|
1
|
Rodrigues MFL, Souza-Monteiro D, Nazário RMF, Aragão WAB, Chemelo VS, Eiró-Quirino L, Bittencourt LO, Collares FM, Gerlach RF, Pessanha S, Lima RR. Lead Toxicity and Maternal Exposure: Characterisation of Alveolar Bone Changes on Offspring Rats. Biol Trace Elem Res 2024:10.1007/s12011-024-04412-0. [PMID: 39453595 DOI: 10.1007/s12011-024-04412-0] [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: 08/06/2024] [Accepted: 10/05/2024] [Indexed: 10/26/2024]
Abstract
Lead poisoning is a global public health concern. Maternal exposure during intrauterine and lactational periods can present a higher susceptibility of harm to the offspring. Thus, pregnant female Wistar rats (Rattus norvegicus) were randomly divided in two experimental groups: control group and Lead group. The animals were exposed to 50 mg/kg of Lead Acetate daily for 42 days (21 days of gestational period + 21 days of lactational period). After the exposure period, the mandibles of the offspring were collected for lead quantification, Raman spectroscopy analysis, micro-CT, morphometric e histochemical analysis. Lead exposure altered the physical-chemical composition of alveolar bone and caused histological damage associated with a reduction in osteocyte density and collagen area fraction, increase in collagen maturity, as well as a reduction in bone volume fraction. An increase in trabecular spaces with anatomical compromise of the vertical dimensions of the bone was observed. Thus, the results suggest that developing alveolar bone is susceptible to toxic effects of lead when organisms are exposed during intrauterine and lactation periods.
Collapse
Affiliation(s)
- Matheus Ferreira Lima Rodrigues
- Laboratory of Functional and Structural Biology, Institute of Biological Sciences, Federal University of Pará, 01 Augusto Corrêa Street, Guamá, Belém, PA, Zip Code 66075-110, Brazil
| | - Deiweson Souza-Monteiro
- Laboratory of Functional and Structural Biology, Institute of Biological Sciences, Federal University of Pará, 01 Augusto Corrêa Street, Guamá, Belém, PA, Zip Code 66075-110, Brazil
| | - Rayssa Maitê Farias Nazário
- Laboratory of Functional and Structural Biology, Institute of Biological Sciences, Federal University of Pará, 01 Augusto Corrêa Street, Guamá, Belém, PA, Zip Code 66075-110, Brazil
| | - Walessa Alana Bragança Aragão
- Laboratory of Functional and Structural Biology, Institute of Biological Sciences, Federal University of Pará, 01 Augusto Corrêa Street, Guamá, Belém, PA, Zip Code 66075-110, Brazil
| | - Victória Santos Chemelo
- Laboratory of Functional and Structural Biology, Institute of Biological Sciences, Federal University of Pará, 01 Augusto Corrêa Street, Guamá, Belém, PA, Zip Code 66075-110, Brazil
| | - Luciana Eiró-Quirino
- Laboratory of Functional and Structural Biology, Institute of Biological Sciences, Federal University of Pará, 01 Augusto Corrêa Street, Guamá, Belém, PA, Zip Code 66075-110, Brazil
| | - Leonardo Oliveira Bittencourt
- Laboratory of Functional and Structural Biology, Institute of Biological Sciences, Federal University of Pará, 01 Augusto Corrêa Street, Guamá, Belém, PA, Zip Code 66075-110, Brazil
| | - Fabrício Mezzomo Collares
- Department of Dental Materials, School of Dentistry, Federal University of Rio Grande Do Sul, Porto Alegre, Porto Alegre, RS, Brazil
| | - Raquel Fernanda Gerlach
- Department of Basic and Oral Biology, Faculty of Dentistry of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, SP, Brazil
| | - Sofia Pessanha
- Laboratory of Instrumentation Biomedical Engineering and Radiation Physics, NOVA School of Sciences and Technology, LA-REAL, Campus Caparica, 2829-516, Caparica, Portugal
| | - Rafael Rodrigues Lima
- Laboratory of Functional and Structural Biology, Institute of Biological Sciences, Federal University of Pará, 01 Augusto Corrêa Street, Guamá, Belém, PA, Zip Code 66075-110, Brazil.
| |
Collapse
|
|
2
|
Roseti L, Borciani G, Grassi F, Desando G, Gambari L, Grigolo B. Nutraceuticals in osteoporosis prevention. Front Nutr 2024; 11:1445955. [PMID: 39416651 PMCID: PMC11479890 DOI: 10.3389/fnut.2024.1445955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2024] [Accepted: 09/03/2024] [Indexed: 10/19/2024] Open
Abstract
Nutraceuticals are gaining popularity as they can contribute to bone health by delaying the onset or slowing down the progression of pathological bone loss. Osteoporosis's bone loss is a concern for older adults and a crucial aspect of aging. Maintaining healthy bones is the key to living a full and active life. Our review explores the current knowledge on the role of nutraceuticals in preventing osteoporosis by focusing on three main aspects. First, we provide an overview of osteoporosis. Second, we discuss the latest findings on natural nutraceuticals and their efficacy in reducing bone loss, emphasizing clinical trials. Third, we conduct a structured analysis to evaluate nutraceuticals' pros and cons and identify translational gaps. In conclusion, we must address several challenges to consolidate our knowledge, better support clinicians in their prescriptions, and provide people with more reliable nutritional recommendations to help them lead healthier lives.
Collapse
Affiliation(s)
| | - Giorgia Borciani
- RAMSES Laboratory, Rizzoli RIT-Research, Innovation & Technology Department, Istituto di Ricerca Codivilla Putti, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
| | | | | | | | | |
Collapse
|
|
3
|
Wang R, Liu C, Wei W, Lin Y, Zhou L, Chen J, Wu D. Increased bone mass but delayed mineralization: in vivo and in vitro study for zoledronate in bone regeneration. BMC Oral Health 2024; 24:1146. [PMID: 39334089 PMCID: PMC11438265 DOI: 10.1186/s12903-024-04906-2] [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: 03/24/2024] [Accepted: 09/12/2024] [Indexed: 09/30/2024] Open
Abstract
BACKGROUND Bisphosphonates (BPs) are widely used to inhibit excessive osteoclast activity. However, the potential to compromise bone defect healing has limited their broader application. To better understand the influence of BPs on bone regeneration, we established a bone grafting model with Zoledronate administration, aiming to deepen the understanding of bone remodeling and mineralization processes. METHODS A bone grafting model was established in the distal femurs of male Sprague-Dawley rats. The experimental group received systemic administration of Zoledronate (ZOL, 0.2 mg/kg, administered twice). Histological analysis and immunohistochemistry (IHC) were employed to assess osteoblastic and macrophage activity, tartrate-resistant acid phosphatase (TRAP) staining was used to evaluate osteoclastogenesis. Mineralization was assessed through Micro-CT analysis, Raman spectroscopy, and back-scatter scanning electron microscopy (BSE-SEM). Additionally, the in vitro effects of ZOL on osteoblast and osteoclast activity were investigated to further elucidate its impact on bone regeneration. RESULTS In vivo, the ZOL group showed increased bone mass, as observed in histological and radiological assessments. However, Micro-CT, Raman spectroscopy, and BSE-SEM detection revealed lower mineralization levels in ZOL group's regenerated bone. Acid-etched SEM analysis showed abnormal osteocyte characteristics in ZOL-group's regenerated bone. Simultaneously, elevated osteopontin (OPN), F4/80 expression along with reduced TRAP expressing was found in the grafting region of ZOL group. In vitro, ZOL did not negatively impact osteogenetic activity (ALP, BMP4, OCN expression) at the tested concentrations (0.02-0.5 g/ml) but significantly impaired mineralization and inhibited osteoclast formation, even at the lowest concentration. CONCLUSIONS This study highlights a less recognized negative effect of ZOL on bone mineralization during bone regeneration. More research is needed to elucidate the underlying mechanism.
Collapse
Affiliation(s)
- Rongchang Wang
- Fujian Key Laboratory of Oral Diseases, School and Hospital of Stomatology, Fujian Medical University, Fujian, China
| | - Chaowei Liu
- Fujian Key Laboratory of Oral Diseases, School and Hospital of Stomatology, Fujian Medical University, Fujian, China
| | - Wenwei Wei
- Fujian Key Laboratory of Oral Diseases, School and Hospital of Stomatology, Fujian Medical University, Fujian, China
| | - Yanjun Lin
- Fujian Key Laboratory of Oral Diseases, School and Hospital of Stomatology, Fujian Medical University, Fujian, China
| | - Lin Zhou
- Fujian Key Laboratory of Oral Diseases, School and Hospital of Stomatology, Fujian Medical University, Fujian, China
| | - Jiang Chen
- Fujian Key Laboratory of Oral Diseases, School and Hospital of Stomatology, Fujian Medical University, Fujian, China
| | - Dong Wu
- Fujian Key Laboratory of Oral Diseases, School and Hospital of Stomatology, Fujian Medical University, Fujian, China.
- Research Center of Dental and Craniofacial Implants, School and Hospital of Stomatology, Fujian Medical University, Fujian, China.
| |
Collapse
|
|
4
|
Thuong LHH, Hsu CJ, Chen HT, Kuo YH, Tang CH. Caffeic acid derivative MPMCA suppresses osteoclastogenesis and facilitates osteoclast apoptosis: implications for the treatment of bone loss disorders. Aging (Albany NY) 2024; 16:11926-11938. [PMID: 39189924 PMCID: PMC11386915 DOI: 10.18632/aging.206067] [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: 03/13/2024] [Accepted: 07/18/2024] [Indexed: 08/28/2024]
Abstract
Osteoclast activity plays a crucial role in the pathological mechanisms of osteoporosis and bone remodeling. The treatment of these disorders involves the use of pharmacological medicines that work by inhibiting the activity of osteoclasts. Nevertheless, the prevalent and infrequent negative consequences of current antiresorptive and bone anabolic treatments pose significant drawbacks, hence restricting their prolonged administration in patients, particularly those who are elderly and/or suffer from many medical conditions. We are currently in the process of creating a new molecule called N-(4-methoxyphen) methyl caffeamide (MPMCA), which is a derivative of caffeic acid. This compound has shown potential in preventing the production of osteoclasts and causing existing osteoclasts to undergo cell apoptosis. Our investigation discovered that MPMCA hinders osteoclast function via suppressing the MAPK pathways. The expectation is that the findings of this study will stimulate the advancement of a novel approach to treating anti-resorption.
Collapse
Affiliation(s)
- Le Huynh Hoai Thuong
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
| | - Chin-Jung Hsu
- School of Chinese Medicine, China Medical University, Taichung, Taiwan
- Department of Orthopedic Surgery, China Medical University Hospital, Taichung, Taiwan
| | - Hsien-Te Chen
- Department of Orthopedic Surgery, China Medical University Hospital, Taichung, Taiwan
- Department of Sports Medicine, China Medical University, Taichung, Taiwan
| | - Yueh-Hsiung Kuo
- Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, China Medical University, Taichung, Taiwan
- Chinese Medicine Research Center, China Medical University, Taichung, Taiwan
| | - Chih-Hsin Tang
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
- Chinese Medicine Research Center, China Medical University, Taichung, Taiwan
- Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan
- Department of Medical Laboratory Science and Biotechnology, College of Medical and Health Science, Asia University, Taichung, Taiwan
- Department of Medical Research, China Medical University Hsinchu Hospital, Hsinchu, Taiwan
| |
Collapse
|
|
5
|
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.
Collapse
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
| |
Collapse
|
|
6
|
Chen Z, Chen Y, Wang Y, Deng J, Wang X, Wang Q, Liu Y, Ding J, Yu L. Polyetheretherketone implants with hierarchical porous structure for boosted osseointegration. Biomater Res 2023; 27:61. [PMID: 37370127 DOI: 10.1186/s40824-023-00407-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Accepted: 06/19/2023] [Indexed: 06/29/2023] Open
Abstract
BACKGROUND Good osseointegration is the key to the long-term stability of bone implants. Thermoplastic polyetheretherketone (PEEK) has been widely used in orthopedics; however, its inherent biological inertia causes fibrous tissue to wrap its surface, which leads to poor osseointegration and thus greatly limits its clinical applications. METHODS Herein, we developed a facile yet effective surface modification strategy. A commonly used sulfonation coupled with "cold pressing" treatment in the presence of porogenic agent formed a three-dimensional hierarchical porous structure on PEEK surface. Subsequently, the effects of porous surface on the in vitro adhesion, proliferation and differentiation of rat bone marrow-derived mesenchymal stem cells (BMSCs) were evaluated. Finally, the osteoinduction and osseointegration of surface-porous PEEK implant were examined in the rat distal femoral defect model. RESULTS In vitro results showed that the surface modification did not significantly affect the mechanical performance and cytocompatibility of PEEK substance, and the porous structure on the modified PEEK substrate provided space for cellular ingrowth and enhanced osteogenic differentiation and mineralization of BMSCs. In vivo tests demonstrated that the surface-porous PEEK implant could effectively promote new bone formation and had higher bone-implant contact rate, thereby achieving good bone integration with the surrounding host bone. In addition, this modification technique was also successfully demonstrated on a medical PEEK interbody fusion cage. CONCLUSION The present study indicates that topological morphology plays a pivotal role in determining implant osseointegration and this facile and effective modification strategy developed by us is expected to achieve practical applications quickly.
