chai H, Huang Q, Jiao Z, Wang S, Sun C, Geng D, Xu W. Osteocytes Exposed to Titanium Particles Inhibit Osteoblastic Cell Differentiation via Connexin 43. Int J Mol Sci 2023; 24:10864. [PMID: 37446062 DOI: 10.3390/ijms241310864] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2023] [Revised: 06/24/2023] [Accepted: 06/27/2023] [Indexed: 07/15/2023] Open
Abstract
Periprosthetic osteolysis (PPO) induced by wear particles is the most severe complication of total joint replacement; however, the mechanism behind PPO remains elusive. Previous studies have shown that osteocytes play important roles in wear-particle-induced osteolysis. In this study, we investigated the effects of connexin 43 (Cx43) on the regulation of osteocyte-to-osteoblast differentiation. We established an in vivo murine model of calvarial osteolysis induced by titanium (Ti) particles. The osteolysis characteristic and osteogenesis markers in the osteocyte-selective Cx43 (CKO)-deficient and wild-type (WT) mice were observed. The calvarial osteolysis induced by Ti particles was partially attenuated in CKO mice. The expression of β-catenin and osteogenesis markers increased significantly in CKO mice. In vitro, the osteocytic cell line MLO-Y4 was treated with Ti particles. The co-culturing of MLO-Y4 cells with MC3T3-E1 osteoblastic cells was used to observe the effects of Ti-treated osteocytes on osteoblast differentiation. When Cx43 of MLO-Y4 cells was silenced or overexpressed, β-catenin was detected. Additionally, co-immunoprecipitation detection of Cx43 and β-catenin binding in MLO-Y4 cells and MC3T3-E1 cells was performed. Finally, β-catenin expression in MC3T3-E1 cells and osteoblast differentiation were evaluated after 18α-glycyrrhetinic acid (18α-GA) was used to block the intercellular communication of Cx43 between MLO-Y4 and MC3T3-E1 cells. Ti particles increased Cx43 expression and decreased β-catenin expression in MLO-Y4 cells. The silencing of Cx43 increased the β-catenin expression, and the over-expression of Cx43 decreased the β-catenin expression. In the co-culture model, Ti treatment of MLO-Y4 cells inhibited the osteoblastic differentiation of MC3T3-E1 cells and Cx43 silencing in MLO-Y4 cells attenuated the inhibitory effects on osteoblastic differentiation. With Cx43 silencing in the MLO-Y4 cells, the MC3T3-E1 cells, co-cultured alongside MLO-Y4, displayed decreased Cx43 expression, increased β-catenin expression, activation of Runx2, and promotion of osteoblastic differentiation in vitro co-culture. Finally, Cx43 expression was found to be negatively correlated to the activity of the Wnt signaling pathway, mostly through the Cx43 binding of β-catenin from its translocation to the nucleus. The results of our study suggest that Ti particles increased Cx43 expression in osteocytes and that osteocytes may participate in the regulation of osteoblast function via the Cx43 during PPO.
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Affiliation(s)
- Hao Chai
- Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China
| | - Qun Huang
- Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China
| | - Zixue Jiao
- Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China
| | - Shendong Wang
- Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China
| | - Chunguang Sun
- Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China
| | - Dechun Geng
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, Suzhou 215004, China
| | - Wei Xu
- Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China
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13
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Xu H, Wang W, Liu X, Huang W, Zhu C, Xu Y, Yang H, Bai J, Geng D. Targeting strategies for bone diseases: signaling pathways and clinical studies. Signal Transduct Target Ther 2023; 8:202. [PMID: 37198232 DOI: 10.1038/s41392-023-01467-8] [Citation(s) in RCA: 48] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2023] [Revised: 04/02/2023] [Accepted: 04/19/2023] [Indexed: 05/19/2023] Open
Abstract
Since the proposal of Paul Ehrlich's magic bullet concept over 100 years ago, tremendous advances have occurred in targeted therapy. From the initial selective antibody, antitoxin to targeted drug delivery that emerged in the past decades, more precise therapeutic efficacy is realized in specific pathological sites of clinical diseases. As a highly pyknotic mineralized tissue with lessened blood flow, bone is characterized by a complex remodeling and homeostatic regulation mechanism, which makes drug therapy for skeletal diseases more challenging than other tissues. Bone-targeted therapy has been considered a promising therapeutic approach for handling such drawbacks. With the deepening understanding of bone biology, improvements in some established bone-targeted drugs and novel therapeutic targets for drugs and deliveries have emerged on the horizon. In this review, we provide a panoramic summary of recent advances in therapeutic strategies based on bone targeting. We highlight targeting strategies based on bone structure and remodeling biology. For bone-targeted therapeutic agents, in addition to improvements of the classic denosumab, romosozumab, and PTH1R ligands, potential regulation of the remodeling process targeting other key membrane expressions, cellular crosstalk, and gene expression, of all bone cells has been exploited. For bone-targeted drug delivery, different delivery strategies targeting bone matrix, bone marrow, and specific bone cells are summarized with a comparison between different targeting ligands. Ultimately, this review will summarize recent advances in the clinical translation of bone-targeted therapies and provide a perspective on the challenges for the application of bone-targeted therapy in the clinic and future trends in this area.
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Affiliation(s)
- Hao Xu
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu, 215006, P. R. China
| | - Wentao Wang
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu, 215006, P. R. China
| | - Xin Liu
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu, 215006, P. R. China
| | - Wei Huang
- Department of Orthopedics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230031, Anhui, China
| | - Chen Zhu
- Department of Orthopedics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230031, Anhui, China
| | - Yaozeng Xu
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu, 215006, P. R. China
| | - Huilin Yang
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu, 215006, P. R. China.
- Orthopaedic Institute, Medical College, Soochow University, Suzhou, 215006, Jiangsu, China.
| | - Jiaxiang Bai
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu, 215006, P. R. China.
- Orthopaedic Institute, Medical College, Soochow University, Suzhou, 215006, Jiangsu, China.
| | - Dechun Geng
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu, 215006, P. R. China.
- Orthopaedic Institute, Medical College, Soochow University, Suzhou, 215006, Jiangsu, China.
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Aobulikasimu A, Liu T, Piao J, Sato S, Ochi H, Okawa A, Tsuji K, Asou Y. SIRT6-PAI-1 axis is a promising therapeutic target in aging-related bone metabolic disruption. Sci Rep 2023; 13:7991. [PMID: 37198221 DOI: 10.1038/s41598-023-33297-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Accepted: 04/11/2023] [Indexed: 05/19/2023] Open
Abstract
The mechanistic regulation of bone mass in aged animals is poorly understood. In this study, we examined the role of SIRT6, a longevity-associated factor, in osteocytes, using mice lacking Sirt6 in Dmp-1-expressing cells (cKO mice) and the MLO-Y4 osteocyte-like cell line. cKO mice exhibited increased osteocytic expression of Sost, Fgf23 and senescence inducing gene Pai-1 and the senescence markers p16 and Il-6, decreased serum phosphate levels, and low-turnover osteopenia. The cKO phenotype was reversed in mice that were a cross of PAI-1-null mice with cKO mice. Furthermore, senescence induction in MLO-Y4 cells increased the Fgf23 and Sost mRNA expression. Sirt6 knockout and senescence induction increased HIF-1α binding to the Fgf23 enhancer sequence. Bone mass and serum phosphate levels were higher in PAI-1-null aged mice than in wild-type mice. Therefore, SIRT6 agonists or PAI-1 inhibitors may be promising therapeutic options for aging-related bone metabolism disruptions.
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Affiliation(s)
- Alkebaier Aobulikasimu
- Department of Orthopedics Surgery, Tokyo Medical and Dental University, 1-5-45 Yushima Bunkyo-Ku, Tokyo, 113-8519, Japan
| | - Tao Liu
- Department of Orthopedics Surgery, Tokyo Medical and Dental University, 1-5-45 Yushima Bunkyo-Ku, Tokyo, 113-8519, Japan
| | - Jinying Piao
- Department of Orthopedics Surgery, Tokyo Medical and Dental University, 1-5-45 Yushima Bunkyo-Ku, Tokyo, 113-8519, Japan
| | - Shingo Sato
- Department of Orthopedics Surgery, Tokyo Medical and Dental University, 1-5-45 Yushima Bunkyo-Ku, Tokyo, 113-8519, Japan
| | - Hiroki Ochi
- Department of Rehabilitation for Movement Functions, Research Institute, National Rehabilitation Center for Persons With Disabilities, Tokorozawa-Shi, Saitama, Japan
| | - Atsushi Okawa
- Department of Orthopedics Surgery, Tokyo Medical and Dental University, 1-5-45 Yushima Bunkyo-Ku, Tokyo, 113-8519, Japan
| | - Kunikazu Tsuji
- Department of Orthopedics Surgery, Tokyo Medical and Dental University, 1-5-45 Yushima Bunkyo-Ku, Tokyo, 113-8519, Japan
| | - Yoshinori Asou
- Department of Orthopedics Surgery, Tokyo Medical and Dental University, 1-5-45 Yushima Bunkyo-Ku, Tokyo, 113-8519, Japan.
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Jiao Z, Chai H, Wang S, Sun C, Huang Q, Xu W. SOST gene suppression stimulates osteocyte Wnt/β-catenin signaling to prevent bone resorption and attenuates particle-induced osteolysis. J Mol Med (Berl) 2023; 101:607-620. [PMID: 37121919 PMCID: PMC10163143 DOI: 10.1007/s00109-023-02319-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Revised: 04/01/2023] [Accepted: 04/11/2023] [Indexed: 05/02/2023]
Abstract
The most common cause for prosthetic revision surgery is wear particle-induced periprosthetic osteolysis, which leads to aseptic loosening of the prosthesis. Both SOST gene and its synthetic protein, sclerostin, are hallmarks of osteocytes. According to our previous findings, blocking SOST induces bone formation and protects against bone loss and deformation caused by titanium (Ti) particles by activating the Wnt/β-catenin cascade. Although SOST has been shown to influence osteoblasts, its ability to control wear-particle-induced osteolysis via targeting osteoclasts remains unclear. Mice were subjected to development of a cranial osteolysis model. Micro CT, HE staining, and TRAP staining were performed to evaluate bone loss in the mouse model. Bone marrow-derived monocyte-macrophages (BMMs) made from the C57BL/6 mice were exposed to the medium of MLO-Y4 (co-cultured with Ti particles) to transform them into osteoclasts. Bioinformatics methods were used to predict and validate the interaction among SOST, Wnt/β-catenin, RANKL/OPG, TNF-α, and IL-6. Local bone density and bone volume improved after SOST inhibition, both the number of lysis pores and the rate of skull erosion decreased. Histological research showed that β-catenin and OPG expression were markedly increased after SOST inhibition, whereas TRAP and RANKL levels were markedly decreased. In-vitro, Ti particle treatment elevated the expression of sclerostin, suppressed the expression of β-catenin, and increased the RANKL/OPG ratio in the MLO-Y4 cell line. TNF-α and IL-6 also elevated after treatment with Ti particles. The expression levels of NFATc1, CTSK, and TRAP in osteoclasts were significantly increased, and the number of positive cells for TRAP staining was increased. Additionally, the volume of bone resorption increased at the same time. In contrast, when SOST expression was inhibited in the MLO-Y4 cell line, these effects produced by Ti particles were reversed. All the results strongly show that SOST inhibition triggered the osteocyte Wnt/β-catenin signaling cascade and prevented wear particle-induced osteoclastogenesis, which might reduce periprosthetic osteolysis. KEY MESSAGES: SOST is a molecular regulator in maintaining bone homeostasis. SOST plays in regulating bone homeostasis through the Wnt/β-catenin signaling pathway. SOST gene suppression stimulates osteocyte Wnt/β-catenin signaling to prevent bone resorption and attenuates particle-induced osteolysis.
