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Guerrero Vargas JA, Carvalho Trojan L, de Las Casas EB, Garzón Alvarado DA. Finite element analysis of the influence of interdigitation pattern and collagen fibers on the mechanical behavior of the midpalatal suture. Med Biol Eng Comput 2023; 61:2367-2377. [PMID: 37076651 DOI: 10.1007/s11517-023-02838-7] [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: 10/26/2022] [Accepted: 04/06/2023] [Indexed: 04/21/2023]
Abstract
The midpalatal suture (MPS) corresponds to the tissue that joins the two maxillary bones. Understanding the mechanical behavior of this tissue is of particular interest to those patients who require orthodontic treatments such as Rapid Maxillary Expansion (RME). The objective of this research was to observe the influence of interdigitation and collagen fibers on the mechanical response of MPS. To this end, a finite element analysis in two-dimensional models of the bone-suture-bone interface was performed considering the characteristics of the MPS. The geometry of the suture was modeled with 4 different levels of interdigitation: null, moderate, scalloped and fractal. The influence of collagen fibers, aligned transversely along the suture, was considered by incorporating linked structures of the bone fronts. According to the results, the factor that has the greatest impact on the magnitude and distribution of stresses is the interdigitation degree. A higher level of interdigitation produces an increase in tissue stiffness and a lower influence of collagen fibers on the mechanical response of the tissue. Therefore, this research contributes to the understanding of the MPS biomechanics by providing information that may be useful to health staff when evaluating the feasibility of procedures such as RME.
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Affiliation(s)
- J A Guerrero Vargas
- Department of Mechanical Engineering, Faculty of Engineering, Universidad ECCI, Vicerrectoría de Investigación, Carrera 19 No 49-20 Sede P, Bogotá, Colombia.
| | - L Carvalho Trojan
- Department of Structural Engineering, School of Engineering, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - E Barbosa de Las Casas
- Department of Structural Engineering, School of Engineering, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - D A Garzón Alvarado
- Department of Mechanical and Mechatronic Engineering, Faculty of Engineering, Universidad Nacional de Colombia, Bogotá, Colombia
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Zubidat D, Hanna C, Randhawa AK, Smith BH, Chedid M, Kaidbay DHN, Nardelli L, Mkhaimer YG, Neal RM, Madsen CD, Senum SR, Gregory AV, Kline TL, Zoghby ZM, Broski SM, Issa NS, Harris PC, Torres VE, Sfeir JG, Chebib FT. Bone health in autosomal dominant polycystic kidney disease (ADPKD) patients after kidney transplantation. Bone Rep 2023; 18:101655. [PMID: 36659900 PMCID: PMC9842864 DOI: 10.1016/j.bonr.2023.101655] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Revised: 12/29/2022] [Accepted: 01/09/2023] [Indexed: 01/12/2023] Open
Abstract
ADPKD is caused by pathogenic variants in PKD1 or PKD2, encoding polycystin-1 and -2 proteins. Polycystins are expressed in osteoblasts and chondrocytes in animal models, and loss of function is associated with low bone mineral density (BMD) and volume. However, it is unclear whether these variants impact bone strength in ADPKD patients. Here, we examined BMD in ADPKD after kidney transplantation (KTx). This retrospective observational study retrieved data from adult patients who received a KTx over the past 15 years. Patients with available dual-energy X-ray absorptiometry (DXA) of the hip and/or lumbar spine (LS) post-transplant were included. ADPKD patients (n = 340) were matched 1:1 by age (±2 years) at KTx and sex with non-diabetic non-ADPKD patients (n = 340). Patients with ADPKD had slightly higher BMD and T-scores at the right total hip (TH) as compared to non-ADPKD patients [BMD: 0.951 vs. 0.897, p < 0.001; T-score: -0.62 vs. -0.99, p < 0.001] and at left TH [BMD: 0.960 vs. 0.893, p < 0.001; T-score: -0.60 vs. -1.08, p < 0.001], respectively. Similar results were found at the right femoral neck (FN) between ADPKD and non-ADPKD [BMD: 0.887 vs. 0.848, p = 0.001; T-score: -1.20 vs. -1.41, p = 0.01] and at left FN [BMD: 0.885 vs. 0.840, p < 0.001; T-score: -1.16 vs. -1.46, p = 0.001]. At the LS level, ADPKD had a similar BMD and lower T-score compared to non-ADPKD [BMD: 1.120 vs. 1.126, p = 0.93; T-score: -0.66 vs. -0.23, p = 0.008]. After adjusting for preemptive KTx, ADPKD patients continued to have higher BMD T-scores in TH and FN. Our findings indicate that BMD by DXA is higher in patients with ADPKD compared to non-ADPKD patients after transplantation in sites where cortical but not trabecular bone is predominant. The clinical benefit of the preserved cortical bone BMD in patients with ADPKD needs to be explored in future studies.
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Affiliation(s)
- Dalia Zubidat
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, MN, USA
| | - Christian Hanna
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, MN, USA
- Division of Pediatric Nephrology and Hypertension, Department of Pediatric Adolescent Medicine, Mayo Clinic, Rochester, MN, USA
| | - Amarjyot K. Randhawa
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, MN, USA
| | - Byron H. Smith
- Division of Clinical Trials and Biostatistics, Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA
| | - Maroun Chedid
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, MN, USA
| | - Daniel-Hasan N. Kaidbay
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, MN, USA
| | - Luca Nardelli
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, MN, USA
| | - Yaman G. Mkhaimer
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, MN, USA
| | - Reem M. Neal
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, MN, USA
| | - Charles D. Madsen
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, MN, USA
| | - Sarah R. Senum
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, MN, USA
| | | | | | - Ziad M. Zoghby
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, MN, USA
| | | | - Naim S. Issa
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, MN, USA
| | - Peter C. Harris
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, MN, USA
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA
| | - Vicente E. Torres
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, MN, USA
| | - Jad G. Sfeir
- Division of Endocrinology, Department of Medicine, Mayo Clinic, Rochester, MN, USA
- Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA
| | - Fouad T. Chebib
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Jacksonville, FL, USA
- Corresponding author at: 4500 San Pablo Rd S, Jacksonville, FL 32224, USA.