Collapse
Affiliation(s)
- Zhiyong Chen
- State Key Laboratory of Molecular Engineering of Polymers, Department of Macromolecular Science, Shanghai Stomatological Hospital & School of Stomatology, Fudan University, Shanghai, 200438, China
| | - Yu Chen
- State Key Laboratory of Molecular Engineering of Polymers, Department of Macromolecular Science, Shanghai Stomatological Hospital & School of Stomatology, Fudan University, Shanghai, 200438, China
| | - Yang Wang
- State Key Laboratory of Molecular Engineering of Polymers, Department of Macromolecular Science, Shanghai Stomatological Hospital & School of Stomatology, Fudan University, Shanghai, 200438, China
| | - JiaJia Deng
- Department of Orthodontics, Shanghai Stomatological Hospital & School of Stomatology, Shanghai Key Laboratory of Craniomaxillofacial Development and Diseases, Fudan University, Shanghai, 200001, China
| | - Xin Wang
- State Key Laboratory of Molecular Engineering of Polymers, Department of Macromolecular Science, Shanghai Stomatological Hospital & School of Stomatology, Fudan University, Shanghai, 200438, China
| | - Qingqing Wang
- Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Medical College of Zhejiang University, Hangzhou, 310016, Zhejiang, China
| | - Yuehua Liu
- Department of Orthodontics, Shanghai Stomatological Hospital & School of Stomatology, Shanghai Key Laboratory of Craniomaxillofacial Development and Diseases, Fudan University, Shanghai, 200001, China
| | - Jiandong Ding
- State Key Laboratory of Molecular Engineering of Polymers, Department of Macromolecular Science, Shanghai Stomatological Hospital & School of Stomatology, Fudan University, Shanghai, 200438, China
| | - Lin Yu
- State Key Laboratory of Molecular Engineering of Polymers, Department of Macromolecular Science, Shanghai Stomatological Hospital & School of Stomatology, Fudan University, Shanghai, 200438, China.
| |
Collapse
|
|
7
|
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.
Collapse
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.
| |
Collapse
|
|
8
|
Hofstaetter JG, Atkins GJ, Kato H, Kogawa M, Blouin S, Misof BM, Roschger P, Evdokiou A, Yang D, Solomon LB, Findlay DM, Ito N. A Mild Case of Autosomal Recessive Osteopetrosis Masquerading as the Dominant Form Involving Homozygous Deep Intronic Variations in the CLCN7 Gene. Calcif Tissue Int 2022; 111:430-444. [PMID: 35618777 PMCID: PMC9474465 DOI: 10.1007/s00223-022-00988-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Accepted: 05/06/2022] [Indexed: 11/28/2022]
Abstract
Osteopetrosis is a heterogeneous group of rare hereditary diseases characterized by increased bone mass of poor quality. Autosomal-dominant osteopetrosis type II (ADOII) is most often caused by mutation of the CLCN7 gene leading to impaired bone resorption. Autosomal recessive osteopetrosis (ARO) is a more severe form and is frequently accompanied by additional morbidities. We report an adult male presenting with classical clinical and radiological features of ADOII. Genetic analyses showed no amino-acid-converting mutation in CLCN7 but an apparent haploinsufficiency and suppression of CLCN7 mRNA levels in peripheral blood mononuclear cells. Next generation sequencing revealed low-frequency intronic homozygous variations in CLCN7, suggesting recessive inheritance. In silico analysis of an intronic duplication c.595-120_595-86dup revealed additional binding sites for Serine- and Arginine-rich Splicing Factors (SRSF), which is predicted to impair CLCN7 expression. Quantitative backscattered electron imaging and histomorphometric analyses revealed bone tissue and material abnormalities. Giant osteoclasts were present and additionally to lamellar bone, and abundant woven bone and mineralized cartilage were observed, together with increased frequency and thickness of cement lines. Bone mineralization density distribution (BMDD) analysis revealed markedly increased average mineral content of the dense bone (CaMean T-score + 10.1) and frequency of bone with highest mineral content (CaHigh T-score + 19.6), suggesting continued mineral accumulation and lack of bone remodelling. Osteocyte lacunae sections (OLS) characteristics were unremarkable except for an unusually circular shape. Together, our findings suggest that the reduced expression of CLCN7 mRNA in osteoclasts, and possibly also osteocytes, causes poorly remodelled bone with abnormal bone matrix with high mineral content. This together with the lack of adequate bone repair mechanisms makes the material brittle and prone to fracture. While the skeletal phenotype and medical history were suggestive of ADOII, genetic analysis revealed that this is a possible mild case of ARO due to deep intronic mutation.
Collapse
Affiliation(s)
- Jochen G Hofstaetter
- 1st Medical Dept., Hanusch Hospital, Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of OEGK and AUVA Trauma Centre Meidling, Vienna, Austria
- Michael Ogon Laboratory, Orthopaedic Hospital Vienna-Speising, Vienna, Austria
| | - Gerald J Atkins
- Centre for Orthopaedic & Trauma Research, Faculty of Health and Medical Sciences, Adelaide Health and Medical Sciences Building, The University of Adelaide, North Terrace, Adelaide, SA, 5005, Australia.
| | - Hajime Kato
- Division of Nephrology and Endocrinology, The University of Tokyo Hospital, Tokyo, Japan
- Osteoporosis Center, The University of Tokyo Hospital, Tokyo, Japan
| | - Masakazu Kogawa
- Centre for Orthopaedic & Trauma Research, Faculty of Health and Medical Sciences, Adelaide Health and Medical Sciences Building, The University of Adelaide, North Terrace, Adelaide, SA, 5005, Australia
| | - Stéphane Blouin
- 1st Medical Dept., Hanusch Hospital, Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of OEGK and AUVA Trauma Centre Meidling, Vienna, Austria
| | - Barbara M Misof
- 1st Medical Dept., Hanusch Hospital, Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of OEGK and AUVA Trauma Centre Meidling, Vienna, Austria
| | - Paul Roschger
- 1st Medical Dept., Hanusch Hospital, Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of OEGK and AUVA Trauma Centre Meidling, Vienna, Austria
| | - Andreas Evdokiou
- Centre for Orthopaedic & Trauma Research, Faculty of Health and Medical Sciences, Adelaide Health and Medical Sciences Building, The University of Adelaide, North Terrace, Adelaide, SA, 5005, Australia
| | - Dongqing Yang
- Centre for Orthopaedic & Trauma Research, Faculty of Health and Medical Sciences, Adelaide Health and Medical Sciences Building, The University of Adelaide, North Terrace, Adelaide, SA, 5005, Australia
| | - Lucian B Solomon
- Centre for Orthopaedic & Trauma Research, Faculty of Health and Medical Sciences, Adelaide Health and Medical Sciences Building, The University of Adelaide, North Terrace, Adelaide, SA, 5005, Australia
- Department of Orthopaedics and Trauma, Royal Adelaide Hospital, Adelaide, SA, 5000, Australia
| | - David M Findlay
- Centre for Orthopaedic & Trauma Research, Faculty of Health and Medical Sciences, Adelaide Health and Medical Sciences Building, The University of Adelaide, North Terrace, Adelaide, SA, 5005, Australia
| | - Nobuaki Ito
- Centre for Orthopaedic & Trauma Research, Faculty of Health and Medical Sciences, Adelaide Health and Medical Sciences Building, The University of Adelaide, North Terrace, Adelaide, SA, 5005, Australia
- Division of Nephrology and Endocrinology, The University of Tokyo Hospital, Tokyo, Japan
- Osteoporosis Center, The University of Tokyo Hospital, Tokyo, Japan
| |
Collapse
|
|
9
|
Bhatnagar A, Kekatpure AL. Postmenopausal Osteoporosis: A Literature Review. Cureus 2022; 14:e29367. [PMID: 36299953 PMCID: PMC9586717 DOI: 10.7759/cureus.29367] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Accepted: 09/20/2022] [Indexed: 11/23/2022] Open
Abstract
A substantial proportion of the population of females in India falls in the perimenopausal and postmenopausal age groups. One of the complications associated with older age in women is the weakening of bones and the fall in bone mineral density (BMD). This has a severe debilitating consequence in a woman’s life and leads to reduced quality of life along with a greater incidence of fractures. If the fracture involves the hip or the vertebrae, it can cause immobility and be devastating. Postmenopausal osteoporosis is linked with the deficiency of estrogen that occurs with the cessation of the function of the ovaries as age progresses. The function of estrogen in the bone remodeling process is very well understood after years of research; estrogen plays a part in both the formation of bone as well as the prevention of the resorption of bone. A diagnosis can be made by dual-energy X-ray absorptiometry (DEXA). It is the gold standard and can spot low bone density at particular sites. The treatment options are selected according to the severity and rate of progression and factors pertaining to each patient. All postmenopausal women should be made aware of this disorder, and they should be encouraged to cultivate a healthy lifestyle through the implementation of a proper diet and inculcation of a regular exercise routine. Smoking and drinking alcohol should be limited, and calcium and vitamin D supplementation should be started in all women of the postmenopausal age group with or without osteoporosis. In patients who have been diagnosed with the disorder, pharmacological intervention is done. Drugs should be selected based on their side effects and contradictions. Follow-up is essential, and patient compliance should be carefully monitored. This article attempts to review the existing literature on this very prevalent disorder to spread awareness about it so that all postmenopausal women can take the necessary steps to prevent the weakening of their bones, and deal with its progression.
Collapse
|
|
10
|
The Effects of Vitamin E Analogues α-Tocopherol and γ-Tocotrienol on the Human Osteocyte Response to Ultra-High Molecular Weight Polyethylene Wear Particles. PROSTHESIS 2022. [DOI: 10.3390/prosthesis4030039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Polyethylene (PE) liners are a common bearing surface of orthopaedic prostheses. Wear particles of ultra-high molecular weight PE (UHMWPE) contribute to periprosthetic osteolysis, a major cause of aseptic loosening. Vitamin E is added to some PE liners to prevent oxidative degradation. Osteocytes, an important cell type for controlling both bone mineralisation and bone resorption, have been shown to respond UHMWPE particles by upregulating pro-osteoclastogenic and osteocytic osteolysis. Here, we examined the effects of the vitamin E analogues α-tocopherol and γ-tocotrienol alone or in the context of UHMWPE particles on human osteocyte gene expression and mineralisation behaviour. Human osteoblasts differentiated to an osteocyte-like stage were exposed to UHMWPE wear particles in the presence or absence of either α-Tocopherol or γ-Tocotrienol. Both α-Tocopherol and γ-Tocotrienol induced antioxidant-related gene expression. UHMWPE particles independently upregulated antioxidant gene expression, suggesting an effect of wear particles on oxidative stress. Both vitamin E analogues strongly induced OPG mRNA expression and γ-Tocotrienol also inhibited RANKL mRNA expression, resulting in a significantly reduced RANKL:OPG mRNA ratio (p < 0.01) overall. UHMWPE particles reversed the suppressive effect of α-Tocopherol but not of γ-Tocotrienol on this pro-osteoclastogenic index. UHMWPE particles also upregulated osteocytic-osteolysis related gene expression. Vitamin E analogues alone or in combination with UHMWPE particles also resulted in upregulation of these genes. Consistent with this, both vitamin E analogues promoted calcium release from mineralised cultures of osteocyte-like cells. Our findings suggest that while vitamin E may suppress osteocyte support of osteoclastogenesis in the presence of UHMWPE particles, the antioxidant effect may induce osteocytic osteolysis, which could promote periprosthetic osteolysis. It will be important to conduct further studies of vitamin E to determine the long-term effects of its inclusion in prosthetic materials.
Collapse
|
|
11
|
Chen F, Tian L, Pu X, Zeng Q, Xiao Y, Chen X, Zhang X. Enhanced ectopic bone formation by strontium-substituted calcium phosphate ceramics through regulation of osteoclastogenesis and osteoblastogenesis. Biomater Sci 2022; 10:5925-5937. [PMID: 36043373 DOI: 10.1039/d2bm00348a] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
To explore how strontium influences osteoclastogenesis and osteoblastogenesis during material-induced ectopic bone formation, porous strontium-substituted biphasic calcium phosphate (Sr-BCP) and BCP ceramics with equivalent pore structures and comparable grain size and porosity were prepared. In vitro results showed that compared with BCP, Sr-BCP inhibited the osteoclastic differentiation of osteoclast precursors by delaying cell fusion, down-regulating the expression of osteoclast marker genes, and reducing the activity of osteoclast specific proteins, possibly due to the activated ERK signaling pathway but the suppressed p38, JNK and AKT signaling pathways. Meanwhile, Sr-BCP promoted the osteogenic differentiation of mesenchymal stem cells (MSCs) by up-regulating the osteogenic gene expression. Sr-BCP also mediated the expression of important osteoblast-osteoclast coupling factors, as evidenced by the increased Opg/Rankl ratio in mMSCs, and the reduced Rank expression and enhanced EphrinB2 expression in osteoclast precursors. Similar results were observed in an in vivo study based on a murine intramuscular implantation model. The sign of ectopic bone formation was only seen in Sr-BCP at 8 weeks. Compared to BCP, Sr-BCP obviously hindered the formation of TRAP- and CTSK-positive multinucleated osteoclast-like cells during the early implantation time up to 6 weeks, which is consistent with the in vivo PCR results. This suggested that Sr-BCP could clearly accelerate the ectopic bone formation by promoting osteogenesis but suppressing osteoclastogenesis, which might be closely related to the expression of osteoblast-osteoclast coupling factors regulated by Sr2+. These findings may help in the design and fabrication of smart bone substitutes with the desired potential for bone regeneration through modulating both osteoclastic resorption and osteoblastic synthesis.