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Affiliation(s)
- Zixue Jiao
- Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, Jiangsu, China
| | - Hao Chai
- Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, Jiangsu, China
- Department of Orthopedics, Taiyuan Central Hospital of Shanxi Medical University, Taiyuan, 030009, Shanxi, China
| | - Shendong Wang
- Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, Jiangsu, China
| | - Chunguang Sun
- Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, Jiangsu, China
- Department of Orthopedics, Funing People's Hospital, Yancheng, 224400, Jiangsu, China
| | - Qun Huang
- Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, Jiangsu, China
- Department of Orthopedics, Zhangjiagang City First People's Hospital, Zhangjiagang, 215699, Jiangsu, China
| | - Wei Xu
- Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, Jiangsu, China.
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Couto BADA, Fernandes JCH, Saavedra-Silva M, Roca H, Castilho RM, Fernandes GVDO. Antisclerostin Effect on Osseointegration and Bone Remodeling. J Clin Med 2023; 12:jcm12041294. [PMID: 36835830 PMCID: PMC9964545 DOI: 10.3390/jcm12041294] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 01/17/2023] [Accepted: 01/26/2023] [Indexed: 02/10/2023] Open
Abstract
Objective: This study reviewed the literature on local or systemic administration of antisclerostin, presenting results associated with osseointegration of dental/orthopedic implants and stimulation of bone remodeling. Materials and Methods: An extensive electronic search was conducted through MED-LINE/PubMed, PubMed Central, Web of Science databases and specific peer-reviewed journals to identify case reports, case series, randomized controlled trials, clinical trials and animal studies comparing either the systemic or local administration of antisclerostin and its effect in osseointegration and bone remodeling. Articles in English and with no restriction on period were included. Results: Twenty articles were selected for a full-text, and one was excluded. Finally, 19 articles were included in the study (16 animal studies and 3 randomized control trials). These studies were divided into two groups, which evaluated (i) osseointegration and (ii) bone remodeling potential. Initially 4560 humans and 1191 animals were identified. At least 1017 were excluded from the studies (981 humans and 36 animals), totaling 4724 subjects who completed (3579 humans and 1145 animals). (a) Osseointegration: 7 studies described this phenomenon; 4 reported bone-implant contact, which increased in all included studies. Similar results were found for bone mineral density, bone area/volume and bone thickness. (b) Bone remodeling: 13 studies were used for description. The studies reported an increase in BMD with sclerostin antibody treatment. A similar effect was found for bone mineral density/area/volume, trabecular bone and bone formation. Three biomarkers of bone formation were identified: bone-specific alkaline phosphatase (BSAP), osteocalcin and procollagen type 1 N-terminal Pro-peptide (P1NP); and markers for bone resorption were: serum C-telopeptide (sCTX), C-terminal telopeptides of type I collagen (CTX-1), β-isomer of C-terminal telopeptides of type I collagen (β-CTX) and tartrate-resistant acid phosphatase 5b (TRACP-5b). There were limitations: low number of human studies identified; high divergence in the model used (animal or human); the variance in the type of Scl-Ab and doses of administration; and the lack of reference quantitative values in the parameters analyzed by authors' studies (many articles only reported qualitative information). Conclusion: Within the limitations of this review and carefully observing all data, due to the number of articles included and the heterogeneity existing, more studies must be carried out to better evaluate the action of the antisclerostin on the osseointegration of dental implants. Otherwise, these findings can accelerate and stimulate bone remodeling and neoformation.
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Affiliation(s)
| | | | - Mariana Saavedra-Silva
- Departamento de Cirurgía (Área de Estomatología), Facultad de Medicina, Universidad de Salamanca, 37007 Salamanca, Spain
| | - Hernan Roca
- McCauley-Roca Lab’s, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USA
| | - Rogério Moraes Castilho
- Periodontics and Oral Medicine Department, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USA
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17
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Sato M, Shah FA. Contributions of Resin Cast Etching to Visualising the Osteocyte Lacuno-Canalicular Network Architecture in Bone Biology and Tissue Engineering. Calcif Tissue Int 2023; 112:525-542. [PMID: 36611094 PMCID: PMC10106349 DOI: 10.1007/s00223-022-01058-9] [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] [Received: 10/05/2022] [Accepted: 12/21/2022] [Indexed: 01/09/2023]
Abstract
Recent years have witnessed an evolution of imaging technologies towards sophisticated approaches for visualising cells within their natural environment(s) and for investigating their interactions with other cells, with adjacent anatomical structures, and with implanted biomaterials. Resin cast etching (RCE) is an uncomplicated technique involving sequential acid etching and alkali digestion of resin embedded bone to observe the osteocyte lacuno-canalicular network using scanning electron microscopy. This review summarises the applicability of RCE to bone and the bone-implant interface. Quantitative parameters such as osteocyte size, osteocyte density, and number of canaliculi per osteocyte, and qualitative metrics including osteocyte shape, disturbances in the arrangement of osteocytes and canaliculi, and physical communication between osteocytes and implant surfaces can be investigated. Ageing, osteoporosis, long-term immobilisation, spinal cord injury, osteoarthritis, irradiation, and chronic kidney disease have been shown to impact osteocyte lacuno-canalicular network morphology. In addition to titanium, calcium phosphates, and bioactive glass, observation of direct connectivity between osteocytes and cobalt chromium provides new insights into the osseointegration potential of materials conventionally viewed as non-osseointegrating. Other applications include in vivo and in vitro testing of polymer-based tissue engineering scaffolds and tissue-engineered ossicles, validation of ectopic osteochondral defect models, ex vivo organ culture of whole bones, and observing the effects of gene dysfunction/deletion on the osteocyte lacuno-canalicular network. Without additional contrast staining, any resin embedded specimen (including clinical biopsies) can be used for RCE. The multitude of applications described here attest to the versatility of RCE for routine use within correlative analytical workflows, particularly in biomaterials science.
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Affiliation(s)
- Mari Sato
- Oral Biochemistry and Molecular Biology, Graduate School of Dental Medicine, Hokkaido University, Sapporo, Japan
| | - Furqan A Shah
- Department of Biomaterials, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
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BANU S, PUZHANKARA L, KEDLAYA MN, VARGHESE JM, RAMANARAYANAN V. Is sclerostin antibody an effective agent for alveolar bone regeneration in animal models? A scoping review. CUMHURIYET DENTAL JOURNAL 2022. [DOI: 10.7126/cumudj.1110413] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Objectives
The use of Sclerostin Antibody(Scl-Ab) as a bone anabolic agent has shown significant benefit in bone disorders in preclinical animal models and human clinical trials. Currently available evidence on the use of Scl-Ab in alveolar bone regeneration is limited to animal studies and hence this scoping review encompasses the animal studies conducted to ascertain the effectiveness of Scl-Ab on alveolar bone regeneration.
Materials and methods
The search strategy was aimed to locate published animal studies in which the treatment arm includes Sclerostin antibody administration for alveolar bone preservation or regeneration. The search terms used were (((Animal model) OR Rodent) AND Alveolar bone defect) AND Anti sclerostin antibody) OR Sclerostin antibody) AND Alveolar bone regeneration) OR Bone regeneration) AND Bone fill.
Results
Of the 559 results from Medline/PubMed, Scopus, Web of Science, Google scholar and additional articles from the references, six were included in the review. Scl-Ab was found to be effective in improving the bone quality and quantity. It was also observed that Scl-Ab was useful in reduced bone density associated with diseases and conditiona affecting osteoblast activity.
Conclusion
The review concluded that Scl-Ab promotes alveolar bone augmentation and improves bone quality without surgical interventions.
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Affiliation(s)
- Sunaina BANU
- Manipal College of Dental Sciences, Manipal Academy of Higher Education
| | | | | | - Jothi M VARGHESE
- Manipal College of Dental Sciences, Manipal Academy of Higher Education
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19
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Qin Q, Liu Y, Yang Z, Aimaijiang M, Ma R, Yang Y, Zhang Y, Zhou Y. Hypoxia-Inducible Factors Signaling in Osteogenesis and Skeletal Repair. Int J Mol Sci 2022; 23:ijms231911201. [PMID: 36232501 PMCID: PMC9569554 DOI: 10.3390/ijms231911201] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 09/10/2022] [Accepted: 09/14/2022] [Indexed: 11/23/2022] Open
Abstract
Sufficient oxygen is required to maintain normal cellular and physiological function, such as a creature’s development, breeding, and homeostasis. Lately, some researchers have reported that both pathological hypoxia and environmental hypoxia might affect bone health. Adaptation to hypoxia is a pivotal cellular event in normal cell development and differentiation and in pathological settings such as ischemia. As central mediators of homeostasis, hypoxia-inducible transcription factors (HIFs) can allow cells to survive in a low-oxygen environment and are essential for the regulation of osteogenesis and skeletal repair. From this perspective, we summarized the role of HIF-1 and HIF-2 in signaling pathways implicated in bone development and skeletal repair and outlined the molecular mechanism of regulation of downstream growth factors and protein molecules such as VEGF, EPO, and so on. All of these present an opportunity for developing therapies for bone regeneration.
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20
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Moe OW, Maalouf NM, Sakhaee K, Lederer E. Preclinical and Clinical Evidence of Effect of Acid on Bone Health. Adv Chronic Kidney Dis 2022; 29:381-394. [PMID: 36175076 PMCID: PMC11375989 DOI: 10.1053/j.ackd.2022.07.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Acid can have ill effect on bone health in the absence of frank clinical acidosis but affecting the bone mioneral matrix and bone cells via complex pathways botyh ascute;y and chronically. While the reaction of bone to an acid load is conserved in evolution and is adaptive, the capacity can be overwhelmed resulting in dire consequences. The preclinical an clincl evidence of the acdi effect on bone is very convincing and the clinical evidence in both association and interventiopn studies are also quite credible, The adverse effects of acid on bone is underappreoicated, under-investigated, and the potential benefits of alkali therapy is not generrally known.