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Xiao X, Chen J, Zhai Q, Xin L, Zheng X, Wang S, Song J. Suppressing STAT3 activation impairs bone formation during maxillary expansion and relapse. J Appl Oral Sci 2023; 31:e20230009. [PMID: 37162107 PMCID: PMC10167947 DOI: 10.1590/1678-7757-2023-0009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Accepted: 03/22/2023] [Indexed: 05/11/2023] Open
Abstract
OBJECTIVES The mid-palatal expansion technique is commonly used to correct maxillary constriction in dental clinics. However, there is a tendency for it to relapse, and the key molecules responsible for modulating bone formation remain elusive. Thus, this study aimed to investigate whether signal transducer and activator of transcription 3 (STAT3) activation contributes to osteoblast-mediated bone formation during palatal expansion and relapse. METHODOLOGY In total, 30 male Wistar rats were randomly allocated into Ctrl (control), E (expansion only), and E+Stattic (expansion plus STAT3-inhibitor, Stattic) groups. Micro-computed tomography, micromorphology staining, and immunohistochemistry of the mid-palatal suture were performed on days 7 and 14. In vitro cyclic tensile stress (10% magnitude, 0.5 Hz frequency, and 24 h duration) was applied to rat primary osteoblasts and Stattic was administered for STAT3 inhibition. The role of STAT3 in mechanical loading-induced osteoblasts was confirmed by alkaline phosphatase (ALP), alizarin red staining, and western blots. RESULTS The E group showed greater arch width than the E+Stattic group after expansion. The differences between the two groups remained significant after relapse. We found active bone formation in the E group with increased expression of ALP, COL-I, and Runx2, although the expression of osteogenesis-related factors was downregulated in the E+stattic group. After STAT3 inhibition, expansive force-induced bone resorption was attenuated, as TRAP staining demonstrated. Furthermore, the administration of Stattic in vitro partially suppressed tensile stress-enhanced osteogenic markers in osteoblasts. CONCLUSIONS STAT3 inactivation reduced osteoblast-mediated bone formation during palatal expansion and post-expansion relapse, thus it may be a potential therapeutic target to treat force-induced bone formation.
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Affiliation(s)
- Xiaoyue Xiao
- Chongqing Medical University, College of Stomatology, Chongqing Key Laboratory for Oral Diseases and Biomedical Sciences, Municipal Key Laboratory of Oral Biomedical Engineering of Chongqing Higher Education, Chongqing, China
| | - Jianwei Chen
- Sichuan University, West China Hospital of Stomatology, State Key Laboratory of Oral Disease and National Clinical Research Center for Oral Diseases, Chengdu, China
| | - Qiming Zhai
- Chongqing Medical University, College of Stomatology, Chongqing Key Laboratory for Oral Diseases and Biomedical Sciences, Municipal Key Laboratory of Oral Biomedical Engineering of Chongqing Higher Education, Chongqing, China
| | - Liangjing Xin
- Chongqing Medical University, College of Stomatology, Chongqing Key Laboratory for Oral Diseases and Biomedical Sciences, Municipal Key Laboratory of Oral Biomedical Engineering of Chongqing Higher Education, Chongqing, China
| | - Xinhui Zheng
- Chongqing Medical University, College of Stomatology, Chongqing Key Laboratory for Oral Diseases and Biomedical Sciences, Municipal Key Laboratory of Oral Biomedical Engineering of Chongqing Higher Education, Chongqing, China
| | - Si Wang
- Chongqing Medical University, College of Stomatology, Chongqing Key Laboratory for Oral Diseases and Biomedical Sciences, Municipal Key Laboratory of Oral Biomedical Engineering of Chongqing Higher Education, Chongqing, China
| | - Jinlin Song
- Chongqing Medical University, College of Stomatology, Chongqing Key Laboratory for Oral Diseases and Biomedical Sciences, Municipal Key Laboratory of Oral Biomedical Engineering of Chongqing Higher Education, Chongqing, China
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Zhao H, Wang X, Jin A, Wang M, Wang Z, Huang X, Dai J, Wang X, Lin D, Shen SGF. Reducing relapse and accelerating osteogenesis in rapid maxillary expansion using an injectable mesoporous bioactive glass/fibrin glue composite hydrogel. Bioact Mater 2022; 18:507-525. [PMID: 35415307 PMCID: PMC8976096 DOI: 10.1016/j.bioactmat.2022.03.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Revised: 02/24/2022] [Accepted: 03/01/2022] [Indexed: 11/29/2022] Open
Abstract
Rapid maxillary expansion (RME), as a common treatment for craniomaxillofacial deformity, faces the challenge of high relapse rates and unsatisfactory therapeutic effects. In this study, a standardized Sprague-Dawley (SD) rat RME model was first established with a modified expander as well as retainer design and optimized anterior maxillary expanding force of 100 g which exerted the most synchronized mobility of mid-palatal suture and incisors. Via the standardized model, the high relapse rate was proven to be attributed to insufficient osteogenesis in expanded suture, requiring long-term retainer wearing in clinical situations. To reduce the relapse rate, mesoporous bioactive glass/fibrin glue (MBG/FG) composite hydrogels were developed for an in situ minimal invasive injection that enhance osteogenesis in the expanded palate. The component of 1 wt% MBG was adopted for enhanced mechanical strength, matched degradation rate and ion dissolution, excellent in vitro biocompatibility and osteoinductivity. Effects of 1%MBG/FG composite hydrogel on osteogenesis in expanded mid-palatal sutures with/without retention were evaluated in the standardized model. The results demonstrated that injection of 1%MBG/FG composite hydrogel significantly promoted bone formation within the expanded mid-palatal suture, inhibited osteoclastogenesis and benefited the balance of bone remodeling towards osteogenesis. Combination of retainer and injectable biomaterial was demonstrated as a promising treatment to reduce relapse rate and enhance osteogenesis after RME. The model establishment and the composite hydrogel development in this article might provide new insight to other craniomaxillofacial deformity treatment and design of bone-repairing biomaterials with higher regenerative efficiency.