Collapse
Affiliation(s)
- Fuying Chen
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu 610064, China.
| | - Luoqiang Tian
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu 610064, China.
| | - Ximing Pu
- College of Biomedical Engineering, Sichuan University, Chengdu, China
| | - Qin Zeng
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu 610064, China.
| | - Yumei Xiao
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu 610064, China.
| | - Xuening Chen
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu 610064, China.
| | - Xingdong Zhang
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu 610064, China.
| |
Collapse
|
|
12
|
Petean IBF, Silva-Sousa AC, Cronenbold TJ, Mazzi-Chaves JF, Silva LABD, Segato RAB, Castro GAPD, Kuchler EC, Paula-Silva FWG, Damião Sousa-Neto M. Genetic, Cellular and Molecular Aspects involved in Apical Periodontitis. Braz Dent J 2022; 33:1-11. [PMID: 36043561 PMCID: PMC9645190 DOI: 10.1590/0103-6440202205113] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Accepted: 08/03/2022] [Indexed: 11/26/2022] Open
Abstract
The development, establishment and repair of apical periodontitis (AP) is
dependent of several factors, which include host susceptibility, microbial
infection, immune response, quality of root canal treatment and organism's
ability to repair. The understanding of genetic contributions to the risk of
developing AP and presenting persistent AP has been extensively explored in
modern Endodontics. Thus, this article aims to provide a review of the
literature regarding the biochemical mediators involved in immune response
signaling, osteoclastogenesis and bone neoformation, as the genetic components
involved in the development and repair of AP. A narrative review of the
literature was performed through a PUBMED/MEDLINE search and a hand search of
the major AP textbooks. The knowledge regarding the cells, receptors and
molecules involved in the host's immune-inflammatory response during the
progression of AP added to the knowledge of bone biology allows the
identification of factors inherent to the host that can interfere both in the
progression and in the repair of these lesions. The main outcomes of studies
evaluated in the review that investigated the correlation between genetic
polymorphisms and AP in the last five years, demonstrate that genetic factors of
the individual are involved in the success of root canal treatment. The
discussion of this review gives subsides that may help to glimpse the
development of new therapies based on the identification of therapeutic targets
and the development of materials and techniques aimed at acting at the molecular
level for clinical, radiographic and histological success of root canal
treatment.
Collapse
Affiliation(s)
- Igor Bassi Ferreira Petean
- Department of Restorative Dentistry, School of Dentistry of Ribeirão Preto, University of São Paulo, Brazil
| | - Alice Corrêa Silva-Sousa
- Department of Restorative Dentistry, School of Dentistry of Ribeirão Preto, University of São Paulo, Brazil
| | | | | | - Lea Assed Bezerra da Silva
- Department of Pediatric Dentistry, School of Dentistry of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Raquel Assed Bezerra Segato
- Department of Pediatric Dentistry, School of Dentistry of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | | | - Erika Calvano Kuchler
- Department of Pediatric Dentistry, School of Dentistry of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.,Department of Orthodontics, University of Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany
| | | | - Manoel Damião Sousa-Neto
- Department of Restorative Dentistry, School of Dentistry of Ribeirão Preto, University of São Paulo, Brazil
| |
Collapse
|
|
13
|
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.
Collapse
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
| |
Collapse
|
|
14
|
Impact of degradable magnesium implants on osteocytes in single and triple cultures. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2022; 134:112692. [DOI: 10.1016/j.msec.2022.112692] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 01/12/2022] [Accepted: 01/29/2022] [Indexed: 11/21/2022]
|
|
15
|
Atake OJ, Eames BF. Mineralized Cartilage and Bone-Like Tissues in Chondrichthyans Offer Potential Insights Into the Evolution and Development of Mineralized Tissues in the Vertebrate Endoskeleton. Front Genet 2021; 12:762042. [PMID: 35003210 PMCID: PMC8727550 DOI: 10.3389/fgene.2021.762042] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 11/30/2021] [Indexed: 11/25/2022] Open
Abstract
The impregnation of biominerals into the extracellular matrix of living organisms, a process termed biomineralization, gives rise to diverse mineralized (or calcified) tissues in vertebrates. Preservation of mineralized tissues in the fossil record has provided insights into the evolutionary history of vertebrates and their skeletons. However, current understanding of the vertebrate skeleton and of the processes underlying its formation is biased towards biomedical models such as the tetrapods mouse and chick. Chondrichthyans (sharks, skates, rays, and chimaeras) and osteichthyans are the only vertebrate groups with extant (living) representatives that have a mineralized skeleton, but the basal phylogenetic position of chondrichthyans could potentially offer unique insights into skeletal evolution. For example, bone is a vertebrate novelty, but the internal supporting skeleton (endoskeleton) of extant chondrichthyans is commonly described as lacking bone. The molecular and developmental basis for this assertion is yet to be tested. Subperichondral tissues in the endoskeleton of some chondrichthyans display mineralization patterns and histological and molecular features of bone, thereby challenging the notion that extant chondrichthyans lack endoskeletal bone. Additionally, the chondrichthyan endoskeleton demonstrates some unique features and others that are potentially homologous with other vertebrates, including a polygonal mineralization pattern, a trabecular mineralization pattern, and an unconstricted perichordal sheath. Because of the basal phylogenetic position of chondrichthyans among all other extant vertebrates with a mineralized skeleton, developmental and molecular studies of chondrichthyans are critical to flesh out the evolution of vertebrate skeletal tissues, but only a handful of such studies have been carried out to date. This review discusses morphological and molecular features of chondrichthyan endoskeletal tissues and cell types, ultimately emphasizing how comparative embryology and transcriptomics can reveal homology of mineralized skeletal tissues (and their cell types) between chondrichthyans and other vertebrates.
Collapse
Affiliation(s)
| | - B. Frank Eames
- Department of Anatomy, Physiology, and Pharmacology, University of Saskatchewan, Saskatoon, SK, Canada
| |
Collapse
|
|
16
|
Krstić J, Mojsilović S, Mojsilović SS, Santibanez JF. Regulation of the mesenchymal stem cell fate by interleukin-17: Implications in osteogenic differentiation. World J Stem Cells 2021; 13:1696-1713. [PMID: 34909118 PMCID: PMC8641017 DOI: 10.4252/wjsc.v13.i11.1696] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 05/14/2021] [Accepted: 10/18/2021] [Indexed: 02/06/2023] Open
Abstract
Bone regeneration is a tightly regulated process that ensures proper repair and functionality after injury. The delicate balance between bone formation and resorption is governed by cytokines and signaling molecules released during the inflammatory response. Interleukin (IL)-17A, produced in the early phase of inflammation, influences the fate of osteoprogenitors. Due to their inherent capacity to differentiate into osteoblasts, mesenchymal stem/stromal cells (MSCs) contribute to bone healing and regeneration. This review presents an overview of IL-17A signaling and the leading cellular and molecular mechanisms by which it regulates the osteogenic differentiation of MSCs. The main findings demonstrating IL-17A’s influence on osteoblastogenesis are described. To this end, divergent information exists about the capacity of IL-17A to regulate MSCs’ osteogenic fate, depending on the tissue context and target cell type, along with contradictory findings in the same cell types. Therefore, we summarize the data showing both the pro-osteogenic and anti-osteogenic roles of IL-17, which may help in the understanding of IL-17A function in bone repair and regeneration.
Collapse
Affiliation(s)
- Jelena Krstić
- Gottfried Schatz Research Center, Medical University of Graz, Graz 8010, Austria
| | - Slavko Mojsilović
- Group for Hematology and Stem Cells, Institute for Medical Research, National Institute of Republic of Serbia, University of Belgrade, Belgrade 11129, Serbia
| | - Sonja S Mojsilović
- Group for Immunology, Institute for Medical Research, National Institute of Republic of Serbia, Belgrade 11129, Serbia
| | - Juan F Santibanez
- Group for Molecular Oncology, Institute for Medical Research, National Institute of Republic of Serbia, University of Belgrade, Belgrade 11000, Serbia
- Centro Integrativo de Biología y Química Aplicada, Universidad Bernardo O’Higgins, Chile 8370993, Chile
| |
Collapse
|
|
17
|
Hanusch B, Prediger M, Tuck SP, Walker J, McNally R, Datta HK. Bone turnover markers as determinants of bone density and fracture in men with distal forearm fractures: the pathogenesis examined in the Mr F study. Osteoporos Int 2021; 32:2267-2277. [PMID: 33990874 DOI: 10.1007/s00198-021-06001-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Accepted: 05/06/2021] [Indexed: 10/21/2022]
Abstract
UNLABELLED The pathogenesis for low-trauma wrist fractures in men is not fully understood. This study found that these men had evidence of significantly higher bone turnover compared with control subjects. Bone turnover markers were negative predictors of bone mineral density and were a predictor of fracture. INTRODUCTION Men with distal forearm fractures have reduced bone density, an increased risk of osteoporosis and of further fractures. The aim of this study was to investigate whether or not men with distal forearm fractures had evidence of altered bone turnover activity. METHODS Fifty eight men with low-trauma distal forearm fracture and 58 age-matched healthy control subjects were recruited. All subjects underwent a DXA scan of the forearm, both hips, and lumbar spine, biochemical investigations, and health questionnaires. Measurements of beta crosslaps (βCTX), procollagen type I N-terminal propeptide (PINP), sclerostin, Dickkopf-1 (Dkk1), and fibroblast growth factor 23 (FGF 23) were made. RESULTS Men with fracture had significantly higher PINP than controls at 39.2 ng/ml (SD 19.5) versus 33.4 ng/ml (SD13.1) (p<0.001). They also had significantly higher βCTX at 0.45 ng/ml (SD 0.21) versus 0.37 ng/ml (SD 0.17) (p= 0.037). Fracture subjects had significantly lower aBMD and PINP was a negative predictor of aBMD at the total hip and βCTX a negative predictor of forearm aBMD. Sclerostin was a positive predictor of aBMD at the lumbar spine and hip sites. Sex hormone binding globulin (SHBG) at 37nmol/L (SD 15.0) was lower in fracture cohort compared to 47.9 nmol/L (SD 19.2) (p=0.001) in control. Multiple regression revealed that the best model for prediction of fracture included SHBG, P1NP, and ultra-distal forearm aBMD. The likelihood of distal forearm fracture was decreased by 5.1% for each nmol/L increase in SHBH and by 1.4% for every mg/cm2 increase in ultra-distal forearm aBMD, but increased by 6.1 % for every ng/ml increase in P1NP. Men in the highest quartile of PINP had a significantly greater likelihood of distal forearm fracture than those in the lowest quartile. CONCLUSION The fracture group had significantly higher PINP and βCTX compared with the control group, and these markers were negative predictors of aBMD at the total hip and forearm sites, respectively. Sclerostin was a positive predictor of the variance of spinal and hip aBMD. Likelihood of forearm fracture was best predicted by a combination of SHBG, PINP, and ultra-distal forearm aBMD. Findings of such cross-sectional data should be treated with caution, as longitudinal studies would be required to confirm or refute them.
Collapse
Affiliation(s)
- B Hanusch
- Institute of Cellular Medicine, Newcastle University, Newcastle, Upon Tyne, UK
- James Cook University Hospital, Middlesbrough, UK
| | - M Prediger
- Institute of Cellular Medicine, Newcastle University, Newcastle, Upon Tyne, UK
- Blood Sciences, Royal Victoria Infirmary, Newcastle, Upon Tyne, UK
| | - S P Tuck
- Institute of Cellular Medicine, Newcastle University, Newcastle, Upon Tyne, UK.
- James Cook University Hospital, Middlesbrough, UK.
| | - J Walker
- James Cook University Hospital, Middlesbrough, UK
| | - R McNally
- Institute of Health and Society, Newcastle University, Newcastle, Upon Tyne, UK
| | - H K Datta
- Institute of Cellular Medicine, Newcastle University, Newcastle, Upon Tyne, UK
- James Cook University Hospital, Middlesbrough, UK
| |
Collapse
|
|
18
|
Influence of osteoporosis and mechanical loading on bone around osseointegrated dental implants: A rodent study. J Mech Behav Biomed Mater 2021; 123:104771. [PMID: 34438251 DOI: 10.1016/j.jmbbm.2021.104771] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 08/06/2021] [Accepted: 08/08/2021] [Indexed: 11/20/2022]
Abstract
This study aimed to evaluate the influence of estrogen deficiency and mechanical loading on bone around osseointegrated dental implants in a rat jaw model. The maxillary right first molars of 36 rats were extracted. One week later, the rats were divided into an unloaded group and a loaded group; short head implants and long head implants were inserted respectively. Nine weeks after implantation, the rats were further subjected to ovariectomy (OVX) or sham surgery. All animals were euthanized 21 weeks after OVX. Micro-computed tomography, histological and histomorphometrical evaluation were undertaken. Systemic bone mineral density and bone volume fraction decreased in OVX groups compared with the sham controls. Histomorphometrical observation indicated that unloaded OVX group showed significantly damaged osseointegration and bone loss versus the loaded OVX group. Both the bone density (BD) inside the peri-implant grooves and the percentage of bone-to-implant contact (BIC) were lower in the OVX groups than in the sham-surgery groups, although mechanical loading increased the BIC and BD in the loaded OVX group compared with the unloaded OVX group. An increased number of positive cells for tartrate-resistant acid phosphatase was observed in the OVX groups versus the sham controls. The percentage of sclerostin-positive osteocytes was lower under loaded compared with unloaded conditions in both the OVX groups and the sham controls. In conclusion, estrogen deficiency could be a risk factor for the long-term stability of osseointegrated implants, while mechanical loading could attenuate the negative influence of estrogen deficiency on bone formation and osseointegration.