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Affiliation(s)
- Orson W Moe
- Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, TX; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX; Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX.
| | - Naim M Maalouf
- Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, TX; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX
| | - Khashayar Sakhaee
- Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, TX; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX
| | - Eleanor Lederer
- Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, TX; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX; Medical Service, VA North Texas Health Care System, Dallas, TX
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21
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Chai H, Zhang ZH, Fang JY, She C, Geng DC, Xu W. Osteocytic cells exposed to titanium particles increase sclerostin expression and inhibit osteoblastic cell differentiation mostly via direct cell-to-cell contact. J Cell Mol Med 2022; 26:4371-4385. [PMID: 35762300 PMCID: PMC9345295 DOI: 10.1111/jcmm.17460] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 04/21/2022] [Accepted: 06/06/2022] [Indexed: 12/01/2022] Open
Abstract
The mechanism underlying induction of periprosthetic osteolysis by wear particles remains unclear. In this study, cultured MLO‐Y4 osteocytic cells were exposed to different concentrations of titanium (Ti) particles. The results showed that Ti particles increased expression of the osteocytic marker SOST/sclerostin in a dose‐dependent manner, accelerated apoptosis of MLO‐Y4 cells, increased the expression of IL‐6, TNF‐α and connexin 43. SOST silence alleviated the increase of MLO‐Y4 cells apoptosis, decreased the expression of IL‐6, TNF‐α and connexin 43 caused by Ti particles. The different co‐culture systems of MLO‐Y4 cells with MC3T3‐E1 osteoblastic cells were further used to observe the effects of osteocytic cells' changes induced by Ti particles on osteoblastic cells. MLO‐Y4 cells treated with Ti particles inhibited dramatically differentiation of MC3T3‐E1 cells mostly through direct cell‐to‐cell contact. SOST silence attenuated the inhibition effects of Ti‐induced MLO‐Y4 on MC3T3‐E1 osteoblastic differentiation, which ALP level and mineralization of MC3T3‐E1 cells increased and the expression of ALP, OCN and Runx2 increased compared to the Ti‐treated group. Taken together, Ti particles had negative effects on MLO‐Y4 cells and the impact of Ti particles on osteocytic cells was extensive, which may further inhibit osteoblastic differentiation mostly through intercellular contact directly. SOST/sclerostin plays an important role in the process of mutual cell interaction. These findings may help to understand the effect of osteocytes in wear particle‐induced osteolysis.
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Affiliation(s)
- Hao Chai
- Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
| | - Zai Hang Zhang
- Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
| | - Jing Yi Fang
- The Experiment Center, The Medical College of Soochow University, Suzhou, Jiangsu Province, China
| | - Chang She
- Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
| | - De Chun Geng
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
| | - Wei Xu
- Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
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22
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Yu S, Li D, Zhang N, Ni S, Sun M, Wang L, Xiao H, Liu D, Liu J, Yu Y, Zhang Z, Yeung STY, Zhang S, Lu A, Zhang Z, Zhang B, Zhang G. Drug discovery of sclerostin inhibitors. Acta Pharm Sin B 2022; 12:2150-2170. [PMID: 35646527 PMCID: PMC9136615 DOI: 10.1016/j.apsb.2022.01.012] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 11/03/2021] [Accepted: 12/16/2021] [Indexed: 12/18/2022] Open
Abstract
Sclerostin, a protein secreted from osteocytes, negatively regulates the WNT signaling pathway by binding to the LRP5/6 co-receptors and further inhibits bone formation and promotes bone resorption. Sclerostin contributes to musculoskeletal system-related diseases, making it a promising therapeutic target for the treatment of WNT-related bone diseases. Additionally, emerging evidence indicates that sclerostin contributes to the development of cancers, obesity, and diabetes, suggesting that it may be a promising therapeutic target for these diseases. Notably, cardiovascular diseases are related to the protective role of sclerostin. In this review, we summarize three distinct types of inhibitors targeting sclerostin, monoclonal antibodies, aptamers, and small-molecule inhibitors, from which monoclonal antibodies have been developed. As the first-in-class sclerostin inhibitor approved by the U.S. FDA, the monoclonal antibody romosozumab has demonstrated excellent effectiveness in the treatment of postmenopausal osteoporosis; however, it conferred high cardiovascular risk in clinical trials. Furthermore, romosozumab could only be administered by injection, which may cause compliance issues for patients who prefer oral therapy. Considering these above safety and compliance concerns, we therefore present relevant discussion and offer perspectives on the development of next-generation sclerostin inhibitors by following several ways, such as concomitant medication, artificial intelligence-based strategy, druggable modification, and bispecific inhibitors strategy.
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23
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Mizoguchi T, Ono N. The diverse origin of bone-forming osteoblasts. J Bone Miner Res 2021; 36:1432-1447. [PMID: 34213032 PMCID: PMC8338797 DOI: 10.1002/jbmr.4410] [Citation(s) in RCA: 70] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 06/29/2021] [Accepted: 06/29/2021] [Indexed: 12/17/2022]
Abstract
Osteoblasts are the only cells that can give rise to bones in vertebrates. Thus, one of the most important functions of these metabolically active cells is mineralized matrix production. Because osteoblasts have a limited lifespan, they must be constantly replenished by preosteoblasts, their immediate precursors. Because disruption of the regulation of bone-forming osteoblasts results in a variety of bone diseases, a better understanding of the origin of these cells by defining the mechanisms of bone development, remodeling, and regeneration is central to the development of novel therapeutic approaches. In recent years, substantial new insights into the origin of osteoblasts-largely owing to rapid technological advances in murine lineage-tracing approaches and other single-cell technologies-have been obtained. Collectively, these findings indicate that osteoblasts involved in bone formation under various physiological, pathological, and therapeutic conditions can be obtained from numerous sources. The origins of osteoblasts include, but are not limited to, chondrocytes in the growth plate, stromal cells in the bone marrow, quiescent bone-lining cells on the bone surface, and specialized fibroblasts in the craniofacial structures, such as sutures and periodontal ligaments. Because osteoblasts can be generated from local cellular sources, bones can flexibly respond to regenerative and anabolic cues. However, whether osteoblasts derived from different cellular sources have distinct functions remains to be investigated. Currently, we are at the initial stage to aptly unravel the incredible diversity of the origins of bone-forming osteoblasts. © 2021 American Society for Bone and Mineral Research (ASBMR).
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Affiliation(s)
| | - Noriaki Ono
- University of Texas Health Science Center at Houston School of Dentistry, Houston, TX, USA
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24
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Yan T, Xie Y, He H, Fan W, Huang F. Role of nitric oxide in orthodontic tooth movement (Review). Int J Mol Med 2021; 48:168. [PMID: 34278439 PMCID: PMC8285047 DOI: 10.3892/ijmm.2021.5001] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 06/08/2021] [Indexed: 12/14/2022] Open
Abstract
Nitric oxide (NO) is an ubiquitous signaling molecule that mediates numerous cellular processes associated with cardiovascular, nervous and immune systems. NO also plays an essential role in bone homeostasis regulation. The present review article summarized the effects of NO on bone metabolism during orthodontic tooth movement in order to provide insight into the regulatory role of NO in orthodontic tooth movement. Orthodontic tooth movement is a process in which the periodontal tissue and alveolar bone are reconstructed due to the effect of orthodontic forces. Accumulating evidence has indicated that NO and its downstream signaling molecule, cyclic guanosine monophosphate (cGMP), mediate the mechanical signals during orthodontic-related bone remodeling, and exert complex effects on osteogenesis and osteoclastogenesis. NO has a regulatory effect on the cellular activities and functional states of osteoclasts, osteocytes and periodontal ligament fibroblasts involved in orthodontic tooth movement. Variations of NO synthase (NOS) expression levels and NO production in periodontal tissues or gingival crevicular fluid (GCF) have been found on the tension and compression sides during tooth movement in both orthodontic animal models and patients. Furthermore, NO precursor and NOS inhibitor administration increased and reduced the tooth movement in animal models, respectively. Further research is required in order to further elucidate the underlying mechanisms and the clinical application prospect of NO in orthodontic tooth movement.
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Affiliation(s)
- Tong Yan
- Department of Pediatric Dentistry, Hospital of Stomatology, Sun Yat‑sen University, Guangzhou, Guangdong 510055, P.R. China
| | - Yongjian Xie
- Department of Orthodontic Dentistry, Hospital of Stomatology, Sun Yat‑sen University, Guangzhou, Guangdong 510055, P.R. China
| | - Hongwen He
- Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Sun Yat‑sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Wenguo Fan
- Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Sun Yat‑sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Fang Huang
- Department of Pediatric Dentistry, Hospital of Stomatology, Sun Yat‑sen University, Guangzhou, Guangdong 510055, P.R. China
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25
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Yadav PS, Feng S, Cong Q, Kim H, Liu Y, Yang Y. Stat3 loss in mesenchymal progenitors causes Job syndrome-like skeletal defects by reducing Wnt/β-catenin signaling. Proc Natl Acad Sci U S A 2021; 118:e2020100118. [PMID: 34172578 PMCID: PMC8256036 DOI: 10.1073/pnas.2020100118] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Job syndrome is a rare genetic disorder caused by STAT3 mutations and primarily characterized by immune dysfunction along with comorbid skeleton developmental abnormalities including osteopenia, recurrent fracture of long bones, and scoliosis. So far, there is no definitive cure for the skeletal defects in Job syndrome, and treatments are limited to management of clinical symptoms only. Here, we have investigated the molecular mechanism whereby Stat3 regulates skeletal development and osteoblast differentiation. We showed that removing Stat3 function in the developing limb mesenchyme or osteoprogenitor cells in mice resulted in shortened and bow limbs with multiple fractures in long bones that resembled the skeleton symptoms in the Job Syndrome. However, Stat3 loss did not alter chondrocyte differentiation and hypertrophy in embryonic development, while osteoblast differentiation was severely reduced. Genome-wide transcriptome analyses as well as biochemical and histological studies showed that Stat3 loss resulted in down-regulation of Wnt/β-catenin signaling. Restoration of Wnt/β-catenin signaling by injecting BIO, a small molecule inhibitor of GSK3, or crossing with a Lrp5 gain of function (GOF) allele, rescued the bone reduction phenotypes due to Stat3 loss to a great extent. These studies uncover the essential functions of Stat3 in maintaining Wnt/β-catenin signaling in early mesenchymal or osteoprogenitor cells and provide evidence that bone defects in the Job Syndrome are likely caused by Wnt/β-catenin signaling reduction due to reduced STAT3 activities in bone development. Enhancing Wnt/β-catenin signaling could be a therapeutic approach to reduce bone symptoms of Job syndrome patients.
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Affiliation(s)
- Prem Swaroop Yadav
- Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA 02115
| | - Shuhao Feng
- Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA 02115
| | - Qian Cong
- Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA 02115
| | - Hanjun Kim
- Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA 02115
| | - Yuchen Liu
- Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA 02115
| | - Yingzi Yang
- Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA 02115;
- Harvard Stem Cell Institute, Cambridge, MA 02138
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26
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Osteocyte Dysfunction in Joint Homeostasis and Osteoarthritis. Int J Mol Sci 2021; 22:ijms22126522. [PMID: 34204587 PMCID: PMC8233862 DOI: 10.3390/ijms22126522] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 06/13/2021] [Accepted: 06/16/2021] [Indexed: 01/29/2023] Open
Abstract
Structural disturbances of the subchondral bone are a hallmark of osteoarthritis (OA), including sclerotic changes, cystic lesions, and osteophyte formation. Osteocytes act as mechanosensory units for the micro-cracks in response to mechanical loading. Once stimulated, osteocytes initiate the reparative process by recruiting bone-resorbing cells and bone-forming cells to maintain bone homeostasis. Osteocyte-expressed sclerostin is known as a negative regulator of bone formation through Wnt signaling and the RANKL pathway. In this review, we will summarize current understandings of osteocytes at the crossroad of allometry and mechanobiology to exploit the relationship between osteocyte morphology and function in the context of joint aging and osteoarthritis. We also aimed to summarize the osteocyte dysfunction and its link with structural and functional disturbances of the osteoarthritic subchondral bone at the molecular level. Compared with normal bones, the osteoarthritic subchondral bone is characterized by a higher bone volume fraction, a larger trabecular bone number in the load-bearing region, and an increase in thickness of pre-existing trabeculae. This may relate to the aberrant expressions of sclerostin, periostin, dentin matrix protein 1, matrix extracellular phosphoglycoprotein, insulin-like growth factor 1, and transforming growth factor-beta, among others. The number of osteocyte lacunae embedded in OA bone is also significantly higher, yet the volume of individual lacuna is relatively smaller, which could suggest abnormal metabolism in association with allometry. The remarkably lower percentage of sclerostin-positive osteocytes, together with clustering of Runx-2 positive pre-osteoblasts, may suggest altered regulation of osteoblast differentiation and osteoblast-osteocyte transformation affected by both signaling molecules and the extracellular matrix. Aberrant osteocyte morphology and function, along with anomalies in molecular signaling mechanisms, might explain in part, if not all, the pre-osteoblast clustering and the uncoupled bone remodeling in OA subchondral bone.