A standardized rat RME model was established with optimized parameters. Sufficient osteogenesis was the prerequisite of reducing relapse ratio. Design of an injectable MBG/FG composite hydrogel for osteogenic enhancement. Combinatory treatment of injection and retention was developed for relapse reduction.
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Katsianou MA, Papavassiliou KA, Gargalionis AN, Agrogiannis G, Korkolopoulou P, Panagopoulos D, Themistocleous MS, Piperi C, Basdra EK, Papavassiliou AG. Polycystin-1 regulates cell proliferation and migration through AKT/mTORC2 pathway in a human craniosynostosis cell model. J Cell Mol Med 2022; 26:2428-2437. [PMID: 35285136 PMCID: PMC8995461 DOI: 10.1111/jcmm.17266] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 02/28/2022] [Accepted: 03/03/2022] [Indexed: 11/30/2022] Open
Abstract
Craniosynostosis is the premature fusion of skull sutures and has a severe pathological impact on childrens' life. Mechanical forces are capable of triggering biological responses in bone cells and regulate osteoblastogenesis in cranial sutures, leading to premature closure. The mechanosensitive proteins polycystin-1 (PC1) and polycystin-2 (PC2) have been documented to play an important role in craniofacial proliferation and development. Herein, we investigated the contribution of PC1 to the pathogenesis of non-syndromic craniosynostosis and the associated molecular mechanisms. Protein expression of PC1 and PC2 was detected in bone fragments derived from craniosynostosis patients via immunohistochemistry. To explore the modulatory role of PC1 in primary cranial suture cells, we further abrogated the function of PC1 extracellular mechanosensing domain using a specific anti-PC1 IgPKD1 antibody. Effect of IgPKD1 treatment was evaluated with cell proliferation and migration assays. Activation of PI3K/AKT/mTOR pathway components was further detected via Western blot in primary cranial suture cells following IgPKD1 treatment. PC1 and PC2 are expressed in human tissues of craniosynostosis. PC1 functional inhibition resulted in elevated proliferation and migration of primary cranial suture cells. PC1 inhibition also induced activation of AKT, exhibiting elevated phospho (p)-AKT (Ser473) levels, but not 4EBP1 or p70S6K activation. Our findings indicate that PC1 may act as a mechanosensing molecule in cranial sutures by modulating osteoblastic cell proliferation and migration through the PC1/AKT/mTORC2 cascade with a potential impact on the development of non-syndromic craniosynostosis.
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Affiliation(s)
- Maria A. Katsianou
- Department of Biological ChemistryMedical SchoolNational and Kapodistrian University of AthensAthensGreece
| | - Kostas A. Papavassiliou
- Department of Biological ChemistryMedical SchoolNational and Kapodistrian University of AthensAthensGreece
| | - Antonios N. Gargalionis
- Department of Biological ChemistryMedical SchoolNational and Kapodistrian University of AthensAthensGreece
| | - George Agrogiannis
- First Department of PathologyMedical SchoolNational and Kapodistrian University of AthensAthensGreece
| | - Penelope Korkolopoulou
- First Department of PathologyMedical SchoolNational and Kapodistrian University of AthensAthensGreece
| | | | | | - Christina Piperi
- Department of Biological ChemistryMedical SchoolNational and Kapodistrian University of AthensAthensGreece
| | - Efthimia K. Basdra
- Department of Biological ChemistryMedical SchoolNational and Kapodistrian University of AthensAthensGreece
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Katsianou M, Papavassiliou KA, Zoi I, Gargalionis AN, Panagopoulos D, Themistocleous MS, Piperi C, Papavassiliou AG, Basdra EK. Polycystin-1 modulates RUNX2 activation and osteocalcin gene expression via ERK signalling in a human craniosynostosis cell model. J Cell Mol Med 2021; 25:3216-3225. [PMID: 33656806 PMCID: PMC8034462 DOI: 10.1111/jcmm.16391] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Revised: 02/06/2021] [Accepted: 02/09/2021] [Indexed: 12/13/2022] Open
Abstract
Craniosynostosis refers to the premature fusion of one or more cranial sutures leading to skull shape deformities and brain growth restriction. Among the many factors that contribute to abnormal suture fusion, mechanical forces seem to play a major role. Nevertheless, the underlying mechanobiology-related mechanisms of craniosynostosis still remain unknown. Understanding how aberrant mechanosensation and mechanotransduction drive premature suture fusion will offer important insights into the pathophysiology of craniosynostosis and result in the development of new therapies, which can be used to intervene at an early stage and prevent premature suture fusion. Herein, we provide evidence for the first time on the role of polycystin-1 (PC1), a key protein in cellular mechanosensitivity, in craniosynostosis, using primary cranial suture cells isolated from patients with trigonocephaly and dolichocephaly, two common types of craniosynostosis. Initially, we showed that PC1 is expressed at the mRNA and protein level in both trigonocephaly and dolichocephaly cranial suture cells. Followingly, by utilizing an antibody against the mechanosensing extracellular N-terminal domain of PC1, we demonstrated that PC1 regulates runt-related transcription factor 2 (RUNX2) activation and osteocalcin gene expression via extracellular signal-regulated kinase (ERK) signalling in our human craniosynostosis cell model. Altogether, our study reveals a novel mechanotransduction signalling axis, PC1-ERK-RUNX2, which affects osteoblastic differentiation in cranial suture cells from trigonocephaly and dolichocephaly patients.