Collapse
|
|
19
|
Abstract
Gravity determines shape of body tissue and affects the functions of life, both in plants and animals. The cellular response to gravity is an active process of mechanotransduction. Although plants and animals share some common mechanisms of gravity sensing in spite of their distant phylogenetic origin, each species has its own mechanism to sense and respond to gravity. In this review, we discuss current understanding regarding the mechanisms of cellular gravity sensing in plants and animals. Understanding gravisensing also contributes to life on Earth, e.g., understanding osteoporosis and muscle atrophy. Furthermore, in the current age of Mars exploration, understanding cellular responses to gravity will form the foundation of living in space.
Collapse
|
|
20
|
Linero C, Choi SJ. Effect of blood flow restriction during low-intensity resistance training on bone markers and physical functions in postmenopausal women. J Exerc Sci Fit 2021; 19:57-65. [PMID: 33293983 PMCID: PMC7683332 DOI: 10.1016/j.jesf.2020.09.001] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 07/20/2020] [Accepted: 09/11/2020] [Indexed: 11/23/2022] Open
Abstract
BACKGROUND The aim of this study was to investigate the effects of 12-week low intensity resistance training (RT) with blood flow restriction on bone mineral density (BMD), bone turnover markers (BTM), physical functions, and blood lactate concentration in postmenopausal women with osteoporosis or osteopenia. METHODS 26 study participants (56 ± 1.8yrs, T-score: -2.5 ± 0.7) were randomly assigned into Moderate to High-Intensity RT (MHIRT, n = 7), BFR combined with Low-Intensity RT (LIBFR, n = 7), Low-Intensity RT (LIRT, n = 6), or Control group (CON, n = 6). Exercise group performed leg press, leg extension, biceps curl, and triceps extension 3 times a week for 12 weeks. Training intensity were set at 60% of 1-repetition maximum (1-RM) for MHIRT, and at 30% of 1-RM for LIBFR and LIRT, and reset every 4 weeks for increasing intensity. RESULTS Lower, and upper limb 1-RM only increased in MHIRT (65%, p < 0.001), and LIBFR (40%, p < 0.05), while LIRT only showed increment on lower limb 1-RM (28%, p < 0.05). All exercise groups demonstrated significant increment on blood lactate concentration after training session (p < 0.001). However, LIBFR showed 2.7 folds higher increment than LIRT (p < 0.001). Although no changes were observed in MHIRT, LIBFR, and LIRT, CON showed significant decrease in BMD (p < 0.05). While, LIRT showed no responses on BTM, LIBFR significantly increased bone formation markers (P1NP) about 7.05 ng/ml (p < 0.05). Lastly, balance improvement was only found in MHIRT, and LIBFR (p < 0.05). CONCLUSION 12-week LIBFR can be implied as a safe, and effective method to improve muscle strength, P1NP, and balance similar to MHIRT in postmenopausal women with osteoporosis or osteopenia.
Collapse
Affiliation(s)
- Christian Linero
- Department of Sport and Health Sciences, Kyungsung University, Busan, South Korea
| | - Seung-Jun Choi
- Department of Sport and Health Sciences, Kyungsung University, Busan, South Korea
| |
Collapse
|
|
21
|
Lerebours C, Weinkamer R, Roschger A, Buenzli PR. Mineral density differences between femoral cortical bone and trabecular bone are not explained by turnover rate alone. Bone Rep 2020; 13:100731. [PMID: 33392366 PMCID: PMC7772649 DOI: 10.1016/j.bonr.2020.100731] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 10/12/2020] [Accepted: 10/25/2020] [Indexed: 11/24/2022] Open
Abstract
Bone mineral density distributions (BMDDs) are a measurable property of bone tissues that depends strongly on bone remodelling and mineralisation processes. These processes can vary significantly in health and disease and across skeletal sites, so there is high interest in analysing these processes from experimental BMDDs. Here, we propose a rigorous hypothesis-testing approach based on a mathematical model of mineral heterogeneity in bone due to remodelling and mineralisation, to help explain differences observed between the BMDD of human femoral cortical bone and the BMDD of human trabecular bone. Recent BMDD measurements show that femoral cortical bone possesses a higher bone mineral density, but a similar mineral heterogeneity around the mean compared to trabecular bone. By combining this data with the mathematical model, we are able to test whether this difference in BMDD can be explained by (i) differences in turnover rate; (ii) differences in osteoclast resorption behaviour; and (iii) differences in mineralisation kinetics between the two bone types. We find that accounting only for differences in turnover rate is inconsistent with the fact that both BMDDs have a similar spread around the mean, and that accounting for differences in osteoclast resorption behaviour leads to biologically inconsistent bone remodelling patterns. We conclude that the kinetics of mineral accumulation in bone matrix must therefore be different in femoral cortical bone and trabecular bone. Although both cortical and trabecular bone are made up of lamellar bone, the different mineralisation kinetics in the two types of bone point towards more profound structural differences than usually assumed.
Collapse
Affiliation(s)
- Chloé Lerebours
- School of Mathematical Sciences, Monash University, Clayton, Australia
| | - Richard Weinkamer
- Max Planck Institute of Colloids and Interfaces, Department of Biomaterials, Potsdam, Germany
| | - Andreas Roschger
- Max Planck Institute of Colloids and Interfaces, Department of Biomaterials, Potsdam, Germany.,Department of the Chemistry and Physics of Materials, Paris-Lodron University of Salzburg, Salzburg, Austria
| | - Pascal R Buenzli
- School of Mathematical Sciences, Queensland University of Technology, Brisbane, Australia
| |
Collapse
|
|
22
|
Wu GJ, Chen JT, Cherng YG, Chang CC, Liu SH, Chen RM. Genistein Improves Bone Healing via Triggering Estrogen Receptor Alpha-Mediated Expressions of Osteogenesis-Associated Genes and Consequent Maturation of Osteoblasts. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2020; 68:10639-10650. [PMID: 32897066 DOI: 10.1021/acs.jafc.0c02830] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
Osteoporosis-associated fractures may cause higher morbidity and mortality. Our previous study showed the effects of genistein, a phytoestrogen, on the induction of estrogen receptor alpha (ERα) gene expression and stimulation of osteoblast mineralization. In this study, rat calvarial osteoblasts and an animal bone defect model were used to investigate the effects of genistein on bone healing. Treatment with genistein caused a time-dependent increase in alkaline phosphatase (ALP) activity in rat osteoblasts. Levels of cytosolic and nuclear ERα significantly augmented following exposure to genistein. Subsequently, genistein elevated levels of ALP mRNA and protein in rat osteoblasts. Moreover, genistein induced other osteogenesis-associated osteocalcin and Runx2 mRNA and protein expressions. Knocking-down ERα using RNA interference concurrently inhibited genistein-induced Runx2, osteocalcin, and ALP mRNA expression. Attractively, administration of ICR mice suffering bone defects with genistein caused significant increases in the callus width, chondrocyte proliferation, and ALP synthesis. Results of microcomputed tomography revealed that administration of genistein increased trabecular bone numbers and improved the bone thickness and volume. This study showed that genistein can improve bone healing via triggering ERα-mediated osteogenesis-associated gene expressions and subsequent osteoblast maturation.
Collapse
Affiliation(s)
- Gong-Jhe Wu
- Department of Anesthesiology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan
- Department of Anesthesiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Jui-Tai Chen
- Department of Anesthesiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Yih-Giun Cherng
- Department of Anesthesiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Chuen-Chau Chang
- Department of Anesthesiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
- Anesthesiology and Health Policy Research Center, Taipei Medical University, Taipei 11031, Taiwan
| | - Shing-Hwa Liu
- Institute of Toxicology, College of Medicine, National Taiwan University, Taipei 10051, Taiwan
| | - Ruei-Ming Chen
- Anesthesiology and Health Policy Research Center, Taipei Medical University, Taipei 11031, Taiwan
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| |
Collapse
|
|
23
|
Reznikov N, Hoac B, Buss DJ, Addison WN, Barros NMT, McKee MD. Biological stenciling of mineralization in the skeleton: Local enzymatic removal of inhibitors in the extracellular matrix. Bone 2020; 138:115447. [PMID: 32454257 DOI: 10.1016/j.bone.2020.115447] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 05/14/2020] [Accepted: 05/20/2020] [Indexed: 12/12/2022]
Abstract
Biomineralization is remarkably diverse and provides myriad functions across many organismal systems. Biomineralization processes typically produce hardened, hierarchically organized structures usually having nanostructured mineral assemblies that are formed through inorganic-organic (usually protein) interactions. Calcium‑carbonate biomineral predominates in structures of small invertebrate organisms abundant in marine environments, particularly in shells (remarkably it is also found in the inner ear otoconia of vertebrates), whereas calcium-phosphate biomineral predominates in the skeletons and dentitions of both marine and terrestrial vertebrates, including humans. Reconciliation of the interplay between organic moieties and inorganic crystals in bones and teeth is a cornerstone of biomineralization research. Key molecular determinants of skeletal and dental mineralization have been identified in health and disease, and in pathologic ectopic calcification, ranging from small molecules such as pyrophosphate, to small membrane-bounded matrix vesicles shed from cells, and to noncollagenous extracellular matrix proteins such as osteopontin and their derived bioactive peptides. Beyond partly knowing the regulatory role of the direct actions of inhibitors on vertebrate mineralization, more recently the importance of their enzymatic removal from the extracellular matrix has become increasingly understood. Great progress has been made in deciphering the relationship between mineralization inhibitors and the enzymes that degrade them, and how adverse changes in this physiologic pathway (such as gene mutations causing disease) result in mineralization defects. Two examples of this are rare skeletal diseases having osteomalacia/odontomalacia (soft bones and teeth) - namely hypophosphatasia (HPP) and X-linked hypophosphatemia (XLH) - where inactivating mutations occur in the gene for the enzymes tissue-nonspecific alkaline phosphatase (TNAP, TNSALP, ALPL) and phosphate-regulating endopeptidase homolog X-linked (PHEX), respectively. Here, we review and provide a concept for how existing and new information now comes together to describe the dual nature of regulation of mineralization - through systemic mineral ion homeostasis involving circulating factors, coupled with molecular determinants operating at the local level in the extracellular matrix. For the local mineralization events in the extracellular matrix, we present a focused concept in skeletal mineralization biology called the Stenciling Principle - a principle (building upon seminal work by Neuman and Fleisch) describing how the action of enzymes to remove tissue-resident inhibitors defines with precision the location and progression of mineralization.
Collapse
Affiliation(s)
- N Reznikov
- Object Research Systems Inc., 760 St. Paul West, Montreal, Quebec H3C 1M4, Canada.
| | - B Hoac
- Faculty of Dentistry, McGill University, 3640 University St., Montreal, Quebec H3A 0C7, Canada
| | - D J Buss
- Department of Anatomy and Cell Biology, McGill University, 3640 University St., Montreal, Quebec H3A 0C7, Canada
| | - W N Addison
- Department of Molecular Signaling and Biochemistry, Kyushu Dental University, 2-6-1 Manazuru, Kokurakita-ku, Kitakyushu, Fukuoka, Japan
| | - N M T Barros
- Departamento de Biofísica, São Paulo, Departamento de Ciências Biológicas, Universidade Federal de São Paulo, Diadema, Brazil
| | - M D McKee
- Faculty of Dentistry, McGill University, 3640 University St., Montreal, Quebec H3A 0C7, Canada; Department of Anatomy and Cell Biology, McGill University, 3640 University St., Montreal, Quebec H3A 0C7, Canada.
| |
Collapse
|
|
24
|
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: 100] [Impact Index Per Article: 20.0] [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.
Collapse
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
| |
Collapse
|
|
25
|
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.