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27
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Ashifa N, Viswanathan K, Sundaram R, Srinivasan S. Sclerostin and its role as a bone modifying agent in periodontal disease. J Oral Biosci 2021; 63:104-110. [PMID: 33878470 DOI: 10.1016/j.job.2021.04.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Revised: 04/07/2021] [Accepted: 04/12/2021] [Indexed: 01/09/2023]
Abstract
BACKGROUND Periodontitis is a highly prevalent inflammatory disease affecting the periodontium that results from an imbalance between periodontopathogens and host mechanisms. Continuous progression of the disease may lead to tissue and bone destruction, eventually resulting in tooth loss. The extent of bone loss depends on the dysregulated host immune response. Various host-elicited molecules play a major role in disease progression. The discovery of the glycoprotein sclerostin and its role as a regulator of bone mass has led to a better understanding of bone metabolism. HIGHLIGHT Sclerostin, which is primarily expressed by osteocytes, is a negative regulator of bone formation. It is a potent antagonist of the canonical Wingless-related integration site (Wnt) pathway, which is actively involved in bone homeostasis. Sclerostin is known to stimulate bone resorption by altering the osteoprotegerin (OPG)/receptor activator of nuclear factor kappa- β ligand (RANKL) balance. Additionally, in periodontitis, activation of the inflammatory cascade also increases the synthesis of sclerostin. CONCLUSION The recently discovered sclerostin antibody has emerged as a positive therapeutic tool for the treatment of metabolic bone diseases. It has been reported to improve bone strength, bone formation, osseointegration around implants and lower the risk of bone fractures in various animal and human models. This review describes the properties and action of sclerostin, its role in periodontal diseases, and the advent and efficacy of sclerostin antibodies.
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Affiliation(s)
- Nisha Ashifa
- Department of Periodontology, Rajah Muthiah Dental College & Hospital, Annamalai University, Annamalai Nagar, Chidambaram, 608002, Tamil Nadu, India.
| | - Krishnan Viswanathan
- Department of Periodontology, Rajah Muthiah Dental College & Hospital, Annamalai University, Annamalai Nagar, Chidambaram, 608002, Tamil Nadu, India.
| | - Rajasekar Sundaram
- Department of Periodontology, Rajah Muthiah Dental College & Hospital, Annamalai University, Annamalai Nagar, Chidambaram, 608002, Tamil Nadu, India.
| | - Sivapragasam Srinivasan
- Department of Periodontology, Rajah Muthiah Dental College & Hospital, Annamalai University, Annamalai Nagar, Chidambaram, 608002, Tamil Nadu, India.
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28
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Han L, Gong S, Wang R, Liu S, Wang B, Chen G, Gong T, Xu W. Knockdown of POSTN Inhibits Osteogenic Differentiation of Mesenchymal Stem Cells From Patients With Steroid-Induced Osteonecrosis. Front Cell Dev Biol 2021; 8:606289. [PMID: 33409280 PMCID: PMC7779561 DOI: 10.3389/fcell.2020.606289] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Accepted: 12/03/2020] [Indexed: 12/12/2022] Open
Abstract
Steroid-induced osteonecrosis of femoral head (SONFH) is a common and serious complication caused by long-term and/or excessive use of glucocorticoids (GCs). The decreased activity and abnormal differentiation of bone marrow mesenchymal stem cells (BMSCs) are considered to be one of the major reasons for the onset and progression of this disease. Periostin (POSTN) is a matricellular protein which plays an important role in regulating osteoblast function and bone formation. Sclerostin (SOST) is a secreted antagonist of Wnt signaling that is mainly expressed in osteocytes to inhibit bone formation. However, the exact role of POSTN and SOST in SONFH has not been reported yet. Therefore, we detected the differential expression of POSTN and SOST in BMSCs of SONFH Group patients, and Control Group was patients with traumatic ONFH (TONFH) and developmental dysplasia of the hip (DDH). Furthermore, we used lentiviral transfection to knockdown POSTN expression in BMSCs of patients with SONFH to study the effect of POSTN knockdown on the SOST expression and osteogenic differentiation of BMSCs. The results indicated that the endogenous expression of POSTN and SOST in BMSCs of SONFH Group was upregulated, compared with Control Group. POSTN was upregulated gradually while SOST was downregulated gradually at days 0, 3, and 7 of osteogenic differentiation of BMSCs in Control Group. Contrarily, POSTN was gradually downregulated while SOST was gradually upregulated during osteogenic differentiation of BMSCs in SONFH Group. This could be due to increased expression of SOST in BMSCs, which was caused by excessive GCs. In turn, the increased expression of POSTN in BMSCs may play a role in antagonizing the continuous rising of SOST during the osteogenic differentiation of BMSCs in patients with SONFH. POSTN knockdown significantly attenuated osteo-specific gene expression, alkaline phosphatase activity, and calcium nodule formation in vitro; thus inhibiting the osteogenic differentiation of BMSCs in patients with SONFH. Besides, POSTN knockdown upregulated SOST expression, increased GSK-3β activity, and downregulated β-catenin. These findings suggest that POSTN have an essential role in regulating the expression of SOST and osteogenic differentiation of BMSCs in patients with SONFH, and POSTN knockdown suppresses osteogenic differentiation by upregulating SOST and partially inactivating Wnt/β-catenin signaling pathway. Therefore, targeting POSTN and SOST may serve as a promising therapeutic target for the prevention and treatment of SONFH.
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Affiliation(s)
- Lizhi Han
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Song Gong
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ruoyu Wang
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shaokai Liu
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Bo Wang
- Department of Rehabilitation, Wuhan No.1 Hospital, Wuhan Hospital of Traditional Chinese and Western Medicine, Wuhan, China
| | - Guo Chen
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Tianlun Gong
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Weihua Xu
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Takemura A, Pajevic PD, Egawa T, Teshigawara R, Hayashi T, Ishihara A. Effects of mild hyperbaric oxygen on osteoporosis induced by hindlimb unloading in rats. J Bone Miner Metab 2020; 38:631-638. [PMID: 32350615 DOI: 10.1007/s00774-020-01100-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Accepted: 03/20/2020] [Indexed: 10/24/2022]
Abstract
INTRODUCTION Disuse-induced bone loss is caused by a suppression of osteoblastic bone formation and an increase in osteoclastic bone resorption. There are few data available for the effects of environmental conditions, i.e., atmospheric pressure and/or oxygen concentration, on osteoporosis. This study examined the effects of mild hyperbaric oxygen at 1317 hPa with 40% oxygen on unloading-induced osteoporosis. MATERIALS AND METHODS Eighteen 8-week old male Wistar rats were randomly divided into three groups: the control for 21 days without unloading and mild hyperbaric oxygen (NOR, n = 6), the unloading for 21 days and recovery for 10 days without mild hyperbaric oxygen (HU + NOR, n = 6), and the unloading for 21 days and recovery for 10 days with mild hyperbaric oxygen (HU + MHO, n = 6). RESULTS The cortical thickness and trabecular bone surface area were decreased in the HU + NOR group compared to the NOR group. There were no differences between the NOR and HU + MHO groups. Osteoclast surface area and Sclerostin (Sost) mRNA expression levels were decreased in the HU + MHO group compared to the HU + NOR group. These results suggested that the loss of the cortical and trabecular bone is inhibited by mild hyperbaric oxygen, because of an inhibition of osteoclasts and enhancement of bone formation with decreased Sost expression. CONCLUSIONS We conclude that exposure to mild hyperbaric oxygen partially protects from the osteoporosis induced by hindlimb unloading.
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Affiliation(s)
- Ai Takemura
- Laboratory of Cell Biology and Life Science, Graduate School of Human and Environmental Studies, Kyoto University, Kyoto, 606-8501, Japan.
- Department of Sports Research, Japan Institute of Sport Sciences, Tokyo, 115-0056, Japan.
| | - Paola Divieti Pajevic
- Department of Translational Dental Medicine, Boston University Goldman School of Dental Medicine, Boston, MA, 02118, USA
| | - Tatsuro Egawa
- Laboratory of Sports and Exercise Medicine, Graduate School of Human and Environmental Studies, Kyoto University, Kyoto, 606-8501, Japan
| | - Rika Teshigawara
- Laboratory of Developmental Epigenome, Graduate School of Medicine, Kyoto University, Kyoto, 606-8507, Japan
| | - Tatsuya Hayashi
- Laboratory of Sports and Exercise Medicine, Graduate School of Human and Environmental Studies, Kyoto University, Kyoto, 606-8501, Japan
| | - Akihiko Ishihara
- Laboratory of Cell Biology and Life Science, Graduate School of Human and Environmental Studies, Kyoto University, Kyoto, 606-8501, Japan
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Schupbach D, Comeau-Gauthier M, Harvey E, Merle G. Wnt modulation in bone healing. Bone 2020; 138:115491. [PMID: 32569871 DOI: 10.1016/j.bone.2020.115491] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 06/09/2020] [Accepted: 06/11/2020] [Indexed: 12/31/2022]
Abstract
Genetic studies have been instrumental in the field of orthopaedics for finding tools to improve the standard management of fractures and delayed unions. The Wnt signaling pathway that is crucial for development and maintenance of many organs also has a very promising pathway for enhancement of bone regeneration. The Wnt pathway has been shown to have a direct effect on stem cells during bone regeneration, making Wnt a potential target to stimulate bone repair after trauma. A more complete view of how Wnt influences animal bone regeneration has slowly come to light. This review article provides an overview of studies done investigating the modulation of the canonical Wnt pathway in animal bone regeneration models. This not only includes a summary of the recent work done elucidating the roles of Wnt and β-catenin in fracture healing, but also the results of thirty transgenic studies, and thirty-eight pharmacological studies. Finally, we discuss the discontinuation of sclerostin clinical trials, ongoing clinical trials with lithium, the results of Dkk antibody clinical trials, the shift into combination therapies and the future opportunities to enhance bone repair and regeneration through the modulation of the Wnt signaling pathway.