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Affiliation(s)
- Maira Katsianou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Kostas A Papavassiliou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Ilianna Zoi
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Antonios N Gargalionis
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | | | | | - Christina Piperi
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Athanasios G Papavassiliou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Efthimia K Basdra
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
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Guerrero JA, Silva RS, de Abreu Lima IL, Rodrigues BCD, Barrioni BR, Amaral FA, Tabanez AP, Garlet GP, Alvarado DAG, Silva TA, de Las Casas EB, Macari S. Maxillary suture expansion: A mouse model to explore the molecular effects of mechanically-induced bone remodeling. J Biomech 2020; 108:109880. [PMID: 32635995 DOI: 10.1016/j.jbiomech.2020.109880] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2019] [Revised: 05/18/2020] [Accepted: 06/09/2020] [Indexed: 12/15/2022]
Abstract
The aim of this study was to analyze the effect of rapid maxillary expansion (RME) on hard tissues. Opening loops bonded to the first and second maxillary molars on both sides were used to apply distracting forces of 0.28 N, 0.42 N and 0.56 N at the midpalatal suture for 7 and 14 days. Microcomputed tomography (MicroCT), histomorphometry and quantitative polymerase chain reaction (qPCR) analysis were performed to evaluate RME effectiveness, midpalatal suture remodeling, cell counting of osteoblasts, osteoclasts and chondrocytes and the expression of bone remodeling markers, respectively. All forces at the two different time points resulted in similar RME and enhanced of bone remodeling. Accordingly, increased number of osteoblasts and reduced chondrocytes counting and no difference in osteoclasts were seen after all RME protocols. RME yielded increased expression of bone remodeling markers as osteocalcin (Ocn), dentin matrix acidic phosphoprotein-1 (Dmp1), runt-related transcription factor 2 (Runx2), collagen type I Alpha 1 (Col1a1), alkaline phosphatase (ALP), receptor activator of nuclear factor kappa B (RANK), receptor activator of nuclear factor kappa B ligand (Rankl), osteoprotegerin (Opg), cathepsin K (Ctsk), matrix metalloproteinases 9 and 13 (Mmp9 and 13), transforming growth fator beta 1, 2 and 3 (Tgfb 1, Tgfb 2 and Tgfb3), bone morphogenetic protein 2 (Bmp-2), sclerostin (Sost), beta-catenin-like protein 1 (Ctnnbl) and Wnt signaling pathways 3, 3a and 5a (Wnt 3, Wnt 3a and Wnt 5a). These findings characterize the cellular changes and potential molecular pathways involved in RME, proving the reliability of this protocol as a model for mechanical-induced bone remodeling.
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Affiliation(s)
- Jose Alejandro Guerrero
- Institute of Biotechnology, Department of Mechanical and Mechatronic Engineering, Faculty of Engineering, National University of Colombia, Bogotá, Colombia
| | - Raquel Souto Silva
- Departament of Social and Preventive Dentistry, Faculty of Dentistry, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Izabella Lucas de Abreu Lima
- Departament of Pediatric Dentistry, Faculty of Dentistry, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | | | - Breno Rocha Barrioni
- Department of Metallurgical and Materials Engineering, Faculty of Engineering, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Flávio Almeida Amaral
- Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - André Petenuci Tabanez
- Department of Biological Sciences, Faculty of Dentistry of Bauru, University of São Paulo, Bauru, SP, Brazil
| | - Gustavo Pompermaier Garlet
- Department of Biological Sciences, Faculty of Dentistry of Bauru, University of São Paulo, Bauru, SP, Brazil
| | - Diego Alexander Garzon Alvarado
- Institute of Biotechnology, Department of Mechanical and Mechatronic Engineering, Faculty of Engineering, National University of Colombia, Bogotá, Colombia
| | - Tarcília Aparecida Silva
- Department of Clinic, Pathology and Dental Surgery, Faculty of Dentistry, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Estevam Barbosa de Las Casas
- Department of Structural Engineering, Faculty of Engineering, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Soraia Macari
- Department of Restorative Dentistry, Faculty of Dentistry, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.
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8
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Guerrero-Vargas JA, Silva TA, Macari S, de Las Casas EB, Garzón-Alvarado DA. Influence of interdigitation and expander type in the mechanical response of the midpalatal suture during maxillary expansion. COMPUTER METHODS AND PROGRAMS IN BIOMEDICINE 2019; 176:195-209. [PMID: 31200906 DOI: 10.1016/j.cmpb.2019.05.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Revised: 05/02/2019] [Accepted: 05/11/2019] [Indexed: 06/09/2023]
Abstract
BACKGROUND AND OBJECTIVE The orthopedic Maxillary Expansion (ME) procedure is used for treating the transverse maxillary deficiency. This pathology consists in a smaller transverse dimension in the maxilla and leads to malocclusion. The treatment takes advantage of the existence of the midpalatal suture (MPS), which corresponds to the junction at the palatine bones of its horizontal portions. The technique employs a device, conventionally a palatal expander attached to the posterior teeth, to separate the two maxillary bones in the MPS. The objective of this study was to analyze, using the Finite Element Method, the biomechanical behavior of the MPS when an expansion is applied. METHODS A Computer Tomography image of the maxilla was reconstructed, the suture geometry was modeled with different interdigitation levels and types of hyrax devices. A total of 12 geometric models (three levels for interdigitation and four types of hyrax devices) were prepared and analyzed taking into account the chewing forces and the expansion displacement. For each case, maximum principal stresses on the maxilla (bone), and equivalent stresses on the expander device (stainless steel) were observed. In the MPS, maximum principal stresses and directional displacement were evaluated. RESULTS The results showed that the interdigitation does not have an important influence on the deformation behavior of the maxilla but it affects the stress distribution. In addition, the type of expander device and anchorage have a direct relationship with the treatment effectiveness; larger deformation in the expansion direction was obtained with skeletal when compared to dental anchorage. CONCLUSIONS A study that allows a better understanding of the oral biomechanics during the application of ME was presented. To our knowledge, it is the first study based on computational simulations that takes into account bone structures, like maxilla and part of the skull, to analyze the interdigitation influence on the MPS behavior when exposed to a ME.