Collapse
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.
| |
Collapse
|
|
26
|
Langdahl BL. Overview of treatment approaches to osteoporosis. Br J Pharmacol 2020; 178:1891-1906. [PMID: 32060897 DOI: 10.1111/bph.15024] [Citation(s) in RCA: 103] [Impact Index Per Article: 20.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2019] [Revised: 01/16/2020] [Accepted: 01/31/2020] [Indexed: 12/28/2022] Open
Abstract
Efficient therapies are available for the treatment of osteoporosis. Anti-resorptive therapies, including bisphosphonates and denosumab, increase bone mineral density (BMD) and reduce the risk of fractures by 20-70%. Bone-forming or dual-action treatments stimulate bone formation and increase BMD more than the anti-resorptive therapies. Two studies have demonstrated that these treatments are superior to anti-resorptives in preventing fractures in patients with severe osteoporosis. Bone-forming or dual-action treatments should be followed by anti-resorptive treatment to maintain the fracture risk reduction. The BMD gains seen with bone-forming and dual-action treatments are greater in treatment-naïve patients compared to patients pretreated with anti-resorptive treatments. However, the antifracture efficacy seems to be preserved. Treatment failure will often lead to switch of treatment from orally to parentally administrated anti-resorptives treatment or from anti-resorptive to bone-forming or dual-action treatment. Osteoporosis is a chronic condition and therefore needs a long-term management plan with a personalized approach to treatment. LINKED ARTICLES: This article is part of a themed issue on The molecular pharmacology of bone and cancer-related bone diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.9/issuetoc.
Collapse
Affiliation(s)
- Bente L Langdahl
- Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
| |
Collapse
|
|
27
|
Chen X, Wang M, Chen F, Wang J, Li X, Liang J, Fan Y, Xiao Y, Zhang X. Correlations between macrophage polarization and osteoinduction of porous calcium phosphate ceramics. Acta Biomater 2020; 103:318-332. [PMID: 31857257 DOI: 10.1016/j.actbio.2019.12.019] [Citation(s) in RCA: 83] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Revised: 12/09/2019] [Accepted: 12/13/2019] [Indexed: 01/08/2023]
Abstract
The host immune response is critical for in situ osteogenesis, but correlations between local inflammatory reactions and biomaterial osteoinduction are still poorly understood. This study used a murine intramuscular implantation model to demonstrate that calcium phosphate ceramics with different phase compositions exhibited divergent osteoinductivities. The osteoinductive potential of each ceramic was closely associated with the immunomodulatory capacity of the material, and especially with the regulation of macrophage polarization and functional status. Biphasic calcium phosphate (BCP) ceramics with superior osteoinductive potential enhanced the fraction of CD206+ M2 macrophages, up-regulated expression of M2 phenotypic markers in vitro, and increased the ARG+ M2 population in vivo. This suggested that BCP ceramics could ameliorate long-term inflammation and build a pro-osteogenic microenvironment. However, β-tricalcium phosphate (β-TCP) ceramics with no obvious osteoinductivity increased the fraction of CCR7+ M1 macrophages, promoted the secretion of M1 phenotypic markers in vitro, and maintained a high proportion of iNOS+ M1 macrophages in vivo. It indicated that β-TCP ceramics could exacerbate inflammation and inhibit ectopic bone formation. Hydroxyapatite ceramics with an intermediate osteoinductivity exhibited a moderate amount of both M1 and M2 macrophages. These findings highlight the critical role of macrophage polarization in biomaterial-dependent osteoinduction, which not only deepens our understanding of osteoinductive mechanisms but also provides a strategy to design bone substitutes by endowing materials with the proper immunomodulatory abilities to achieve the desired clinic performance. STATEMENT OF SIGNIFICANCE: Calcium phosphate (CaP) ceramics with osteoinductive capacities are able to induce ectopic bone formation in non-osseous sites. However, its underlying mechanism is largely unknown. Previous studies have demonstrated an indispensable role of macrophages in osteogenesis, inspiring us that local inflammatory reaction may affect material-dependent osteoinduction. This study indicated that CaP ceramics with different phase composition could present divergent osteoinductive capacities through modulating polarization and functional status of macrophages, as biphasic calcium phosphate with potent osteoinductivity ameliorated long-term inflammation and induced a healing-associated M2 phenotype to initiate bone formation. These findings not only get an insight into the mechanism of CaP-involved osteoinduction, but also help the design of tissue-inducing implants by endowing biomaterials with proper immunomodulatory ability.
Collapse
Affiliation(s)
- Xuening Chen
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, China
| | - Menglu Wang
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, China
| | - Fuying Chen
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, China
| | - Jing Wang
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, China
| | - Xiangfeng Li
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, China
| | - Jie Liang
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, China.
| | - Yujiang Fan
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, China
| | - Yumei Xiao
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, China.
| | - Xingdong Zhang
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, China
| |
Collapse
|
|
28
|
Human osteocyte expression of Nerve Growth Factor: The effect of Pentosan Polysulphate Sodium (PPS) and implications for pain associated with knee osteoarthritis. PLoS One 2019; 14:e0222602. [PMID: 31557169 PMCID: PMC6762051 DOI: 10.1371/journal.pone.0222602] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2019] [Accepted: 09/03/2019] [Indexed: 01/05/2023] Open
Abstract
Pentosan polysulphate sodium (PPS) is a promising therapeutic agent for blocking knee pain in individuals with knee osteoarthritis (KOA). The mode of action of PPS in this context is unknown. We hypothesised that the osteocyte, being the principal cell type in the sub-chondral bone, was capable of expressing the pain mediator Nerve Growth Factor (NGF), and that this may be altered in the presence of PPS. We tested the expression of NGF and the response to PPS in the presence or absence of the proinflammatory cytokine tumour necrosis factor-alpha (TNFα), in human osteocytes. For this we differentiated human primary osteoblasts grown from subchondral bone obtained at primary knee arthroplasty for KOA to an osteocyte-like stage over 28d. We also tested NGF expression in fresh osteocytes obtained by sequential digestion from KOA bone and by immunofluorescence in KOA bone sections. We demonstrate for the first time the production and secretion of NGF/proNGF by this cell type derived from patients with KOA, implicating osteocytes in the pain response in this pathological condition and possibly others. PPS inhibited TNFα-induced levels of proNGF secretion and TNFα induced NGF mRNA expression. Together, this provides evidence that PPS may act to suppress the release of NGF in the subchondral bone to ameliorate pain associated with knee osteoarthritis.
Collapse
|
|
29
|
Sølling ASK, Harsløf T, Langdahl B. Current Status of Bone-Forming Therapies for the Management of Osteoporosis. Drugs Aging 2019; 36:625-638. [DOI: 10.1007/s40266-019-00675-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
|
|
30
|
Herbert AJ, Williams AG, Hennis PJ, Erskine RM, Sale C, Day SH, Stebbings GK. The interactions of physical activity, exercise and genetics and their associations with bone mineral density: implications for injury risk in elite athletes. Eur J Appl Physiol 2019; 119:29-47. [PMID: 30377780 PMCID: PMC6342881 DOI: 10.1007/s00421-018-4007-8] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2018] [Accepted: 10/04/2018] [Indexed: 01/30/2023]
Abstract
Low bone mineral density (BMD) is established as a primary predictor of osteoporotic risk and can also have substantial implications for athlete health and injury risk in the elite sporting environment. BMD is a highly multi-factorial phenotype influenced by diet, hormonal characteristics and physical activity. The interrelationships between such factors, and a strong genetic component, suggested to be around 50-85% at various anatomical sites, determine skeletal health throughout life. Genome-wide association studies and case-control designs have revealed many loci associated with variation in BMD. However, a number of the candidate genes identified at these loci have no known associated biological function or have yet to be replicated in subsequent investigations. Furthermore, few investigations have considered gene-environment interactions-in particular, whether specific genes may be sensitive to mechanical loading from physical activity and the outcome of such an interaction for BMD and potential injury risk. Therefore, this review considers the importance of physical activity on BMD, genetic associations with BMD and how subsequent investigation requires consideration of the interaction between these determinants. Future research using well-defined independent cohorts such as elite athletes, who experience much greater mechanical stress than most, to study such phenotypes, can provide a greater understanding of these factors as well as the biological underpinnings of such a physiologically "extreme" population. Subsequently, modification of training, exercise or rehabilitation programmes based on genetic characteristics could have substantial implications in both the sporting and public health domains once the fundamental research has been conducted successfully.
Collapse
Affiliation(s)
- Adam J. Herbert
- Department of Sport and Exercise, School of Health Sciences, Faculty of Health, Education and Life Sciences, Birmingham City University, Birmingham, UK
| | - Alun G. Williams
- Sports Genomics Laboratory, Manchester Metropolitan University, Cheshire Campus, Crewe Green Road, Crewe, CW1 5DU UK
- Institute of Sport, Exercise and Health, University College London, Tottenham Court Road, London, W17 7HA UK
| | - Philip J. Hennis
- Musculoskeletal Physiology Research Group, Sport, Health and Performance Enhancement Research Centre, Nottingham Trent University, Clifton Lane, Clifton, Nottingham, NG11 8NS UK
| | - Robert M. Erskine
- Research Institute for Sport and Exercise Sciences, Liverpool John Moores University, Byrom Street, Liverpool, L3 3AF UK
- Institute of Sport, Exercise and Health, University College London, Tottenham Court Road, London, W17 7HA UK
| | - Craig Sale
- Musculoskeletal Physiology Research Group, Sport, Health and Performance Enhancement Research Centre, Nottingham Trent University, Clifton Lane, Clifton, Nottingham, NG11 8NS UK
| | - Stephen H. Day
- Department of Biomedical Science & Physiology, School of Sciences, Faculty of Science and Engineering, University of Wolverhampton, Wolverhampton, UK
| | - Georgina K. Stebbings
- Sports Genomics Laboratory, Manchester Metropolitan University, Cheshire Campus, Crewe Green Road, Crewe, CW1 5DU UK
| |
Collapse
|
|
31
|
Abstract
Vitamin D is a principal factor required for mineral and skeletal homeostasis. Vitamin D deficiency during development causes rickets and in adults can result in osteomalacia and increased risk of fracture. 1,25-Dihydroxyvitamin D3 (1,25(OH)2D3), the hormonally active form of vitamin D, is responsible for the biological actions of vitamin D which are mediated by the vitamin D receptor (VDR). Mutations in the VDR result in early-onset rickets and low calcium and phosphate, indicating the essential role of 1,25(OH)2D3/VDR signaling in the regulation of mineral homeostasis and skeletal health. This chapter summarizes our current understanding of the production of the vitamin D endocrine hormone, 1,25(OH)2D3, and the actions of 1,25(OH)2D3 which result in the maintenance of skeletal homeostasis. The primary role of 1,25(OH)2D3 is to increase calcium absorption from the intestine and thus to increase the availability of calcium for bone mineralization. Specific actions of 1,25(OH)2D3 on the intestine, kidney, and bone needed to maintain calcium homeostasis are summarized, and the impact of vitamin D status on bone health is discussed.
Collapse
Affiliation(s)
- Sylvia Christakos
- Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers New Jersey Medical School, Newark, NJ, USA.
| | - Shanshan Li
- Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers New Jersey Medical School, Newark, NJ, USA
| | - Jessica DeLa Cruz
- Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers New Jersey Medical School, Newark, NJ, USA
| | - Lieve Verlinden
- Clinical and Experimental Medicine and Endocrinology, KU Leuven, Leuven, Belgium
| | - Geert Carmeliet
- Clinical and Experimental Medicine and Endocrinology, KU Leuven, Leuven, Belgium
| |
Collapse
|
|
32
|
Buenzli PR, Lerebours C, Roschger A, Roschger P, Weinkamer R. Late stages of mineralization and their signature on the bone mineral density distribution. Connect Tissue Res 2018; 59:74-80. [PMID: 29745820 DOI: 10.1080/03008207.2018.1424149] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
PURPOSE Experimental measurements of bone mineral density distributions (BMDDs) enable a determination of secondary mineralization kinetics in bone, but the maximum degree of mineralization and how this maximum is approached remain uncertain. We thus test computationally different hypotheses on late stages of bone mineralization by simulating BMDDs in low-turnover conditions. MATERIALS AND METHODS An established computational model of the BMDD that accounts for mineralization and remodeling processes was extended to limit mineralization to various maximum calcium capacities of bone. Simulated BMDDs obtained by reducing turnover rate from the reference trabecular BMDD under different assumptions on late stage mineralization kinetics were compared with experimental BMDDs of low-turnover bone. RESULTS Simulations show that an abrupt stopping of mineralization near a maximum calcium capacity induces a pile-up of minerals in the BMDD statistics that is not observed experimentally. With a smooth decrease of mineralization rate, imposing low maximum calcium capacities helps to match peak location and width of simulated low-turnover BMDDs with peak location and width of experimental BMDDs, but results in a distinctive asymmetric peak shape. No tuning of turnover rate and maximum calcium capacity was able to explain the differences found in experimental BMDDs between trabecular bone (high turnover) and femoral cortical bone (low turnover). CONCLUSIONS Secondary mineralization in human bone does not stop abruptly, but continues slowly up to a calcium content greater than 30 wt% Ca. The similar mineral heterogeneity seen in trabecular and femoral cortical bones at different peak locations was unexplained by the turnover differences tested.