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Affiliation(s)
- Drew Schupbach
- Department of Surgery, Division of Orthopedic Surgery, McGill University, Montreal General Hospital, 1650 Cedar Avenue, Room A10-110, Montreal, Québec H3G 1A4, Canada; Experimental Surgery, Faculty of Medicine, McGill University, Montreal General Hospital, 1650 Cedar Avenue, Room A7-117, Montreal, Québec H3G 1A4, Canada.
| | - Marianne Comeau-Gauthier
- Department of Surgery, Division of Orthopedic Surgery, McGill University, Montreal General Hospital, 1650 Cedar Avenue, Room A10-110, Montreal, Québec H3G 1A4, Canada; Experimental Surgery, Faculty of Medicine, McGill University, Montreal General Hospital, 1650 Cedar Avenue, Room A7-117, Montreal, Québec H3G 1A4, Canada.
| | - Edward Harvey
- Department of Surgery, Division of Orthopedic Surgery, McGill University, Montreal General Hospital, 1650 Cedar Avenue, Room A10-110, Montreal, Québec H3G 1A4, Canada.
| | - Geraldine Merle
- Department of Surgery, Division of Orthopedic Surgery, McGill University, Montreal General Hospital, 1650 Cedar Avenue, Room A10-110, Montreal, Québec H3G 1A4, Canada; Department of Chemical Engineering, Polytechnique Montreal, 2500, chemin de Polytechnique, Montréal, Québec H3T 1J4, Canada.
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Wang M, Xia F, Wei Y, Wei X. Molecular mechanisms and clinical management of cancer bone metastasis. Bone Res 2020; 8:30. [PMID: 32793401 PMCID: PMC7391760 DOI: 10.1038/s41413-020-00105-1] [Citation(s) in RCA: 95] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Revised: 09/03/2019] [Accepted: 10/23/2019] [Indexed: 02/05/2023] Open
Abstract
As one of the most common metastatic sites of malignancies, bone has a unique microenvironment that allows metastatic tumor cells to grow and flourish. The fenestrated capillaries in the bone, bone matrix, and bone cells, including osteoblasts and osteoclasts, together maintain the homeostasis of the bone microenvironment. In contrast, tumor-derived factors act on bone components, leading to subsequent bone resorption or excessive bone formation. The various pathways involved also provide multiple targets for therapeutic strategies against bone metastases. In this review, we summarize the current understanding of the mechanism of bone metastases. Based on the general process of bone metastases, we specifically highlight the complex crosstalk between tumor cells and the bone microenvironment and the current management of cancer bone metastases.
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Affiliation(s)
- Manni Wang
- Laboratory of Aging Research and Cancer Drug Targets, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, 610041 Sichuan P.R. China
| | - Fan Xia
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan P.R. China
| | - Yuquan Wei
- Laboratory of Aging Research and Cancer Drug Targets, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, 610041 Sichuan P.R. China
| | - Xiawei Wei
- Laboratory of Aging Research and Cancer Drug Targets, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, 610041 Sichuan P.R. China
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Chen L, Wang Z, Xu W, Dong Q. Titanium particles damage osteocytes and inhibit osteoblast differentiation. J Exp Orthop 2020; 7:47. [PMID: 32623526 PMCID: PMC7335380 DOI: 10.1186/s40634-020-00268-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Accepted: 06/24/2020] [Indexed: 11/20/2022] Open
Abstract
Purposes to study the effect of titanium particles on MLO-Y4 and the effects of osteocytes alterations on osteoblasts. Methods cultured MLO-Y4 osteocytes were exposed to different concentrations of titanium (Ti) particles, cell viability was measured using the Cell Counting Kit-8 (CCK-8) assay, apoptosis of MLO-Y4 cells was evaluated by flow cytometry, Real-time PCR quantification of mRNA expression of SOST, at the same time with Western Blot detection sclerosteosis protein expression levels.MC3T3-E1 cells culture with MLO-Y4 cells exposed to different concentrations of titanium (Ti) particles in vitro, in order to detection of osteoblast osteogenetic activity. Results Our results showed that Ti particles inhibited cell viability of MLO-Y4 osteocytes in a dose-dependent manner. Incubation with Ti particles caused apoptosis of MLO-Y4cells.Treatment with Ti particles significantly increased expression of the osteocytic marker SOST/sclerostin. Furthermore, treatment of MLO-Y4 cells with Ti particles produced a dose-dependent decrease in ALP activity and decreased mineralization of MC3T3-E1 cells through direct cell-cell contact. Conclusions Titanium particles damage osteocytes and inhibit osteoblast differentiation.
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Affiliation(s)
- Li Chen
- Second Department of Orthopaedics, SuZhou Municipal Hospital, Suzhou City, Anhui Province, China
| | - Ziyue Wang
- Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou City, Jiangsu Province, China
| | - Wei Xu
- Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou City, Jiangsu Province, China
| | - Qirong Dong
- Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou City, Jiangsu Province, China.
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Zhang ZH, Jia XY, Fang JY, Chai H, Huang Q, She C, Jia P, Geng DC, Xu W. Reduction of SOST gene promotes bone formation through the Wnt/β-catenin signalling pathway and compensates particle-induced osteolysis. J Cell Mol Med 2020; 24:4233-4244. [PMID: 32134561 PMCID: PMC7171346 DOI: 10.1111/jcmm.15084] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2019] [Revised: 01/14/2020] [Accepted: 01/29/2020] [Indexed: 12/16/2022] Open
Abstract
The increase in bone resorption and/or the inhibition of bone regeneration caused by wear particles are the main causes of periprosthetic osteolysis. The SOST gene and Sclerostin, a protein synthesized by the SOST gene, are the characteristic marker of osteocytes and regulate bone formation and resorption. We aimed to verify whether the SOST gene was involved in osteolysis induced by titanium (Ti) particles and to investigate the effects of SOST reduction on osteolysis. The results showed osteolysis on the skull surface with an increase of sclerostin levels after treated with Ti particles. Similarly, sclerostin expression in MLO-Y4 osteocytes increased when treated with Ti particles in vitro. After reduction of SOST, local bone mineral density and bone volume increased, while number of lytic pores on the skull surface decreased and the erodibility of the skull surface was compensated. Histological analyses revealed that SOST reduction increased significantly alkaline phosphatase- (ALP) and osterix-positive expression on the skull surface which promoted bone formation. ALP activity and mineralization of MC3T3-E1 cells also increased in vitro when SOST was silenced, even if treated with Ti particles. In addition, Ti particles decreased β-catenin expression with an increase in sclerostin levels, in vivo and in vitro. Inversely, reduction of SOST expression increased β-catenin expression. In summary, our results suggested that reduction of SOST gene can activate the Wnt/β-catenin signalling pathway, promoting bone formation and compensated for bone loss induced by Ti particles. Thus, this study provided new perspectives in understanding the mechanisms of periprosthetic osteolysis.
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Affiliation(s)
- Zai Hang Zhang
- Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Xin Yu Jia
- Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Jing Yi Fang
- The Experiment Center, The Medical College of Soochow University, Suzhou, China
| | - Hao Chai
- Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Qun Huang
- Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou, China.,Department of Orthopedics, The Affiliated Zhangjiagang Hospital of Soochow University, Suzhou, China
| | - Chang She
- Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Peng Jia
- Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - De Chun Geng
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Wei Xu
- Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou, China
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Schwarze UY, Dobsak T, Gruber R, Bookstein FL. Anatomical similarity between the Sost-knockout mouse and sclerosteosis in humans. Anat Rec (Hoboken) 2019; 303:2295-2308. [PMID: 31729194 PMCID: PMC7496997 DOI: 10.1002/ar.24318] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Revised: 10/08/2019] [Accepted: 10/17/2019] [Indexed: 12/17/2022]
Abstract
Sclerosteosis, a rare autosomal recessive genetic disorder caused by a mutation of the Sost gene, manifests in the facial skeleton by gigantism, facial distortion, mandibular prognathism, cranial nerve palsy, and, in extreme cases, compression of the medulla oblongata. Mice lacking sclerostin reflect some symptoms of sclerosteosis, but this is the first report of the effect on the facial skeleton. We used geometric morphometrics (GMM) to analyze the deformations of the murine facial skeleton from the wild‐type to the Sost gene knockout. Landmark coordinates were obtained by surface reconstructions from micro‐computed tomography. Centroid size, principal component scores in shape space and form space, and asymmetry were computed by the standard GMM formulas, and dental and skeletal jaw lengths were examined as ratios. We show here that, compared to wild type controls, mice lacking Sost have larger centroid size (effect size, p‐value: 4.59, <.001), higher mean asymmetry (1.14, .065), dental and skeletal mandibular prognathism (1.36, .010 and 5.92, <.001), a smaller foramen magnum (−1.71, .015), and calvaria that are more highly curved (form space p = 4.09, .002; shape space p = 12.82, .002). These features of mice lacking sclerostin largely correspond to the changes of the facial skeleton observed in sclerosteosis. This alignment further supports claims that the Sost gene plays a fundamental role in bony facial development in rodents and humans alike.
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Affiliation(s)
- Uwe Y Schwarze
- Department of Oral Biology, School of Dentistry, Medical University of Vienna, Vienna, Austria.,Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Toni Dobsak
- Austrian Cluster for Tissue Regeneration, Vienna, Austria.,Department of Oral Surgery, Medical University of Vienna, Vienna, Austria
| | - Reinhard Gruber
- Department of Oral Biology, School of Dentistry, Medical University of Vienna, Vienna, Austria.,Austrian Cluster for Tissue Regeneration, Vienna, Austria.,Department of Periodontology, University of Bern, Bern, Switzerland
| | - Fred L Bookstein
- Department of Anthropology, University of Vienna, Vienna, Austria.,Department of Statistics, University of Washington, Seattle, Washington
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Current and Future Concepts for the Treatment of Impaired Fracture Healing. Int J Mol Sci 2019; 20:ijms20225805. [PMID: 31752267 PMCID: PMC6888215 DOI: 10.3390/ijms20225805] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Revised: 11/15/2019] [Accepted: 11/15/2019] [Indexed: 02/06/2023] Open
Abstract
Bone regeneration represents a complex process, of which basic biologic principles have been evolutionarily conserved over a broad range of different species. Bone represents one of few tissues that can heal without forming a fibrous scar and, as such, resembles a unique form of tissue regeneration. Despite a tremendous improvement in surgical techniques in the past decades, impaired bone regeneration including non-unions still affect a significant number of patients with fractures. As impaired bone regeneration is associated with high socio-economic implications, it is an essential clinical need to gain a full understanding of the pathophysiology and identify novel treatment approaches. This review focuses on the clinical implications of impaired bone regeneration, including currently available treatment options. Moreover, recent advances in the understanding of fracture healing are discussed, which have resulted in the identification and development of novel therapeutic approaches for affected patients.
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36
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Shan Y, Wang L, Li G, Shen G, Zhang P, Xu Y. Methylation of bone SOST impairs SP7, RUNX2, and ERα transactivation in patients with postmenopausal osteoporosis. Biochem Cell Biol 2019; 97:369-374. [PMID: 30257098 DOI: 10.1139/bcb-2018-0170] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Sclerostin (SOST), a glycoprotein predominantly secreted by bone tissue osteocytes, is an important regulator of bone formation, and loss of SOST results in Van Buchem disease. DNA methylation regulates SOST expression in human osteocytes, although the detailed underlying mechanisms remain unknown. In this study, we compared 12 patients with bone fractures and postmenopausal osteoporosis with eight patients without postmenopausal osteoporosis to understand the mechanisms via which SOST methylation affects osteoporosis. Serum and bone SOST expression was reduced in patients with osteoporosis. Bisulfite sequencing polymerase chain reaction revealed that the methylation rate was higher in patients with osteoporosis. We identified osterix (SP7), Runt-related transcription factor 2 (RUNX2), and estrogen receptor α (ERα) as candidate transcription factors activating SOST expression. Increased SOST methylation impaired the transactivation function of SP7, RUNX2, and ERα in MG-63 cells. AzadC treatment and SOST overexpression in MG-63 cells altered cell proliferation and apoptosis. Chromatin immunoprecipitation showed that higher methylation was associated with reduced SP7, RUNX2, and ERα binding to the SOST promoter in patients with osteoporosis. Our studies provide new insight into the role of SOST methylation in osteoporosis.