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Affiliation(s)
- J A Guerrero-Vargas
- Department of Mechanical and Mechatronic Engineering, Faculty of Engineering, Universidad Nacional de Colombia, Bogotá, Colombia; Department of Mechanical Engineering, School of Engineering, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil; Department of Mechanical Engineering, Faculty of Engineering, Universidad ECCI, Bogotá, Colombia.
| | - T A Silva
- Department of Clinical, Pathology and Dental Surgery, Faculty of Dentistry, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - S Macari
- Department of Pediatric Dentistry and Orthodontics, Faculty of Dentistry, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - E B de Las Casas
- Department of Structural Engineering, School of Engineering, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - D A Garzón-Alvarado
- Department of Mechanical and Mechatronic Engineering, Faculty of Engineering, Universidad Nacional de Colombia, Bogotá, Colombia
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9
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Katsianou MA, Skondra FG, Gargalionis AN, Piperi C, Basdra EK. The role of transient receptor potential polycystin channels in bone diseases. ANNALS OF TRANSLATIONAL MEDICINE 2018; 6:246. [PMID: 30069448 DOI: 10.21037/atm.2018.04.10] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Transient receptor potential (TRP) channels are cation channels which act as molecular sensors that enable cells to detect and respond to a plethora of mechanical and environmental cues. TRPs are involved in various physiological processes, such as mechanosensation, non-inception and thermosensation, while mutations in genes encoding them can lead to pathological conditions, called "channelopathies". The subfamily of transient receptor potential polycystins (TRPPs), Polycystin 1 (PC1, TRPP1) and Polycystin 2 (PC2, TRPP2), act as mechanoreceptors, sensing external mechanical forces, including strain, stretch and fluid shear stress, triggering a cascade of signaling pathways involved in osteoblastogenesis and ultimately bone formation. Both in vitro studies and research on animal models have already identified their implications in bone homeostasis. However, uncertainty veiling the role of polycystins (PCs) in bone disease urges studies to elucidate further their role in this field. Mutations in TRPPs have been related to autosomal polycystic kidney disease (ADKPD) and research groups try to identify their role beyond their well-established contribution in kidney disease. Such an elucidation would be beneficial for identifying signaling pathways where polycystins are involved in bone diseases related to exertion of mechanical forces such as osteoporosis, osteopenia and craniosynostosis. A better understanding of the implications of TRPPs in bone diseases would possibly lay the cornerstone for effective therapeutic schemes.
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Affiliation(s)
- Maria A Katsianou
- Cellular and Molecular Biomechanics Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Foteini G Skondra
- Cellular and Molecular Biomechanics Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Antonios N Gargalionis
- Cellular and Molecular Biomechanics Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Christina Piperi
- Cellular and Molecular Biomechanics Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Efthimia K Basdra
- Cellular and Molecular Biomechanics Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
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10
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Karamesinis K, Basdra EK. The biological basis of treating jaw discrepancies: An interplay of mechanical forces and skeletal configuration. Biochim Biophys Acta Mol Basis Dis 2018; 1864:1675-1683. [PMID: 29454076 DOI: 10.1016/j.bbadis.2018.02.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2017] [Revised: 02/06/2018] [Accepted: 02/12/2018] [Indexed: 10/18/2022]
Abstract
Jaw discrepancies and malrelations affect a large proportion of the general population and their treatment is of utmost significance for individuals' health and quality of life. The aim of their therapy is the modification of aberrant jaw development mainly by targeting the growth potential of the mandibular condyle through its cartilage, and the architectural shape of alveolar bone through a suture type of structure, the periodontal ligament. This targeted treatment is achieved via external mechanical force application by using a wide variety of intraoral and extraoral appliances. Condylar cartilage and sutures exhibit a remarkable plasticity due to the mechano-responsiveness of the chondrocytes and the multipotent mesenchymal cells of the sutures. The tissues respond biologically and adapt to mechanical force application by a variety of signaling pathways and a final interplay between the proliferative activity and the differentiation status of the cells involved. These targeted therapeutic functional alterations within temporo-mandibular joint ultimately result in the enhancement or restriction of mandibular growth, while within the periodontal ligament lead to bone remodeling and change of its architectural structure. Depending on the form of the malrelation presented, the above treatment approaches, in conjunction or separately, lead to the total correction of jaw discrepancies and the achievement of facial harmony and function. Overall, the treatment of craniofacial and jaw anomalies can be seen as an interplay of mechanical forces and adaptations occurring within temporo-mandibular joint and alveolar bone. The aim of the present review is to present up-to-date knowledge on the mechano-biology behind jaw growth modification and alveolar bone remodeling. Furthermore, future molecular targeted therapeutic strategies are discussed aiming at the improvement of mechanically-driven chondrogenesis and osteogenesis.
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Affiliation(s)
- Konstantinos Karamesinis
- Department of Biological Chemistry, Cellular and Molecular Biomechanics Unit, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Efthimia K Basdra
- Department of Biological Chemistry, Cellular and Molecular Biomechanics Unit, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece.
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11
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Koehne T, Kahl-Nieke B, Amling M, Korbmacher-Steiner H. Inhibition of bone resorption by bisphosphonates interferes with orthodontically induced midpalatal suture expansion in mice. Clin Oral Investig 2018; 22:2345-2351. [PMID: 29344807 DOI: 10.1007/s00784-018-2335-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2017] [Accepted: 01/03/2018] [Indexed: 02/06/2023]
Abstract
OBJECTIVES Craniofacial sutures are important growth sites for skull development and are sensitive to mechanical stress. In order to determine the role of bone resorption in stress-mediated sutural bone growth, midpalatal suture expansion was performed in mice receiving alendronate, an anti-resorptive bisphosphonate. MATERIALS AND METHODS The midpalatal sutures of 8-week-old C57BL/6 mice were expanded by orthodontic wires over the period of 2 weeks. Mice with maxillary expansion without drug treatment as well as untreated animals served as controls. Skulls were analyzed with micro-computed tomography (micro-CT), immunohistochemistry and histology. RESULTS Maxillary expansion in mice without drug treatment resulted in an increase of TRAP-positive osteoclasts. In contrast, no increase in osteoclasts was observed in expanded sutures of mice with bisphosphonate treatment. Double calcein labeling demonstrated rapid bone formation on the oral edges of the expanded sutures in mice without bisphosphonate treatment. Less bone formation was observed in bisphosphonate-treated mice after expansion. Histology revealed that the sutural architecture was reestablished in expanded sutures of mice without bisphosphonate treatment. In contrast, the sutural architecture was disorganized and the cartilage had an irregular form, following expansion in bisphosphonate-treated mice. Finally, micro-CT imaging demonstrated that the total amount of maxillary expansion was significantly lower in mice with bisphosphonate treatment as compared to those of mice without drug treatment. CONCLUSIONS In conclusion, our results indicate that osteoclast-mediated bone resorption is needed for maxillary suture expansion and reorganization of sutural architecture. CLINICAL SIGNIFICANCE Orthodontic palatal expansion can be complicated in patients with inherited or drug-induced diseases of osteoclast dysfunction.