Collapse
Affiliation(s)
- Pascal R Buenzli
- a School of Mathematical Sciences , Queensland University of Technology , Brisbane , Australia.,b School of Mathematical Sciences , Monash University , Clayton , Australia
| | - Chloé Lerebours
- b School of Mathematical Sciences , Monash University , Clayton , Australia
| | - Andreas Roschger
- c Department of Biomaterials , Max Planck Institute of Colloids and Interfaces , Potsdam , Germany
| | - Paul Roschger
- d Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of WGKK and AUVA Trauma Centre Meidling , 1st Medical Department, Hanusch Hospital , Vienna , Austria
| | - Richard Weinkamer
- c Department of Biomaterials , Max Planck Institute of Colloids and Interfaces , Potsdam , Germany
| |
Collapse
|
|
33
|
Study of Osteocyte Behavior by High-Resolution Intravital Imaging Following Photo-Induced Ischemia. Molecules 2018; 23:molecules23112874. [PMID: 30400346 PMCID: PMC6278482 DOI: 10.3390/molecules23112874] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2018] [Revised: 10/26/2018] [Accepted: 10/28/2018] [Indexed: 11/17/2022] Open
Abstract
Ischemic injuries and local hypoxia can result in osteocytes dysfunction and play a key role in the pathogenesis of avascular osteonecrosis. Conventional imaging techniques including magnetic resonance imaging (MRI) and computed tomography (CT) can reveal structural and functional changes within bony anatomy; however, characterization of osteocyte behavioral dynamics in the setting of osteonecrosis at the single cell resolution is limited. Here, we demonstrate an optical approach to study real-time osteocyte functions in vivo. Using nicotinamide adenine dinucleotide (NADH) as a biomarker for metabolic dynamics in osteocytes, we showed that NADH level within osteocytes transiently increase significantly after local ischemia through non-invasive photo-induced thrombosis of afferent arterioles followed by a steady decline. Our study presents a non-invasive optical approach to study osteocyte behavior through the modulation of local environmental conditions. Thus it provides a powerful toolkit to study cellular processes involved in bone pathologies in vivo.
Collapse
|
|
34
|
Dedic C, Hung TS, Shipley AM, Maeda A, Gardella T, Miller AL, Divieti Pajevic P, Kunkel JG, Rubinacci A. Calcium fluxes at the bone/plasma interface: Acute effects of parathyroid hormone (PTH) and targeted deletion of PTH/PTH-related peptide (PTHrP) receptor in the osteocytes. Bone 2018; 116:135-143. [PMID: 30053608 PMCID: PMC6158063 DOI: 10.1016/j.bone.2018.07.020] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Revised: 07/20/2018] [Accepted: 07/24/2018] [Indexed: 01/10/2023]
Abstract
Calcium ion concentration ([Ca2+]) in the systemic extracellular fluid, ECF-[Ca2+], is maintained around a genetically predetermined set-point, which combines the operational level of the kidney and bone/ECF interfaces. The ECF-[Ca2+] is maintained within a narrow oscillation range by the regulatory action of Parathyroid Hormone (PTH), Calcitonin, FGF-23, and 1,25(OH)2D3. This model implies two correction mechanisms, i.e. tubular Ca2+ reabsorption and osteoclast Ca2+ resorption. Although their alterations have an effect on the ECF-[Ca2+] maintenance, they cannot fully account for rapid correction of the continuing perturbations of plasma [Ca2+], which occur daily in life. The existence of Ca2+ fluxes at quiescent bone surfaces fulfills the role of a short-term error correction mechanism in Ca2+ homeostasis. To explore the hypothesis that PTH regulates the cell system responsible for the fast Ca2+ fluxes at the bone/ECF interface, we have performed direct real-time measurements of Ca2+ fluxes at the surface of ex-vivo metatarsal bones maintained in physiological conditions mimicking ECF, and exposed to PTH. To further characterize whether the PTH receptor on osteocytes is a critical component of the minute-to-minute ECF-[Ca2+] regulation, metatarsal bones from mice lacking the PTH receptor in these cells were tested ex vivo for rapid Ca2+ exchange. We performed direct real-time measurements of Ca2+ fluxes and concentration gradients by a scanning ion-selective electrode technique (SIET). To validate ex vivo measurements, we also evaluated acute calcemic response to PTH in vivo in mice lacking PTH receptors in osteocytes vs littermate controls. Our data demonstrated that Ca2+ fluxes at the bone-ECF interface in excised bones as well as acute calcemic response in the short-term were unaffected by PTH exposure and its signaling through its receptor in osteocytes. Rapid minute-to-minute regulation of the ECF-[Ca2+] was found to be independent of PTH actions on osteocytes. Similarly, mice lacking PTH receptor in osteocytes, responded to PTH challenge with similar calcemic increases.
Collapse
Affiliation(s)
- Christopher Dedic
- Molecular and Cell Biology, Goldman School of Dental Medicine, Boston University, Boston, MA, USA
| | - Tin Shing Hung
- Division of Life Sciences, State Key Laboratory for Molecular Neuroscience, HKUST, Hong Kong, China
| | | | - Akira Maeda
- Endocrine Unit, Massachusetts General Hospital, Boston, USA; Chugai Pharmaceutical, Japan
| | | | - Andrew L Miller
- Division of Life Sciences, State Key Laboratory for Molecular Neuroscience, HKUST, Hong Kong, China
| | - Paola Divieti Pajevic
- Molecular and Cell Biology, Goldman School of Dental Medicine, Boston University, Boston, MA, USA
| | - Joseph G Kunkel
- Pickus Center for Biomedical Research, University of New England, Biddeford, ME, USA
| | - Alessandro Rubinacci
- Bone Metabolism Unit, Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milano, Italy.
| |
Collapse
|
|
35
|
Toscani D, Bolzoni M, Ferretti M, Palumbo C, Giuliani N. Role of Osteocytes in Myeloma Bone Disease: Anti-sclerostin Antibody as New Therapeutic Strategy. Front Immunol 2018; 9:2467. [PMID: 30410490 PMCID: PMC6209728 DOI: 10.3389/fimmu.2018.02467] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2018] [Accepted: 10/05/2018] [Indexed: 11/16/2022] Open
Abstract
Osteocytes are terminally differentiated cells of the osteoblast lineage. They are involved in the regulation of bone remodeling by increasing osteoclast formation or decreasing bone formation by the secretion of the osteoblast inhibitor sclerostin. Monoclonal antibody anti-sclerostin, Romosozumab, has been developed and tested in clinical trials in patients with osteoporosis. In the last years, the role of osteocytes in the development of osteolytic bone lesions that occurs in multiple myeloma, have been underlined. Myeloma cells increase osteocyte death through the up-regulation of both apoptosis and autophagy that, in turn, triggers osteoclast formation, and activity. When compared to healthy controls, myeloma patients with bone disease have higher osteocyte cell death, but the treatment with proteasome inhibitor bortezomib has been shown to maintain osteocyte viability. In preclinical mouse models of multiple myeloma, treatment with blocking anti-sclerostin antibody increased osteoblast numbers and bone formation rate reducing osteolytic bone lesions. Moreover, the combination of anti-sclerostin antibody and the osteoclast inhibitor zoledronic acid increased bone mass and fracture resistance synergistically. However, anti-sclerostin antibody did not affect tumor burden in vivo or the efficacy of anti-myeloma drugs in vitro. Nevertheless, the combination therapy of anti-sclerostin antibody and the proteasome inhibitor carfilzomib, displayed potent anti-myeloma activity as well as positive effects on bone disease in vivo. In conclusion, all these data suggest that osteocytes are involved in myeloma bone disease and may be considered a novel target for the use of antibody-mediated anti-sclerostin therapy also in multiple myeloma patients.
Collapse
Affiliation(s)
- Denise Toscani
- Department Medicine and Surgery, University of Parma, Parma, Italy
| | - Marina Bolzoni
- Department Medicine and Surgery, University of Parma, Parma, Italy
| | - Marzia Ferretti
- Department of Biomedical, Metabolic and Neural Sciences, Human Morphology Section, University of Modena and Reggio Emilia, Modena, Italy
| | - Carla Palumbo
- Department of Biomedical, Metabolic and Neural Sciences, Human Morphology Section, University of Modena and Reggio Emilia, Modena, Italy
| | - Nicola Giuliani
- Department Medicine and Surgery, University of Parma, Parma, Italy
| |
Collapse
|
|
36
|
Langdahl BL, Andersen JD. Treatment of Osteoporosis: Unmet Needs and Emerging Solutions. J Bone Metab 2018; 25:133-140. [PMID: 30237992 PMCID: PMC6135648 DOI: 10.11005/jbm.2018.25.3.133] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Revised: 08/15/2018] [Accepted: 08/16/2018] [Indexed: 01/07/2023] Open
Abstract
Efficient therapies are available for the treatment of osteoporosis, however, there are still unmet needs. Anti-resorptive therapies only increase bone mineral density to a certain extent and reduce the risk of non-vertebral fractures by 20%, only one anabolic option is available in most parts of the world-the effect of which levels off over time, and the evidence for combination therapy targeting both resorption and formation is limited. In addition, identification and treatment of patients with high and imminent fracture risk following a recent fracture and long-term adherence to treatment are 2 other very prominent challenges to the management of osteoporosis. The current review will focus on emerging osteoporosis treatments and optimized use of the existing treatments that may help overcome the currently unmet needs in the management of osteoporosis.
Collapse
Affiliation(s)
- Bente Lomholt Langdahl
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Jane Dahl Andersen
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
| |
Collapse
|
|
37
|
Heni H, Ebner JK, Schmidt G, Aktories K, Orth JHC. Involvement of Osteocytes in the Action of Pasteurella multocida Toxin. Toxins (Basel) 2018; 10:toxins10080328. [PMID: 30104531 PMCID: PMC6115833 DOI: 10.3390/toxins10080328] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2018] [Revised: 08/06/2018] [Accepted: 08/08/2018] [Indexed: 01/24/2023] Open
Abstract
Pasteurella multocida toxin (PMT) causes progressive atrophic rhinitis with severe turbinate bone degradation in pigs. It has been reported that the toxin deamidates and activates heterotrimeric G proteins, resulting in increased differentiation of osteoclasts and blockade of osteoblast differentiation. So far, the action of PMT on osteocytes, which is the most abundant cell type in bone tissue, is not known. In MLO-Y4 osteocytes, PMT deamidated heterotrimeric G proteins, resulting in loss of osteocyte dendritic processes, stress fiber formation, cell spreading and activation of RhoC but not of RhoA. Moreover, the toxin caused processing of membrane-bound receptor activator of NF-κB ligand (RANKL) to release soluble RANKL and enhanced the secretion of osteoclastogenic TNF-α. In a co-culture model of osteocytes and bone marrow cells, PMT-induced osteoclastogenesis was largely increased as compared to the mono-culture model. The enhancement of osteoclastogenesis observed in the co-culture was blocked by sequestering RANKL with osteoprotegerin and by an antibody against TNF-α indicating involvement of release of the osteoclastogenic factors from osteocytes. Data support the crucial role of osteocytes in bone metabolism and osteoclastogenesis and identify osteocytes as important target cells of PMT in progressive atrophic rhinitis.
Collapse
Affiliation(s)
- Hannah Heni
- Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Medizinische Fakultät, Albert-Ludwigs-Universität Freiburg, Albertstr. 25, 79104 Freiburg, Germany.
- Hermann-Staudinger-Graduiertenschule, Universität Freiburg, 79104 Freiburg, Germany.
| | - Julia K Ebner
- Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Medizinische Fakultät, Albert-Ludwigs-Universität Freiburg, Albertstr. 25, 79104 Freiburg, Germany.
- Spemann Graduate School of Biology and Medicine (SGBM), Universität Freiburg, 79104 Freiburg, Germany.
- Faculty of Biology, Universität Freiburg, 79104 Freiburg, Germany.
| | - Gudula Schmidt
- Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Medizinische Fakultät, Albert-Ludwigs-Universität Freiburg, Albertstr. 25, 79104 Freiburg, Germany.
| | - Klaus Aktories
- Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Medizinische Fakultät, Albert-Ludwigs-Universität Freiburg, Albertstr. 25, 79104 Freiburg, Germany.
- BIOSS Centre for Biological Signalling Studies, Universität Freiburg, 79104 Freiburg, Germany.
| | - Joachim H C Orth
- Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Medizinische Fakultät, Albert-Ludwigs-Universität Freiburg, Albertstr. 25, 79104 Freiburg, Germany.
| |
Collapse
|
|
38
|
Liu DM, Mosialou I, Liu JM. Bone: Another potential target to treat, prevent and predict diabetes. Diabetes Obes Metab 2018; 20:1817-1828. [PMID: 29687585 DOI: 10.1111/dom.13330] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2018] [Revised: 04/16/2018] [Accepted: 04/18/2018] [Indexed: 12/30/2022]
Abstract
Type 2 diabetes mellitus is now a worldwide health problem with increasing prevalence. Mounting efforts have been made to treat, prevent and predict this chronic disease. In recent years, increasing evidence from mice and clinical studies suggests that bone-derived molecules modulate glucose metabolism. This review aims to summarize our current understanding of the interplay between bone and glucose metabolism and to highlight potential new means of therapeutic intervention. The first molecule recognized as a link between bone and glucose metabolism is osteocalcin (OCN), which functions in its active form, that is, undercarboxylated OCN (ucOC). ucOC acts in promoting insulin expression and secretion, facilitating insulin sensitivity, and favouring glucose and fatty acid uptake and utilization. A second bone-derived molecule, lipocalin2, functions in suppressing appetite in mice through its action on the hypothalamus. Osteocytes, the most abundant cells in bone matrix, are suggested to act on the browning of white adipose tissue and energy expenditure through secretion of bone morphogenetic protein 7 and sclerostin. The involvement of bone resorption in glucose homeostasis has also been examined. However, there is evidence indicating the implication of the receptor activator of nuclear factor κ-B ligand, neuropeptide Y, and other known and unidentified bone-derived factors that function in glucose homeostasis. We summarize recent advances and the rationale for treating, preventing and predicting diabetes by skeleton intervention.