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Affiliation(s)
- Yu Shan
- a Department of Orthopedics, the Second Affiliated Hospital of Soochow University, Suzhou 215004, China
- b Department of Orthopedics, the First People's Hospital of Wujiang, Suzhou 215300, China
| | - Liang Wang
- a Department of Orthopedics, the Second Affiliated Hospital of Soochow University, Suzhou 215004, China
| | - Guangfei Li
- a Department of Orthopedics, the Second Affiliated Hospital of Soochow University, Suzhou 215004, China
| | - Guangsi Shen
- a Department of Orthopedics, the Second Affiliated Hospital of Soochow University, Suzhou 215004, China
| | - Peng Zhang
- a Department of Orthopedics, the Second Affiliated Hospital of Soochow University, Suzhou 215004, China
| | - Youjia Xu
- a Department of Orthopedics, the Second Affiliated Hospital of Soochow University, Suzhou 215004, China
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Ni LH, Tang RN, Yuan C, Song KY, Wang LT, Wang XC, Zhang YX, Zhang XL, Zhu DD, Liu BC. FK506 prevented bone loss in streptozotocin-induced diabetic rats via enhancing osteogenesis and inhibiting adipogenesis. ANNALS OF TRANSLATIONAL MEDICINE 2019; 7:265. [PMID: 31355232 DOI: 10.21037/atm.2019.05.44] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Background Type 1 diabetes mellitus (DM) is associated with severe osteoporosis, which is still a great challenge in the clinic. This work aimed to investigate the skeletal effects of FK506 in a rat model of streptozocin induced type 1 DM. Methods Rats were divided into three groups: control (CTL), DM rats and DM rats treated with FK506. Dual energy X-ray absorption, micro-computed tomography, bone mechanics and bone histology were used for skeletal analysis. Bone marrow adipocytes infiltrations were detected by oil red O stain and H&E stain. In addition, the protein expression of adipocyte-specific makers (PPAR-γ, C/EBP-αβ), osteoblast-specific markers (Runx2, Osterix) and nuclear translocation of β-catenin in femurs were determined by western blot. Results In the study, bone mineral density of femurs and lumbar vertebras in diabetic rats were increased after FK506 administration. FK506 treatment resulted in higher cancellous bone volume but had no significant effect on cortical bones in diabetic rats. The ultimate force and work to failure were increased in DM+FK506 group, while they were reduced in the DM group. Compared with the CTL, the infiltration of bone marrow adipocytes was significantly increased in the DM group, which was reduced after the treatment of FK506. Besides, the expression levels of Runx2 and Osterix were up-regulated, and that of PPAR-γ and C/EBP-α were down-regulated in diabetic rats after FK506 treatment. In addition, the nuclear translocation of β-catenin protein levels were increased in diabetic rats after the treatment of FK506. Conclusions Our study indicated that FK506 could alleviate bone loss in diabetic rats. This effects could be due to the results of enhancing osteogenesis and inhibiting adipogenesis, which might be regulated by activation the nuclear translocation of β-catenin.
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Affiliation(s)
- Li-Hua Ni
- Institute of Nephrology, Zhongda Hospital, Southeast University School of Medicine, Nanjing 210009, China
| | - Ri-Ning Tang
- Institute of Nephrology, Zhongda Hospital, Southeast University School of Medicine, Nanjing 210009, China.,Department of Nephrology, Nanjing Lishui People's Hospital, Zhongda Hospital Lishui Branch, Nanjing 10009, China
| | - Cheng Yuan
- Department of Radiation and Medical Oncology, Zhongnan Hospital, Wuhan University, Wuhan 430071, China
| | - Kai-Yun Song
- Institute of Nephrology, Zhongda Hospital, Southeast University School of Medicine, Nanjing 210009, China
| | - Li-Ting Wang
- Institute of Nephrology, Zhongda Hospital, Southeast University School of Medicine, Nanjing 210009, China
| | - Xiao-Chen Wang
- Institute of Nephrology, Zhongda Hospital, Southeast University School of Medicine, Nanjing 210009, China
| | - Yu-Xia Zhang
- Institute of Nephrology, Zhongda Hospital, Southeast University School of Medicine, Nanjing 210009, China
| | - Xiao-Liang Zhang
- Institute of Nephrology, Zhongda Hospital, Southeast University School of Medicine, Nanjing 210009, China
| | - Dong-Dong Zhu
- Department of Nephrology, Changhai Hospital, The Second Military Medical University, Shanghai 200433, China
| | - Bi-Cheng Liu
- Institute of Nephrology, Zhongda Hospital, Southeast University School of Medicine, Nanjing 210009, China
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Ukon Y, Makino T, Kodama J, Tsukazaki H, Tateiwa D, Yoshikawa H, Kaito T. Molecular-Based Treatment Strategies for Osteoporosis: A Literature Review. Int J Mol Sci 2019; 20:E2557. [PMID: 31137666 PMCID: PMC6567245 DOI: 10.3390/ijms20102557] [Citation(s) in RCA: 73] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Revised: 05/21/2019] [Accepted: 05/22/2019] [Indexed: 02/06/2023] Open
Abstract
Osteoporosis is an unavoidable public health problem in an aging or aged society. Anti-resorptive agents (calcitonin, estrogen, and selective estrogen-receptor modulators, bisphosphonates, anti-receptor activator of nuclear factor κB ligand antibody along with calcium and vitamin D supplementations) and anabolic agents (parathyroid hormone and related peptide analogs, sclerostin inhibitors) have major roles in current treatment regimens and are used alone or in combination based on the pathological condition. Recent advancements in the molecular understanding of bone metabolism and in bioengineering will open the door to future treatment paradigms for osteoporosis, including antibody agents, stem cells, and gene therapies. This review provides an overview of the molecular mechanisms, clinical evidence, and potential adverse effects of drugs that are currently used or under development for the treatment of osteoporosis to aid clinicians in deciding how to select the best treatment option.
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Affiliation(s)
- Yuichiro Ukon
- Department of Orthopedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
| | - Takahiro Makino
- Department of Orthopedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
| | - Joe Kodama
- Department of Orthopedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
| | - Hiroyuki Tsukazaki
- Department of Orthopedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
| | - Daisuke Tateiwa
- Department of Orthopedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
| | - Hideki Yoshikawa
- Department of Orthopedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
| | - Takashi Kaito
- Department of Orthopedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
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Cao Y, Wang B, Wang D, Zhan D, Mai C, Wang P, Wei Q, Liu Y, Wang H, He W, Xu L. Expression of Sclerostin in Osteoporotic Fracture Patients Is Associated with DNA Methylation in the CpG Island of the SOST Gene. Int J Genomics 2019; 2019:7076513. [PMID: 30729116 PMCID: PMC6341240 DOI: 10.1155/2019/7076513] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Revised: 09/26/2018] [Accepted: 10/11/2018] [Indexed: 01/17/2023] Open
Abstract
PURPOSE SOST gene is one of the key factors in regulating bone absorption. Although there are reports showing diverse transcription factors, epigenetic modification could be responsible for regulating SOST gene expression. There is still little exploration on promoter methylation status of SOST gene in osteoporotic bone tissues. The aim of this study is to investigate the involvement of CpG methylation in regulation of SOST expression in patients with primary osteoporosis. METHODS The diagnosis of osteoporosis was established on the basis of dual energy X-ray absorptiometry to measure BMD. All femoral bone tissues were separated in surgeries. After extracting total RNA and protein, we checked the relative expression levels of SOST by quantitative real-time PCR and western blot. Also, immunohistochemical staining was performed to observe the expression of SOST protein in the bone samples. The genomic DNA of non-OPF (non-osteoporotic fracture bone tissues) and OPF (osteoporotic fracture bone tissues) were treated by bisulfite modification, and methylation status of CpG sites in the CpG island of SOST gene promoter was determined by DNA sequencing. RESULTS SOST gene expression in the non-OPF group was lower than that in OPF group. Bisulfite sequencing result showed that SOST gene promoter was slightly demethylated in the OPF group, as compared with non-OPF group. CONCLUSION Our study demonstrated that DNA methylation influenced the transcriptional expression of SOST gene, which probably may play an important role in the pathogenesis of primary osteoporosis.
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Affiliation(s)
- Yanming Cao
- Department of Orthopedics, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Bin Wang
- Department of Orthopedics, People's Hospital of Sanshui, Foshan, China
| | - Ding Wang
- Key Laboratory of Orthopaedics & Traumatology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, The First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Dongxiang Zhan
- Key Laboratory of Orthopaedics & Traumatology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, The First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Caiyuan Mai
- Department of Obstetrics, Guangdong Women and Children's Hospital, Guangzhou 510010, China
| | - Peng Wang
- Key Laboratory of Orthopaedics & Traumatology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, The First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Qiushi Wei
- Key Laboratory of Orthopaedics & Traumatology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, The First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yamei Liu
- Departments of Diagnostics of Traditional Chinese Medicine, Guangzhou University of Traditional Chinese Medicine, Guangzhou, Guangdong 510006, China
| | - Haibin Wang
- Key Laboratory of Orthopaedics & Traumatology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, The First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Wei He
- Key Laboratory of Orthopaedics & Traumatology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, The First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Liangliang Xu
- Key Laboratory of Orthopaedics & Traumatology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, The First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
- Laboratory of Orthopaedics & Traumatology, Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China
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Abstract
Bone morphogenetic proteins (BMPs) constitute the largest subdivision of the transforming growth factor-β family of ligands. BMPs exhibit widespread utility and pleiotropic, context-dependent effects, and the strength and duration of BMP pathway signaling is tightly regulated at numerous levels via mechanisms operating both inside and outside the cell. Defects in the BMP pathway or its regulation underlie multiple human diseases of different organ systems. Yet much remains to be discovered about the BMP pathway in its original context, i.e., the skeleton. In this review, we provide a comprehensive overview of the intricacies of the BMP pathway and its inhibitors in bone development, homeostasis, and disease. We frame the content of the review around major unanswered questions for which incomplete evidence is available. First, we consider the gene regulatory network downstream of BMP signaling in osteoblastogenesis. Next, we examine why some BMP ligands are more osteogenic than others and what factors limit BMP signaling during osteoblastogenesis. Then we consider whether specific BMP pathway components are required for normal skeletal development, and if the pathway exerts endogenous effects in the aging skeleton. Finally, we propose two major areas of need of future study by the field: greater resolution of the gene regulatory network downstream of BMP signaling in the skeleton, and an expanded repertoire of reagents to reliably and specifically inhibit individual BMP pathway components.