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Affiliation(s)
- Till Koehne
- Department of Orthodontics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Bärbel Kahl-Nieke
- Department of Orthodontics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Michael Amling
- Institute of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Heike Korbmacher-Steiner
- Department of Orthodontics, Giessen and Marburg University Hospital, Marburg Campus, Georg-Voigt-Straße 3, 35039, Marburg, Germany.
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12
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Dalagiorgou G, Piperi C, Adamopoulos C, Georgopoulou U, Gargalionis AN, Spyropoulou A, Zoi I, Nokhbehsaim M, Damanaki A, Deschner J, Basdra EK, Papavassiliou AG. Mechanosensor polycystin-1 potentiates differentiation of human osteoblastic cells by upregulating Runx2 expression via induction of JAK2/STAT3 signaling axis. Cell Mol Life Sci 2017; 74:921-936. [PMID: 27699453 PMCID: PMC11107574 DOI: 10.1007/s00018-016-2394-8] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2016] [Revised: 09/15/2016] [Accepted: 09/30/2016] [Indexed: 01/08/2023]
Abstract
Polycystin-1 (PC1) has been proposed as a chief mechanosensing molecule implicated in skeletogenesis and bone remodeling. Mechanotransduction via PC1 involves proteolytic cleavage of its cytoplasmic tail (CT) and interaction with intracellular pathways and transcription factors to regulate cell function. Here we demonstrate the interaction of PC1-CT with JAK2/STAT3 signaling axis in mechanically stimulated human osteoblastic cells, leading to transcriptional induction of Runx2 gene, a master regulator of osteoblastic differentiation. Primary osteoblast-like PC1-expressing cells subjected to mechanical-stretching exhibited a PC1-dependent increase of the phosphorylated(p)/active form of JAK2. Specific interaction of PC1-CT with pJAK2 was observed after stretching while pre-treatment of cells with PC1 (anti-IgPKD1) and JAK2 inhibitors abolished JAK2 activation. Consistently, mechanostimulation triggered PC1-mediated phosphorylation and nuclear translocation of STAT3. The nuclear phosphorylated(p)/DNA-binding competent pSTAT3 levels were augmented after stretching followed by elevated DNA-binding activity. Pre-treatment with a STAT3 inhibitor either alone or in combination with anti-IgPKD1 abrogated this effect. Moreover, PC1-mediated mechanostimulation induced elevation of Runx2 mRNA levels. ChIP assays revealed direct regulation of Runx2 promoter activity by STAT3/Runx2 after mechanical-stretching that was PC1-dependent. Our findings show that mechanical load upregulates expression of Runx2 gene via potentiation of PC1-JAK2/STAT3 signaling axis, culminating to possibly control osteoblastic differentiation and ultimately bone formation.
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Affiliation(s)
- Georgia Dalagiorgou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 75, M. Asias Street, 11527, Athens, Greece
| | - Christina Piperi
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 75, M. Asias Street, 11527, Athens, Greece
| | - Christos Adamopoulos
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 75, M. Asias Street, 11527, Athens, Greece
| | - Urania Georgopoulou
- Molecular Virology Laboratory, Hellenic Pasteur Institute, 11521, Athens, Greece
| | - Antonios N Gargalionis
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 75, M. Asias Street, 11527, Athens, Greece
| | - Anastasia Spyropoulou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 75, M. Asias Street, 11527, Athens, Greece
| | - Ilianna Zoi
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 75, M. Asias Street, 11527, Athens, Greece
| | - Marjan Nokhbehsaim
- Section of Experimental Dento-Maxillo-Facial Medicine, Center of Dento-Maxillo-Facial Medicine, University of Bonn, 53111, Bonn, Germany
| | - Anna Damanaki
- Section of Experimental Dento-Maxillo-Facial Medicine, Center of Dento-Maxillo-Facial Medicine, University of Bonn, 53111, Bonn, Germany
| | - James Deschner
- Section of Experimental Dento-Maxillo-Facial Medicine, Center of Dento-Maxillo-Facial Medicine, University of Bonn, 53111, Bonn, Germany
| | - Efthimia K Basdra
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 75, M. Asias Street, 11527, Athens, Greece.
| | - Athanasios G Papavassiliou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 75, M. Asias Street, 11527, Athens, Greece.
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13
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Ketoff S, Girinon F, Schlager S, Friess M, Schouman T, Rouch P, Khonsari RH. Zygomatic bone shape in intentional cranial deformations: a model for the study of the interactions between skull growth and facial morphology. J Anat 2016; 230:524-531. [PMID: 28032345 DOI: 10.1111/joa.12581] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/17/2016] [Indexed: 11/28/2022] Open
Abstract
Intentional cranial deformations (ICD) were obtained by exerting external mechanical constraints on the skull vault during the first years of life to permanently modify head shape. The repercussions of ICD on the face are not well described in the midfacial region. Here we assessed the shape of the zygomatic bone in different types of ICDs. We considered 14 non-deformed skulls, 19 skulls with antero-posterior deformation, nine skulls with circumferential deformation and seven skulls with Toulouse deformation. The shape of the zygomatic bone was assessed using a statistical shape model after mesh registration. Euclidian distances between mean models and Mahalanobis distances after canonical variate analysis were computed. Classification accuracy was computed using a cross-validation approach. Different ICDs cause specific zygomatic shape modifications corresponding to different degrees of retrusion but the shape of the zygomatic bone alone is not a sufficient parameter for classifying populations into ICD groups defined by deformation types. We illustrate the fact that external mechanical constraints on the skull vault influence midfacial growth. ICDs are a model for the study of the influence of epigenetic factors on craniofacial growth and can help to understand the facial effects of congenital skull malformations such as single or multi-suture synostoses, or of external orthopedic devices such as helmets used to correct deformational plagiocephaly.