Collapse
Affiliation(s)
- Dong-Mei Liu
- Department of Rheumatology, ZhongShan Hospital, FuDan University, Shanghai, China
| | - Ioanna Mosialou
- Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University, New York, New York
| | - Jian-Min Liu
- Department of Endocrine and Metabolic Diseases, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Rui-jin Hospital, Shanghai Jiao-tong University School of Medicine, Shanghai Institute of Endocrine and Metabolic Diseases, Shanghai, China
| |
Collapse
|
|
39
|
Yan Z, Wang P, Wu J, Feng X, Cai J, Zhai M, Li J, Liu X, Jiang M, Luo E, Jing D. Fluid shear stress improves morphology, cytoskeleton architecture, viability, and regulates cytokine expression in a time-dependent manner in MLO-Y4 cells. Cell Biol Int 2018; 42:1410-1422. [DOI: 10.1002/cbin.11032] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2018] [Accepted: 07/13/2018] [Indexed: 12/19/2022]
Affiliation(s)
- Zedong Yan
- Department of Biomedical Engineering; Fourth Military Medical University; Xi'an China
| | - Pan Wang
- Department of Biomedical Engineering; Fourth Military Medical University; Xi'an China
| | - Junjie Wu
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Clinical Research Center for Oral Diseases; Department of Orthodontics; School of Stomatology; Fourth Military Medical University; Xi'an China
| | - Xue Feng
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Clinical Research Center for Oral Diseases; Department of Orthodontics; School of Stomatology; Fourth Military Medical University; Xi'an China
| | - Jing Cai
- College of Basic Medicine; Shaanxi University of Chinese Medicine; Xianyang China
| | - Mingming Zhai
- Department of Biomedical Engineering; Fourth Military Medical University; Xi'an China
| | - Juan Li
- Department of Neurosurgery; Xijing Hospital; Fourth Military Medical University; Xi'an China
| | - Xiyu Liu
- Department of Biomedical Engineering; Fourth Military Medical University; Xi'an China
| | - Maogang Jiang
- Department of Biomedical Engineering; Fourth Military Medical University; Xi'an China
| | - Erping Luo
- Department of Biomedical Engineering; Fourth Military Medical University; Xi'an China
| | - Da Jing
- Department of Biomedical Engineering; Fourth Military Medical University; Xi'an China
| |
Collapse
|
|
40
|
Rolvien T, Vom Scheidt A, Stockhausen KE, Milovanovic P, Djonic D, Hubert J, Hawellek T, Wacker A, Jebens V, Püschel K, Zimmermann EA, Djuric M, Amling M, Busse B. Inter-site variability of the osteocyte lacunar network in the cortical bone underpins fracture susceptibility of the superolateral femoral neck. Bone 2018; 112:187-193. [PMID: 29679732 DOI: 10.1016/j.bone.2018.04.018] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2018] [Revised: 04/02/2018] [Accepted: 04/18/2018] [Indexed: 12/31/2022]
Abstract
BACKGROUND The osteocytic lacunar network is considered to be an integral player in the regulation of bone homeostasis, and reduction in osteocytes is associated with reduced bone strength. Here, we analyzed site-specific patterns in osteocyte characteristics and matrix composition in the cortical compartment of the femoral neck to reveal the structural basis of its fragility. METHODS Cross-sections of the human femoral neck - one of the most common fracture sites - were acquired from 12 female cadavers (age 34-86 years) and analyzed with backscattered scanning electron microscopy and high-resolution micro-computed tomography (μ-CT). The 2D/3D density and size of the osteocyte lacunae as well as bone mineral density distribution (BMDD) were measured in two regions subject to different biomechanical loads in vivo: the inferomedial (medial) region (habitually highly loaded in compression) and the superolateral (lateral) region (lower habitual loading intensity). Using quantitative polarized light microscopy, collagen fiber orientation was quantified in these two regions, accordingly. RESULTS In 2D measurements, the inferomedial region displayed lower mineralization heterogeneity, 19% higher osteocyte lacunar density (p = 0.005), but equal lacunar size compared to the superolateral region. 3D measurements confirmed a significantly higher osteocyte lacunar density in the inferomedial region (p = 0.015). Osteocyte lacunar density decreased in aged individuals, and inter-site differences were reduced. Site-specific osteocyte characteristics were not accompanied by changes in collagen fiber orientation. CONCLUSIONS Since osteocyte characteristics may provide valuable insights into bone mechanical competence, the variations in osteocyte properties might reflect the increased fracture susceptibility of the superolateral neck.
Collapse
Affiliation(s)
- Tim Rolvien
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Lottestrasse 59, 22529 Hamburg, Germany; Department of Orthopedics, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany
| | - Annika Vom Scheidt
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Lottestrasse 59, 22529 Hamburg, Germany
| | - Kilian E Stockhausen
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Lottestrasse 59, 22529 Hamburg, Germany
| | - Petar Milovanovic
- Laboratory for Anthropology, Institute of Anatomy, Faculty of Medicine, University of Belgrade, Dr Subotica 4/2, 11000 Belgrade, Serbia
| | - Danijela Djonic
- Laboratory for Anthropology, Institute of Anatomy, Faculty of Medicine, University of Belgrade, Dr Subotica 4/2, 11000 Belgrade, Serbia
| | - Jan Hubert
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Lottestrasse 59, 22529 Hamburg, Germany; Department of Orthopedics, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany
| | - Thelonius Hawellek
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Lottestrasse 59, 22529 Hamburg, Germany; Department of Orthopedics, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany
| | - Alexander Wacker
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Lottestrasse 59, 22529 Hamburg, Germany; Department of Orthopedics, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany
| | - Volker Jebens
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Lottestrasse 59, 22529 Hamburg, Germany; Department of Orthopedics, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany
| | - Klaus Püschel
- Department of Legal Medicine, University Medical Center Hamburg-Eppendorf, Butenfeld 34, 22529 Hamburg, Germany
| | - Elizabeth A Zimmermann
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Lottestrasse 59, 22529 Hamburg, Germany
| | - Marija Djuric
- Laboratory for Anthropology, Institute of Anatomy, Faculty of Medicine, University of Belgrade, Dr Subotica 4/2, 11000 Belgrade, Serbia
| | - Michael Amling
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Lottestrasse 59, 22529 Hamburg, Germany
| | - Björn Busse
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Lottestrasse 59, 22529 Hamburg, Germany.
| |
Collapse
|
|
41
|
Sølling ASK, Harsløf T, Langdahl B. The clinical potential of romosozumab for the prevention of fractures in postmenopausal women with osteoporosis. Ther Adv Musculoskelet Dis 2018; 10:105-115. [PMID: 29942362 PMCID: PMC6009094 DOI: 10.1177/1759720x18775936] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Accepted: 04/10/2018] [Indexed: 12/14/2022] Open
Abstract
The glycoprotein sclerostin inhibits activation of the canonical Wnt pathway and thereby suppresses bone formation by inhibiting the osteoblasts. Additionally, sclerostin increases bone resorption by stimulating the production of receptor activator of nuclear factor kappa-β-ligand (RANKL). Romosozumab (ROMO) is a monoclonal antibody against sclerostin. Phase III clinical trials in postmenopausal women with osteoporosis have shown that ROMO increases bone mineral density at the lumbar spine and hip and reduces the risk of vertebral and clinical fractures in comparison with placebo. In women with severe osteoporosis, ROMO reduces the risk of vertebral, nonvertebral and clinical fractures in comparison with alendronate. ROMO is the first treatment for osteoporosis with dual action, and may become a valuable tool for improving the treatment of osteoporosis. At present, the approval of ROMO by the authorities is awaiting further investigations of a potential increased risk of cardiovascular events associated with ROMO treatment.
Collapse
Affiliation(s)
| | - Torben Harsløf
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Bente Langdahl
- Department of Endocrinology and Internal Medicine, THG, Aarhus University Hospital, Tage-Hansens Gade 2, 8000 Aarhus C, Denmark
| |
Collapse
|
|
42
|
Dufresne SS, Boulanger-Piette A, Bossé S, Argaw A, Hamoudi D, Marcadet L, Gamu D, Fajardo VA, Yagita H, Penninger JM, Russell Tupling A, Frenette J. Genetic deletion of muscle RANK or selective inhibition of RANKL is not as effective as full-length OPG-fc in mitigating muscular dystrophy. Acta Neuropathol Commun 2018; 6:31. [PMID: 29699580 PMCID: PMC5922009 DOI: 10.1186/s40478-018-0533-1] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2018] [Accepted: 04/10/2018] [Indexed: 01/13/2023] Open
Abstract
Although there is a strong association between osteoporosis and skeletal muscle atrophy/dysfunction, the functional relevance of a particular biological pathway that regulates synchronously bone and skeletal muscle physiopathology is still elusive. Receptor-activator of nuclear factor κB (RANK), its ligand RANKL and the soluble decoy receptor osteoprotegerin (OPG) are the key regulators of osteoclast differentiation and bone remodelling. We thus hypothesized that RANK/RANKL/OPG, which is a key pathway for bone regulation, is involved in Duchenne muscular dystrophy (DMD) physiopathology. Our results show that muscle-specific RANK deletion (mdx-RANKmko) in dystrophin deficient mdx mice improves significantly specific force [54% gain in force] of EDL muscles with no protective effect against eccentric contraction-induced muscle dysfunction. In contrast, full-length OPG-Fc injections restore the force of dystrophic EDL muscles [162% gain in force], protect against eccentric contraction-induced muscle dysfunction ex vivo and significantly improve functional performance on downhill treadmill and post-exercise physical activity. Since OPG serves a soluble receptor for RANKL and as a decoy receptor for TRAIL, mdx mice were injected with anti-RANKL and anti-TRAIL antibodies to decipher the dual function of OPG. Injections of anti-RANKL and/or anti-TRAIL increase significantly the force of dystrophic EDL muscle [45% and 17% gains in force, respectively]. In agreement, truncated OPG-Fc that contains only RANKL domains produces similar gains, in terms of force production, than anti-RANKL treatments. To corroborate that full-length OPG-Fc also acts independently of RANK/RANKL pathway, dystrophin/RANK double-deficient mice were treated with full-length OPG-Fc for 10 days. Dystrophic EDL muscles exhibited a significant gain in force relative to untreated dystrophin/RANK double-deficient mice, indicating that the effect of full-length OPG-Fc is in part independent of the RANKL/RANK interaction. The sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) activity is significantly depressed in dysfunctional and dystrophic muscles and full-length OPG-Fc treatment increased SERCA activity and SERCA-2a expression. These findings demonstrate the superiority of full-length OPG-Fc treatment relative to truncated OPG-Fc, anti-RANKL, anti-TRAIL or muscle RANK deletion in improving dystrophic muscle function, integrity and protection against eccentric contractions. In conclusion, full-length OPG-Fc represents an efficient alternative in the development of new treatments for muscular dystrophy in which a single therapeutic approach may be foreseeable to maintain both bone and skeletal muscle functions.
Collapse
|
|
43
|
Abstract
The bone remodelling cycle replaces old and damaged bone and is a highly regulated, lifelong process essential for preserving bone integrity and maintaining mineral homeostasis. During the bone remodelling cycle, osteoclastic resorption is tightly coupled to osteoblastic bone formation. The remodelling cycle occurs within the basic multicellular unit and comprises five co-ordinated steps; activation, resorption, reversal, formation and termination. These steps occur simultaneously but asynchronously at multiple different locations within the skeleton. Study of rare human bone disease and animal models have helped to elucidate the cellular and molecular mechanisms that regulate the bone remodelling cycle. The key signalling pathways controlling osteoclastic bone resorption and osteoblastic bone formation are receptor activator of nuclear factor-κB (RANK)/RANK ligand/osteoprotegerin and canonical Wnt signalling. Cytokines, growth factors and prostaglandins act as paracrine regulators of the cycle, whereas endocrine regulators include parathyroid hormone, vitamin D, calcitonin, growth hormone, glucocorticoids, sex hormones, and thyroid hormone. Disruption of the bone remodelling cycle and any resulting imbalance between bone resorption and formation leads to metabolic bone disease, most commonly osteoporosis. The advances in understanding the cellular and molecular mechanisms underlying bone remodelling have also provided targets for pharmacological interventions which include antiresorptive and anabolic therapies. This review will describe the remodelling process and its regulation, discuss osteoporosis and summarize the commonest pharmacological interventions used in its management.