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Affiliation(s)
- Jonathan W Lowery
- Division of Biomedical Science, Marian University College of Osteopathic Medicine , Indianapolis, Indiana ; and Department of Developmental Biology, Harvard School of Dental Medicine , Boston, Massachusetts
| | - Vicki Rosen
- Division of Biomedical Science, Marian University College of Osteopathic Medicine , Indianapolis, Indiana ; and Department of Developmental Biology, Harvard School of Dental Medicine , Boston, Massachusetts
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Metzger CE, Narayanan SA. The Role of Osteocytes in Inflammatory Bone Loss. Front Endocrinol (Lausanne) 2019; 10:285. [PMID: 31139147 PMCID: PMC6527760 DOI: 10.3389/fendo.2019.00285] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Accepted: 04/18/2019] [Indexed: 01/18/2023] Open
Abstract
Osteoimmunology investigations to-date have demonstrated the significant interactions between bone surface cells, osteoclasts and osteoblasts, and immune cells. However, there is a paucity of knowledge on osteocytes, cells embedded in the bone matrix, and their role in inflammation and inflammatory bone loss. Osteocytes communicate through various mechanisms; directly via dendritic processes and through secretion of proteins that can influence the formation and activity of osteoblasts and osteoclasts. Some osteocyte proteins (e.g., interleukin-6 and RANKL) also have roles within the immune system. In the context of mechanical loading/unloading, the regulatory role of osteocytes is well understood. More recent data on osteocytes in various inflammatory models suggest they may also aid in orchestrating inflammation-induced changes in bone turnover. In inflammatory conditions, osteocytes express multiple pro-inflammatory cytokines which are associated with increases in bone resorption and declines in bone formation. Cytokines are known to also influence cell population growth, maturation, and responsiveness via various signaling modalities, but how they influence osteocytes has not been greatly explored. Furthermore, osteocytes may play regulatory roles in orchestrating bone's response to immunological changes in inflammatory conditions. This review will address what is known about osteocyte biology in physiological conditions and in response to varying immunological conditions, as well as highlight key areas of interest for future investigations.
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Affiliation(s)
- Corinne E. Metzger
- Department of Health and Kinesiology, Texas A&M University, College Station, TX, United States
- *Correspondence: Corinne E. Metzger
| | - S. Anand Narayanan
- Department of Medical Physiology, Texas A&M Health Science Center, Bryan, TX, United States
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ZHAO XIAOE, YANG ZHENSHAN, GAO ZHEN, GE JUNBANG, WEI QIANG, MA BAOHUA. 6-Bromoindirubin-3’-oxime promotes osteogenic differentiation of canine BMSCs through inhibition of GSK3β activity and activation of the Wnt/β-catenin signaling pathway. ACTA ACUST UNITED AC 2019; 91:e20180459. [PMID: 30916158 DOI: 10.1590/0001-3765201920180459] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2018] [Accepted: 07/09/2018] [Indexed: 12/16/2022]
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Chen M, Hu Y, Li M, Chen M, Shen X, Luo Z, Mu C, Yang W, Liu P, Cai K. Regulation of osteoblast differentiation by osteocytes cultured on sclerostin antibody conjugated TiO 2 nanotube array. Colloids Surf B Biointerfaces 2018; 175:663-670. [PMID: 30590327 DOI: 10.1016/j.colsurfb.2018.12.023] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2018] [Revised: 10/17/2018] [Accepted: 12/10/2018] [Indexed: 12/17/2022]
Abstract
Sclerostin is a negative regulator of the Wnt signaling pathway for osteoblast differentiation. In this study, osteoblasts were co-cultured with osteocytes (MLO-Y4 cells) on the surface of sclerostin antibody-conjugated TiO2 nanotube arrays (TNTs-scl). Field emission scanning electron microscopy (SEM), contact angle measurement and confocal laser scanning microscope (CLSM) were employed to characterize the conjugation of sclerostin antibody onto the surface of TiO2 nanotube arrays. The cellular viability and morphology results displayed TNTs-scl (TNT30-scl and TNT70-scl) were beneficial to the growth of MLO-Y4 cells. There was no apparent change in sclerostin gene expression between MLO-Y4 cells grown on TNTs and TNTs-scl. However, TNTs-scl significantly reduced the amount of sclerostin in the medium. In comparison with the control groups, osteoblasts displayed higher differentiation capability when co-cultured with MLO-Y4 cells on the surface TNTs-scl, which was indicated by the ALP activity, mineralization capability as well as expression levels of key proteins in Wnt signaling. This study provides a simple strategy to engineer titanium surface for bone fracture recovery, especially in osteoporotic conditions.
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Affiliation(s)
- Maohua Chen
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400044, PR China
| | - Yan Hu
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400044, PR China.
| | - Menghuan Li
- School of Life Science, Chongqing University, Chongqing, 400044, PR China
| | - Maowen Chen
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400044, PR China
| | - Xinkun Shen
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400044, PR China
| | - Zhong Luo
- School of Life Science, Chongqing University, Chongqing, 400044, PR China
| | - Caiyun Mu
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400044, PR China
| | - Weihu Yang
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400044, PR China
| | - Peng Liu
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400044, PR China
| | - Kaiyong Cai
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400044, PR China.
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Hassan MG, Zaher AR, Palomo JM, Palomo L. Sclerostin Modulation Holds Promise for Dental Indications. Healthcare (Basel) 2018; 6:healthcare6040134. [PMID: 30477095 PMCID: PMC6316148 DOI: 10.3390/healthcare6040134] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2018] [Revised: 11/13/2018] [Accepted: 11/20/2018] [Indexed: 12/31/2022] Open
Abstract
Sclerostin modulation is a novel therapeutic bone regulation strategy. The anti-sclerostin drugs, proposed in medicine for skeletal bone loss may be developed for jaw bone indications in dentistry. Alveolar bone responsible for housing dentition share common bone remodeling mechanisms with skeletal bone. Manipulating alveolar bone turnover can be used as a strategy to treat diseases such as periodontitis, where large bone defects from disease are a surgical treatment challenge and to control tooth position in orthodontic treatment, where moving teeth through bone in the treatment goal. Developing such therapeutics for dentistry is a future line for research and therapy. Furthermore, it underscores the interprofessional relationship that is the future of healthcare.
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Affiliation(s)
- Mohamed G Hassan
- Division of Craniofacial Anomalies, Department of Orofacial Sciences, University of California San Francisco, San Francisco, CA 94143, USA.
- Department of Orthodontics, Faculty of Dentistry, Alexandria University, Alexandria 21526, Egypt.
- Department of Orthodontics, Faculty of Oral and Dental Medicine, South Valley University, Qena 83523, Egypt.
| | - Abbas R Zaher
- Department of Orthodontics, Faculty of Dentistry, Alexandria University, Alexandria 21526, Egypt.
| | - Juan Martin Palomo
- Department of Orthodontics, School of Dental Medicine, Case Western Reserve University, Cleveland, OH 44106-4905, USA.
| | - Leena Palomo
- Department of Periodontics, School of Dental Medicine, Case Western Reserve University, Cleveland, OH 44106-4905, USA.
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Loss of Myeloid-Specific TGF-β Signaling Decreases CTHRC1 to Downregulate bFGF and the Development of H1993-Induced Osteolytic Bone Lesions. Cancers (Basel) 2018; 10:cancers10120463. [PMID: 30469488 PMCID: PMC6315699 DOI: 10.3390/cancers10120463] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2018] [Revised: 11/05/2018] [Accepted: 11/21/2018] [Indexed: 12/19/2022] Open
Abstract
The role of myeloid cell-specific TGF-β signaling in non-small-cell lung cancer (NSCLC)-induced osteolytic bone lesion development is unknown. We used a genetically engineered mouse model, Tgfbr2LysMCre knockout (KO), which has a loss of TGF-β signaling specifically in myeloid lineage cells, and we found that the area of H1993 cell-induced osteolytic bone lesions was decreased in Tgfbr2LysMCre KO mice, relative to the area in control littermates. The bone lesion areas were correlated with tumor cell proliferation, angiogenesis, and osteoclastogenesis in the microenvironment. The smaller bone lesion area was partially rescued by bFGF, which was expressed by osteoblasts. Interestingly, bFGF was able to rescue the osteoclastogenesis, but not the tumor cell proliferation or angiogenesis. We then focused on identifying osteoclast factors that regulate bFGF expression in osteoblasts. We found that the expression and secretion of CTHRC1 was downregulated in osteoclasts from Tgfbr2LysMCre KO mice; CTHRC1 was able to promote bFGF expression in osteoblasts, possibly through the Wnt/β-catenin pathway. Functionally, bFGF stimulated osteoclastogenesis and inhibited osteoblastogenesis, but had no effect on H1993 cell proliferation. On the other hand, CTHRC1 promoted osteoblastogenesis and H1993 cell proliferation. Together, our data show that myeloid-specific TGF-β signaling promoted osteolytic bone lesion development and bFGF expression in osteoblasts; that osteoclast-secreted CTHRC1 stimulated bFGF expression in osteoblasts in a paracrine manner; and that CTHRC1 and bFGF had different cell-specific functions that contributed to bone lesion development.
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Kim AR, Kim JH, Kim A, Sohn Y, Cha JH, Bak EJ, Yoo YJ. Simvastatin attenuates tibial bone loss in rats with type 1 diabetes and periodontitis. J Transl Med 2018; 16:306. [PMID: 30413166 PMCID: PMC6230277 DOI: 10.1186/s12967-018-1681-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2018] [Accepted: 11/06/2018] [Indexed: 02/02/2023] Open
Abstract
Background Diabetes induces long bone loss and aggravation of periodontitis-induced alveolar bone loss. Simvastatin (SIM), which is a lipid-lowering agent is known to have an anabolic effect on bone. Therefore, we investigated effect of SIM on tibial and alveolar bone loss in type 1 diabetic rats with periodontitis. Methods Rats were divided into control (C), diabetes with periodontitis (DP), and diabetes with periodontitis treated with SIM (DPS) groups. DP and DPS groups were intravenously injected with streptozotocin (50 mg/kg), and C group was injected with citrate buffer. Seven days later (day 0), periodontitis was induced by ligatures of mandibular first molars. DP and DPS groups were orally administered vehicle or SIM (30 mg/kg) from day 0 to days 3, 10, or 20. Alveolar and tibial bone loss was measured using histological and m-CT analysis alone or in combination. Osteoclast number and sclerostin-positive osteocytes in tibiae were evaluated by tartrate-resistant acid phosphatase and immunohistochemical staining, respectively. Glucose, triglyceride (TG), cholesterol (CHO), and low-density lipoprotein (LDL) were evaluated. Results Consistent with diabetes induction, the DP group showed higher glucose and TG levels at all timepoints and higher CHO levels on day 20 than C group. Compared to the DP group, the DPS group exhibited reduced levels of glucose (day 3), TG (days 10 and 20), CHO, and LDL levels (day 20). Bone loss analysis revealed that the DP group had lower bone volume fraction, bone mineral density, bone surface density, and trabecular number in tibiae than C group at all timepoints. Interestingly, the DPS group exhibited elevation of these indices at early stages compared to the DP group. The DPS group showed reduction of osteoclasts (day 3) and sclerostin-positive osteocytes (days 3 and 20) compared with the DP group. There was no difference in alveolar bone loss between DP and DPS groups. Conclusions These results suggest that SIM attenuates tibial, but not alveolar bone loss in type 1 diabetic rats with periodontitis. Moreover, attenuation of tibial bone loss by SIM may be related to inhibition of osteoclast formation and reduction of sclerostin expression.