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Affiliation(s)
- S Ketoff
- Assistance Publique - Hôpitaux de Paris, Hôpital Universitaire Pitié-Salpêtrière, Service de chirurgie maxillofaciale et stomatologie, Paris, France.,Université Pierre-et-Marie-Curie, Sorbonne Universités, Paris, France.,Arts et Métiers ParisTech, Institut de Biomécanique Humaine Georges Charpak, Paris, France
| | - F Girinon
- Arts et Métiers ParisTech, Institut de Biomécanique Humaine Georges Charpak, Paris, France
| | - S Schlager
- Biological Anthropology, University of Freiburg, Freiburg, Germany
| | - M Friess
- Département Hommes, Nature, Sociétés, Muséum National d'Histoire Naturelle, CNRS UMR-7206, Paris, France
| | - T Schouman
- Assistance Publique - Hôpitaux de Paris, Hôpital Universitaire Pitié-Salpêtrière, Service de chirurgie maxillofaciale et stomatologie, Paris, France.,Université Pierre-et-Marie-Curie, Sorbonne Universités, Paris, France.,Arts et Métiers ParisTech, Institut de Biomécanique Humaine Georges Charpak, Paris, France
| | - P Rouch
- Arts et Métiers ParisTech, Institut de Biomécanique Humaine Georges Charpak, Paris, France
| | - R H Khonsari
- Assistance Publique - Hôpitaux de Paris, Hôpital Universitaire Pitié-Salpêtrière, Service de chirurgie maxillofaciale et stomatologie, Paris, France.,Université Pierre-et-Marie-Curie, Sorbonne Universités, Paris, France
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14
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Karamesinis K, Spyropoulou A, Dalagiorgou G, Katsianou MA, Nokhbehsaim M, Memmert S, Deschner J, Vastardis H, Piperi C. Continuous hydrostatic pressure induces differentiation phenomena in chondrocytes mediated by changes in polycystins, SOX9, and RUNX2. J Orofac Orthop 2016; 78:21-31. [PMID: 27909759 DOI: 10.1007/s00056-016-0061-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2016] [Accepted: 06/21/2016] [Indexed: 02/07/2023]
Abstract
PURPOSE The present study aimed to investigate the long-term effects of hydrostatic pressure on chondrocyte differentiation, as indicated by protein levels of transcription factors SOX9 and RUNX2, on transcriptional activity of SOX9, as determined by pSOX9 levels, and on the expression of polycystin-encoding genes Pkd1 and Pkd2. MATERIALS AND METHODS ATDC5 cells were cultured in insulin-supplemented differentiation medium (ITS) and/or exposed to 14.7 kPa of hydrostatic pressure for 12, 24, 48, and 96 h. Cell extracts were assessed for SOX9, pSOX9, and RUNX2 using western immunoblotting. The Pkd1 and Pkd2 mRNA levels were detected by real-time PCR. RESULTS Hydrostatic pressure resulted in an early drop in SOX9 and pSOX9 protein levels at 12 h followed by an increase from 24 h onwards. A reverse pattern was followed by RUNX2, which reached peak levels at 24 h of hydrostatic pressure-treated chondrocytes in ITS culture. Pkd1 and Pkd2 mRNA levels increased at 24 h of combined hydrostatic pressure and ITS treatment, with the latter remaining elevated up to 96 h. CONCLUSIONS Our data indicate that long periods of continuous hydrostatic pressure stimulate chondrocyte differentiation through a series of molecular events involving SOX9, RUNX2, and polycystins-1, 2, providing a theoretical background for functional orthopedic mechanotherapies.
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Affiliation(s)
- Konstantinos Karamesinis
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 75, M. Asias Street, 11527, Athens, Greece.,Department of Orthodontics, Dental School, National and Kapodistrian University of Athens, 11527, Athens, Greece
| | - Anastasia Spyropoulou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 75, M. Asias Street, 11527, Athens, Greece
| | - Georgia Dalagiorgou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 75, M. Asias Street, 11527, Athens, Greece
| | - Maria A Katsianou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 75, M. Asias Street, 11527, Athens, Greece
| | - Marjan Nokhbehsaim
- Section of Experimental Dento-Maxillo-Facial Medicine, University of Bonn, Welschnonnenstrasse 17, 53111, Bonn, Germany
| | - Svenja Memmert
- Department of Orthodontics Dento-Maxillo-Facial Medicine, University of Bonn, Welschnonnenstrasse 17, 53111, Bonn, Germany
| | - James Deschner
- Section of Experimental Dento-Maxillo-Facial Medicine, University of Bonn, Welschnonnenstrasse 17, 53111, Bonn, Germany
| | - Heleni Vastardis
- Department of Orthodontics, Dental School, National and Kapodistrian University of Athens, 11527, Athens, Greece
| | - Christina Piperi
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 75, M. Asias Street, 11527, Athens, Greece.
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15
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Katsianou MA, Adamopoulos C, Vastardis H, Basdra EK. Signaling mechanisms implicated in cranial sutures pathophysiology: Craniosynostosis. BBA CLINICAL 2016; 6:165-176. [PMID: 27957430 PMCID: PMC5144105 DOI: 10.1016/j.bbacli.2016.04.006] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/25/2016] [Revised: 04/19/2016] [Accepted: 04/27/2016] [Indexed: 01/19/2023]
Abstract
Normal extension and skull expansion is a synchronized process that prevails along the osteogenic intersections of the cranial sutures. Cranial sutures operate as bone growth sites allowing swift bone generation at the edges of the bone fronts while they remain patent. Premature fusion of one or more cranial sutures can trigger craniosynostosis, a birth defect characterized by dramatic manifestations in appearance and functional impairment. Up until today, surgical correction is the only restorative measure for craniosynostosis associated with considerable mortality. Clinical studies have identified several genes implicated in the pathogenesis of craniosynostosis syndromes with useful insights into the underlying molecular signaling events that determine suture fate. In this review, we exploit the intracellular signal transduction pathways implicated in suture pathobiology, in an attempt to identify key signaling molecules for therapeutic targeting.