Collapse
Affiliation(s)
- J S Kenkre
- 1 Section of Investigative Medicine, Imperial College London, London, UK
| | - Jhd Bassett
- 2 Molecular Endocrinology Laboratory, Department of Medicine, Imperial College London, London, UK
| |
Collapse
|
|
44
|
Yang D, Anderson PH, Wijenayaka AR, Barratt KR, Triliana R, Stapledon CJM, Zhou H, Findlay DM, Morris HA, Atkins GJ. Both ligand and VDR expression levels critically determine the effect of 1α,25-dihydroxyvitamin-D 3 on osteoblast differentiation. J Steroid Biochem Mol Biol 2018; 177:83-90. [PMID: 28887147 DOI: 10.1016/j.jsbmb.2017.09.005] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2017] [Revised: 08/08/2017] [Accepted: 09/05/2017] [Indexed: 11/25/2022]
Abstract
Previous studies have shown that 1α,25-dihydroxyvitamin D3 (1,25D) through vitamin D receptor (VDR) signalling has both catabolic and anabolic effects on osteoblast differentiation. However, the mechanism of these differential effects by 1,25D is not fully understood. In this study, mice with three different genetic backgrounds, representing a normal VDR level (wild-type, WT), VDR over-expression specifically in mature osteoblasts (ObVDR-B6) and global VDR knockout (VDRKO), were utilised to generate primary osteoblast-like cultures to further elucidate the effects of 1,25D on osteoblast differentiation. Our data confirm the importance of VDR in the late stage of osteogenic differentiation and also for the expression of factors critical for osteoblastic support of osteoclast formation. This study also demonstrates the differential effects of a pharmacological level of 1,25D (1nM) on the expression of osteogenic differentiation markers, including Ocn and Sost, depending on the relative level of VDR. Our findings suggest that 1,25D plays an inhibitory role in matrix mineralisation, possibly through the modulation of the tissue non-specific alkaline phosphatase to ectonucleotide pyrophosphatase/phosphodiesterase 1 axis, in a VDR level-dependent manner. We conclude that the relative VDR level and the 1,25D availability to cells, are important co-determinants for whether 1,25D plays a promoting or suppressive role in osteoblast-mediated osteogenic activity.
Collapse
Affiliation(s)
- Dongqing Yang
- Biomedical Orthopaedic Research Group, Centre for Orthopaedic and Trauma Research, Discipline of Orthopaedics and Trauma, University of Adelaide, Adelaide, SA, 5005, Australia; Discipline of Medicine, University of Adelaide, Adelaide, SA, 5005, Australia
| | - Paul H Anderson
- Discipline of Medicine, University of Adelaide, Adelaide, SA, 5005, Australia; Musculoskeletal Biology Research, Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, 5000, Australia
| | - Asiri R Wijenayaka
- Biomedical Orthopaedic Research Group, Centre for Orthopaedic and Trauma Research, Discipline of Orthopaedics and Trauma, University of Adelaide, Adelaide, SA, 5005, Australia
| | - Kate R Barratt
- Biomedical Orthopaedic Research Group, Centre for Orthopaedic and Trauma Research, Discipline of Orthopaedics and Trauma, University of Adelaide, Adelaide, SA, 5005, Australia; Musculoskeletal Biology Research, Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, 5000, Australia
| | - Rahma Triliana
- Musculoskeletal Biology Research, Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, 5000, Australia
| | - Catherine J M Stapledon
- Biomedical Orthopaedic Research Group, Centre for Orthopaedic and Trauma Research, Discipline of Orthopaedics and Trauma, University of Adelaide, Adelaide, SA, 5005, Australia
| | - Hong Zhou
- Bone Research Program, ANZAC Research Institute, University of Sydney, Sydney, NSW, 2139, Australia
| | - David M Findlay
- Biomedical Orthopaedic Research Group, Centre for Orthopaedic and Trauma Research, Discipline of Orthopaedics and Trauma, University of Adelaide, Adelaide, SA, 5005, Australia
| | - Howard A Morris
- Discipline of Medicine, University of Adelaide, Adelaide, SA, 5005, Australia; Endocrine Bone Research, Chemical Pathology, SA Pathology, Adelaide, SA, 5000, Australia; Musculoskeletal Biology Research, Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, 5000, Australia
| | - Gerald J Atkins
- Biomedical Orthopaedic Research Group, Centre for Orthopaedic and Trauma Research, Discipline of Orthopaedics and Trauma, University of Adelaide, Adelaide, SA, 5005, Australia.
| |
Collapse
|
|
45
|
Chen X, Wang L, Zhao K, Wang H. Osteocytogenesis: Roles of Physicochemical Factors, Collagen Cleavage, and Exogenous Molecules. TISSUE ENGINEERING PART B-REVIEWS 2018; 24:215-225. [PMID: 29304315 DOI: 10.1089/ten.teb.2017.0378] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Osteocytes, the most abundant cell type in mammalian bone, are generally considered as the terminally differentiated cells of osteoblasts that are progressively self-buried or passively embedded in bone matrix. Emerging evidence reveals the essential functions of osteocytes in bone homeostasis and mechanotransduction. However, our knowledge on osteocytes, especially their formation, remains scarce. In this regard, the current review mainly focuses on several key factors that drive the osteocytic differentiation of osteoblasts, that is, osteocytogenesis. Available literature has demonstrated the involvement of physicochemical factors such as matrix composition, oxygen tension, and mechanical stress in the osteoblast-to-osteocyte transition. During cell migration and matrix remodeling, the matrix metalloproteinase-dependent collagen cleavage would play an "active" role in maturation and maintenance of the osteocytes. Besides, some in vitro methodologies are also established to induce the transformation of osteoblastic cell lines and primary mesenchymal cells to preosteocytes through cell transfection or addition of exogenous molecules (e.g., fibroblast growth factor-2, retinoic acid), which could potentiate the effort to form functional bone substitutes through elevated osteocytogenesis. Thus, advances of new technologies would enable comprehensive and in-depth understanding of osteocytes and their development, which in turn help promote the research on osteocyte biology and osteopathology.
Collapse
Affiliation(s)
- Xuening Chen
- 1 National Engineering Research Center for Biomaterials, Sichuan University , Chengdu, China
| | - Lichen Wang
- 2 Department of Biomedical Engineering, Chemistry and Biological Sciences, Stevens Institute of Technology , Hoboken, New Jersey
| | - Kaitao Zhao
- 2 Department of Biomedical Engineering, Chemistry and Biological Sciences, Stevens Institute of Technology , Hoboken, New Jersey
| | - Hongjun Wang
- 2 Department of Biomedical Engineering, Chemistry and Biological Sciences, Stevens Institute of Technology , Hoboken, New Jersey
| |
Collapse
|
|
46
|
Qin J, Yang D, Maher S, Lima-Marques L, Zhou Y, Chen Y, Atkins GJ, Losic D. Micro- and nano-structured 3D printed titanium implants with a hydroxyapatite coating for improved osseointegration. J Mater Chem B 2018; 6:3136-3144. [DOI: 10.1039/c7tb03251j] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
3D printing technology combined with electrochemical nano-structuring and HA modification is a promising approach for the fabrication of Ti implants with improved osseointegration.
Collapse
Affiliation(s)
- Jie Qin
- School of Chemical Engineering
- The University of Adelaide
- Australia
- Departments of Dental Implantology
- School and Hospital of Stomatology
| | - Dongqing Yang
- Centre for Orthopaedic and Trauma Research
- Adelaide Medical School
- Discipline of Orthopaedics and Trauma
- The University of Adelaide
- Australia
| | - Shaheer Maher
- School of Chemical Engineering
- The University of Adelaide
- Australia
- Faculty of Pharmacy
- Assiut University
| | - Luis Lima-Marques
- The Institute for Photonics and Advanced Sensing
- The University of Adelaide
- Australia
| | - Yanmin Zhou
- Departments of Dental Implantology
- School and Hospital of Stomatology
- Jilin University
- China
| | - Yujie Chen
- School of Mechanical Engineering
- The University of Adelaide
- Australia
| | - Gerald J. Atkins
- Centre for Orthopaedic and Trauma Research
- Adelaide Medical School
- Discipline of Orthopaedics and Trauma
- The University of Adelaide
- Australia
| | - Dusan Losic
- School of Chemical Engineering
- The University of Adelaide
- Australia
| |
Collapse
|
|
47
|
Langdahl BL, Ralston SH. How Basic Science Discoveries Have Shaped the Treatment of Bone and Mineral Disorders. J Bone Miner Res 2017; 32:2324-2330. [PMID: 29194750 DOI: 10.1002/jbmr.3316] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Affiliation(s)
- Bente L Langdahl
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Stuart H Ralston
- Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh, UK
| |
Collapse
|
|
48
|
de Oliveira KMH, Garlet GP, De Rossi A, Barreiros D, Queiroz AM, da Silva LAB, Nelson-Filho P, da Silva RAB. Effects of Rosiglitazone on the Outcome of Experimental Periapical Lesions in Mice. J Endod 2017; 43:2061-2069. [DOI: 10.1016/j.joen.2017.06.026] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Revised: 06/15/2017] [Accepted: 06/16/2017] [Indexed: 01/18/2023]
|
|
49
|
Kogawa M, Khalid KA, Wijenayaka AR, Ormsby RT, Evdokiou A, Anderson PH, Findlay DM, Atkins GJ. Recombinant sclerostin antagonizes effects of ex vivo mechanical loading in trabecular bone and increases osteocyte lacunar size. Am J Physiol Cell Physiol 2017; 314:C53-C61. [PMID: 28978523 DOI: 10.1152/ajpcell.00175.2017] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Sclerostin has emerged as an important regulator of bone mass. We have shown that sclerostin can act by targeting late osteoblasts/osteocytes to inhibit bone mineralization and to upregulate osteocyte expression of catabolic factors, resulting in osteocytic osteolysis. Here we sought to examine the effect of exogenous sclerostin on osteocytes in trabecular bone mechanically loaded ex vivo. Bovine trabecular bone cores, with bone marrow removed, were inserted into individual chambers and subjected to daily episodes of dynamic loading. Cores were perfused with either osteogenic media alone or media containing human recombinant sclerostin (rhSCL) (50 ng/ml). Loaded control bone increased in apparent stiffness over time compared with unloaded bone, and this was abrogated in the presence of rhSCL. Loaded bone showed an increase in calcein uptake as a surrogate of mineral accretion, compared with unloaded bone, in which this was substantially inhibited by rhSCL treatment. Sclerostin treatment induced a significant increase in the ionized calcium concentration in the perfusate and the release of β-CTX at several time points, an increased mean osteocyte lacunar size, indicative of osteocytic osteolysis, and the expression of catabolism-related genes. Human primary osteocyte-like cultures treated with rhSCL also released β-CTX from their matrix. These results suggest that osteocytes contribute directly to bone mineral accretion, and to the mechanical properties of bone. Moreover, it appears that sclerostin, acting on osteocytes, can negate this effect by modulating the dimensions of the lacunocanalicular porosity and the composition of the periosteocyte matrix.
Collapse
Affiliation(s)
- M Kogawa
- Biomedical Orthopaedic Research Group, Centre for Orthopaedic and Trauma Research, University of Adelaide , Adelaide, South Australia , Australia
| | - K A Khalid
- Biomedical Orthopaedic Research Group, Centre for Orthopaedic and Trauma Research, University of Adelaide , Adelaide, South Australia , Australia
| | - A R Wijenayaka
- Biomedical Orthopaedic Research Group, Centre for Orthopaedic and Trauma Research, University of Adelaide , Adelaide, South Australia , Australia
| | - R T Ormsby
- Biomedical Orthopaedic Research Group, Centre for Orthopaedic and Trauma Research, University of Adelaide , Adelaide, South Australia , Australia
| | - A Evdokiou
- Discipline of Surgery, Breast Cancer Research Unit, Basil Hetzel Institute, University of Adelaide, Woodville, South Australia, Australia
| | - P H Anderson
- School of Pharmacy and Medical Sciences, University of South Australia , Adelaide, South Australia , Australia
| | - D M Findlay
- Biomedical Orthopaedic Research Group, Centre for Orthopaedic and Trauma Research, University of Adelaide , Adelaide, South Australia , Australia
| | - G J Atkins
- Biomedical Orthopaedic Research Group, Centre for Orthopaedic and Trauma Research, University of Adelaide , Adelaide, South Australia , Australia
| |
Collapse
|
|
50
|
Abstract
PURPOSE OF REVIEW This review assembles recent understanding of the profound loss of muscle and bone in spinal cord injury (SCI). It is important to try to understand these changes, and the context in which they occur, because of their impact on the wellbeing of SC-injured individuals, and the urgent need for viable preventative therapies. RECENT FINDINGS Recent research provides new understanding of the effects of age and systemic factors on the response of bone to loading, of relevance to attempts to provide load therapy for bone in SCI. The rapidly growing dataset describing the biochemical crosstalk between bone and muscle, and the cell and molecular biology of myokines signalling to bone and osteokines regulating muscle metabolism and mass, is reviewed. The ways in which this crosstalk may be altered in SCI is summarised. Therapeutic approaches to the catabolic changes in muscle and bone in SCI require a holistic understanding of their unique mechanical and biochemical context.
Collapse
Affiliation(s)
- Jillian M Clark
- Discipline of Orthopaedics and Trauma, The University of Adelaide, North Terrace, Adelaide, South Australia, 5000, Australia.
| | - David M Findlay
- Discipline of Orthopaedics and Trauma, The University of Adelaide, North Terrace, Adelaide, South Australia, 5000, Australia
| |
Collapse
|