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Affiliation(s)
- Ae Ri Kim
- Department of Oral Biology, Yonsei University College of Dentistry, 134 Sinchon dong, Seodaemun-gu, Seoul, 120-752, Republic of Korea.,Department of Applied Life Science, The Graduate School, Yonsei University, Seoul, Republic of Korea.,BK21 PLUS Project, Yonsei University College of Dentistry, Seoul, Republic of Korea
| | - Ji-Hye Kim
- Department of Dental Hygiene, Jeonju Kijeon College, Jeonju, Republic of Korea
| | - Aeryun Kim
- Department of Applied Life Science, The Graduate School, Yonsei University, Seoul, Republic of Korea
| | - Yongsung Sohn
- DONG-A Pharm, Yongin-si, Gyeonggi-do, Republic of Korea
| | - Jeong-Heon Cha
- Department of Oral Biology, Yonsei University College of Dentistry, 134 Sinchon dong, Seodaemun-gu, Seoul, 120-752, Republic of Korea.,Department of Applied Life Science, The Graduate School, Yonsei University, Seoul, Republic of Korea.,BK21 PLUS Project, Yonsei University College of Dentistry, Seoul, Republic of Korea.,Microbiology and Molecular Biology, Key Laboratory of Oral Medicine, Guangzhou Institute of Oral Disease, Stomatology Hospital of Guangzhou Medical University, Guangzhou, China
| | - Eun-Jung Bak
- Department of Oral Biology, Yonsei University College of Dentistry, 134 Sinchon dong, Seodaemun-gu, Seoul, 120-752, Republic of Korea.
| | - Yun-Jung Yoo
- Department of Oral Biology, Yonsei University College of Dentistry, 134 Sinchon dong, Seodaemun-gu, Seoul, 120-752, Republic of Korea. .,Department of Applied Life Science, The Graduate School, Yonsei University, Seoul, Republic of Korea.
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Briana DD, Gavrili S, Georgantzi S, Marmarinos A, Voulgaris K, Christou C, Gourgiotis D, Malamitsi-Puchner A. Inhibitors of osteoblastogenesis in early human milk and maternal serum: evidence for protective properties of mother's milk on bone. J Matern Fetal Neonatal Med 2018; 33:1095-1099. [PMID: 30122112 DOI: 10.1080/14767058.2018.1514383] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Objective: Lactation is associated with a dramatic increase of maternal bone turnover, leading to a reversible bone loss. Early life nutrition may influence later osteoporosis risk. Proteins synthesized by the group of wingless (Wnt) genes are key mediators of osteoblastogenesis and bone formation. We aimed to investigate maternal milk and serum concentrations of the inhibitors of the Wnt signaling pathway, Dickkopf-1 (DKK-1) and sclerostin.Material and methods: In 80 women, maternal milk and serum concentrations of DKK-1 and sclerostin were determined by ELISA on the 3rd-4th day postpartum. Concentrations were associated with various maternal, gestational and neonatal characteristics.Results: DKK-1 and sclerostin were detectable in early milk [mean ± SD: 817.17 ± 259.61 pg/mL, median (range) 258.04 (2452.40-53.17) pg/mL, respectively] at significantly lower concentrations than in maternal serum [mean ± SD: 3375.36 ± 416.75 pg/mL, median (range) 16 200.54 (58 832.00-3012.60) pg/mL, respectively], (p < .000). Maternal milk sclerostin concentrations positively correlated with respective serum ones (r = 0.599, p = .000). Maternal serum and milk sclerostin concentrations positively correlated with maternal body mass index (r = 0.37, p = .001 and r =0.38, p = .000, respectively), while maternal serum sclerostin concentrations were higher in primiparas (p = .002).Conclusion: DKK-1 and sclerostin are present in early human milk at significantly lower concentrations, compared with maternal serum, probably contributing to the short- and long-term benefits of mother's milk for bone health. Moreover, the large amounts of both substances in maternal serum may represent disruption of the Wnt cascade, contributing to the well-known lactation-associated bone loss, which seems to be greater in primiparas and obese mothers.
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Affiliation(s)
- Despina D Briana
- Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Stavroula Gavrili
- Neonatal Intensive Care Unit, General District Hospital "Alexandra", Athens, Greece
| | - Sophia Georgantzi
- Neonatal Intensive Care Unit, General District Hospital "Alexandra", Athens, Greece
| | - Antonios Marmarinos
- Laboratory of Clinical Biochemistry - Molecular Diagnostics, 2nd Department of Pediatrics, National and Kapodistrian University of Athens, Athens, Greece
| | | | | | - Dimitrios Gourgiotis
- Laboratory of Clinical Biochemistry - Molecular Diagnostics, 2nd Department of Pediatrics, National and Kapodistrian University of Athens, Athens, Greece
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Yu SH, Hao J, Fretwurst T, Liu M, Kostenuik P, Giannobile WV, Jin Q. Sclerostin-Neutralizing Antibody Enhances Bone Regeneration Around Oral Implants. Tissue Eng Part A 2018; 24:1672-1679. [PMID: 29921173 DOI: 10.1089/ten.tea.2018.0013] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND Dental implants are an important option for replacement of missing teeth. A major clinical challenge is how best to accelerate bone regeneration and reduce the healing time for functional restoration after implant placement. A sclerostin-neutralizing antibody (Scl-Ab) has been shown to enhance alveolar bone formation and fracture repair. The aim of this study was to investigate the effects of systemic administration of Scl-Ab on dental implant osseointegration and bone regeneration in an experimental alveolar ridge tooth extraction model. MATERIALS AND METHODS To investigate the effects of Scl-Ab on bone regeneration and dental implant osseointegration, an experimental alveolar bone osteotomy rat model was adopted. One month after extraction of maxillary right first molars, osteotomy defects were created at the coronal aspect of each of the extraction sites, and 1 × 2-mm custom titanium implants were installed into the osteotomies. Coincident with implant placement, Scl-Ab was administered subcutaneously at a dose of 25 mg/kg twice weekly for 10-28 days and compared with a vehicle control. Animals were sacrificed 10, 14, and 28 days after surgery, and maxillae were harvested and analyzed by microcomputed tomography (microCT), histology, and histomorphometry. RESULTS microCT analysis demonstrated that the maxillary bone volume fraction was approximately 2- to 2.5-fold greater in Scl-Ab-treated animals compared with vehicle alone at days 14 and 28. Consistent with those findings, two-dimensional bone fill percentages within the coronal osteotomy sites were highest in Scl-Ab treatment groups at 28 days. In addition, bone-implant contact at 28 days was approximately twofold greater in the Scl-Ab group compared with the vehicle control. CONCLUSIONS These results indicate that systemic Scl-Ab administration enhances osseointegration and bone regeneration around dental implants. This approach offers potential as a treatment modality for patients with low bone mass or bone defects to achieve more predictable bone regeneration at alveolar bone defects and to enhance dental implant osseointegration.
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Affiliation(s)
- Shan Huey Yu
- 1 Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan , Ann Arbor, Michigan
| | - Jie Hao
- 1 Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan , Ann Arbor, Michigan
| | - Tobias Fretwurst
- 1 Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan , Ann Arbor, Michigan.,2 Department of Oral- and Craniomaxillofacial Surgery, Faculty of Medicine, Medical Center-University of Freiburg , Freiburg, Germany
| | - Min Liu
- 3 Amgen, Inc. , Thousand Oaks, California
| | - Paul Kostenuik
- 1 Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan , Ann Arbor, Michigan.,3 Amgen, Inc. , Thousand Oaks, California.,6 Phylon Pharma Services, Newbury Park, California
| | - William V Giannobile
- 1 Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan , Ann Arbor, Michigan.,4 Department of Biomedical Engineering, College of Engineering, University of Michigan College of Engineering , Ann Arbor, Michigan
| | - Qiming Jin
- 5 Department of Cariology, Restorative Sciences, and Endodontics, School of Dentistry, University of Michigan , Ann Arbor, Michigan
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Makino T, Tsukazaki H, Ukon Y, Tateiwa D, Yoshikawa H, Kaito T. The Biological Enhancement of Spinal Fusion for Spinal Degenerative Disease. Int J Mol Sci 2018; 19:ijms19082430. [PMID: 30126106 PMCID: PMC6121547 DOI: 10.3390/ijms19082430] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2018] [Revised: 08/04/2018] [Accepted: 08/14/2018] [Indexed: 12/16/2022] Open
Abstract
In this era of aging societies, the number of elderly individuals who undergo spinal arthrodesis for various degenerative diseases is increasing. Poor bone quality and osteogenic ability in older patients, due to osteoporosis, often interfere with achieving bone fusion after spinal arthrodesis. Enhancement of bone fusion requires shifting bone homeostasis toward increased bone formation and reduced resorption. Several biological enhancement strategies of bone formation have been conducted in animal models of spinal arthrodesis and human clinical trials. Pharmacological agents for osteoporosis have also been shown to be effective in enhancing bone fusion. Cytokines, which activate bone formation, such as bone morphogenetic proteins, have already been clinically used to enhance bone fusion for spinal arthrodesis. Recently, stem cells have attracted considerable attention as a cell source of osteoblasts, promising effects in enhancing bone fusion. Drug delivery systems will also need to be further developed to assure the safe delivery of bone-enhancing agents to the site of spinal arthrodesis. Our aim in this review is to appraise the current state of knowledge and evidence regarding bone enhancement strategies for spinal fusion for degenerative spinal disorders, and to identify future directions for biological bone enhancement strategies, including pharmacological, cell and gene therapy approaches.
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Affiliation(s)
- Takahiro Makino
- Department of Orthopedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
| | - Hiroyuki Tsukazaki
- Department of Orthopedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
| | - Yuichiro Ukon
- Department of Orthopedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
| | - Daisuke Tateiwa
- Department of Orthopedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
| | - Hideki Yoshikawa
- Department of Orthopedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
| | - Takashi Kaito
- Department of Orthopedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
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Baron R, Gori F. Targeting WNT signaling in the treatment of osteoporosis. Curr Opin Pharmacol 2018; 40:134-141. [PMID: 29753194 DOI: 10.1016/j.coph.2018.04.011] [Citation(s) in RCA: 79] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2018] [Accepted: 04/21/2018] [Indexed: 12/17/2022]
Abstract
Osteoporosis is a widespread chronic disease characterized by low bone density, altered microstructure and bone fragility, leading to low impact fractures in affected individuals. The discovery of a few mutations that cause extremely rare human diseases has identified the WNT signaling pathway as a candidate for therapeutic intervention aimed at increasing bone mass and strength. In particular, inhibition of sclerostin, a WNT antagonist secreted by osteocytes, has proven in clinical trials to be a very efficient osteo-anabolic approach. One year of monthly administration of antibodies to sclerostin rapidly decreases bone resorption and increases bone formation and bone density at all sites, decreasing markedly fracture risk in treated patients. Their effect is however limited in time and cardiovascular adverse events have been reported in one clinical trial.
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Affiliation(s)
- Roland Baron
- Harvard Medical School, Endocrine Unit, Massachusetts General Hospital, Boston, MA, USA; Harvard School of Dental Medicine, Division of Bone and Mineral Research, Department of Oral Medicine, Infection and Immunity, Boston, MA, USA.
| | - Francesca Gori
- Harvard School of Dental Medicine, Division of Bone and Mineral Research, Department of Oral Medicine, Infection and Immunity, Boston, MA, USA
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