Cranial sutures operate as bone growth sites. Premature fusion of one or more cranial sutures can trigger craniosynostosis. Several genes are involved in the pathogenesis of craniosynostosis syndromes. An array of molecular signaling events determine suture fate. Herein, the signal transduction pathways implicated in suture pathobiology are discussed.
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Affiliation(s)
- Maria A Katsianou
- Department of Biological Chemistry - Cellular and Molecular Biomechanics Unit, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Christos Adamopoulos
- Department of Biological Chemistry - Cellular and Molecular Biomechanics Unit, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Heleni Vastardis
- Department of Orthodontics, Dental School, National and Kapodistrian University of Athens, 11527, Athens, Greece
| | - Efthimia K Basdra
- Department of Biological Chemistry - Cellular and Molecular Biomechanics Unit, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
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16
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Piperi C, Basdra EK. Polycystins and mechanotransduction: From physiology to disease. World J Exp Med 2015; 5:200-205. [PMID: 26618106 PMCID: PMC4655249 DOI: 10.5493/wjem.v5.i4.200] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2015] [Revised: 07/21/2015] [Accepted: 09/16/2015] [Indexed: 02/06/2023] Open
Abstract
Polycystins are key mechanosensor proteins able to respond to mechanical forces of external or internal origin. They are widely expressed in primary cilium and plasma membrane of several cell types including kidney, vascular endothelial and smooth muscle cells, osteoblasts and cardiac myocytes modulating their physiology. Interaction of polycystins with diverse ion channels, cell-cell and cell-extracellular matrix junctional proteins implicates them in the regulation of cell structure, mechanical force transmission and mechanotransduction. Their intracellular localization in endoplasmic reticulum further regulates subcellular trafficking and calcium homeostasis, finely-tuning overall cellular mechanosensitivity. Aberrant expression or genetic alterations of polycystins lead to severe structural and mechanosensing abnormalities including cyst formation, deregulated flow sensing, aneurysms, defective bone development and cancer progression, highlighting their vital role in human physiology.
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17
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Liu Y, Tang Y, Xiao L, Liu SSY, Yu H. Suture cartilage formation pattern varies with different expansive forces. Am J Orthod Dentofacial Orthop 2014; 146:442-50. [DOI: 10.1016/j.ajodo.2014.06.016] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2013] [Revised: 06/01/2014] [Accepted: 06/01/2014] [Indexed: 01/23/2023]
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18
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Wang H, Sun W, Ma J, Pan Y, Wang L, Zhang W. Polycystin-1 mediates mechanical strain-induced osteoblastic mechanoresponses via potentiation of intracellular calcium and Akt/β-catenin pathway. PLoS One 2014; 9:e91730. [PMID: 24618832 PMCID: PMC3950298 DOI: 10.1371/journal.pone.0091730] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2013] [Accepted: 02/14/2014] [Indexed: 12/16/2022] Open
Abstract
Mechanical regulation of bone formation involves a complex biophysical process, yet the underlying mechanisms remain poorly understood. Polycystin-1 (PC1) is postulated to function as a mechanosensory molecule mediating mechanical signal transduction in renal epithelial cells. To investigate the involvement of PC1 in mechanical strain-induced signaling cascades controlling osteogenesis, PKD1 gene was stably silenced in osteoblastic cell line MC3T3-E1 by using lentivirus-mediated shRNA technology. Here, our findings showed that mechanical tensile strain sufficiently enhanced osteogenic gene expressions and osteoblastic proliferation. However, PC1 deficiency resulted in the loss of the ability to sense external mechanical stimuli thereby promoting osteoblastic osteogenesis and proliferation. The signal pathways implicated in this process were intracellular calcium and Akt/β-catenin pathway. The basal levels of intracellular calcium, phospho-Akt, phospho-GSK-3β and nuclear accumulation of active β-catenin were significantly attenuated in PC1 deficient osteoblasts. In addition, PC1 deficiency impaired mechanical strain-induced potentiation of intracellular calcium, and activation of Akt-dependent and Wnt/β-catenin pathways, which was able to be partially reversed by calcium ionophore A23187 treatment. Furthermore, applications of LiCl or A23187 in PC1 deficient osteoblasts could promote osteoblastic differentiation and proliferation under mechanical strain conditions. Therefore, our results demonstrated that osteoblasts require mechanosensory molecule PC1 to adapt to external mechanical tensile strain thereby inducing osteoblastic mechanoresponse, partially through the potentiation of intracellular calcium and downstream Akt/β-catenin signaling pathway.
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Affiliation(s)
- Hua Wang
- Institute of Stomatology, Nanjing Medical University, Nanjing, China
| | - Wen Sun
- The Research Center for Bone and Stem Cells, Department of Anatomy, Histology and Embryology, Nanjing Medical University, Nanjing, China
| | - Junqing Ma
- Institute of Stomatology, Nanjing Medical University, Nanjing, China
| | - Yongchu Pan
- Institute of Stomatology, Nanjing Medical University, Nanjing, China
| | - Lin Wang
- Institute of Stomatology, Nanjing Medical University, Nanjing, China
- * E-mail: (LW); (WZ)
| | - Weibing Zhang
- Institute of Stomatology, Nanjing Medical University, Nanjing, China
- * E-mail: (LW); (WZ)
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19
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Shalish M, Will LA, Fukai N, Hou B, Olsen BR. Role of polycystin-1 in bone remodeling: orthodontic tooth movement study in mutant mice. Angle Orthod 2014; 84:885-90. [PMID: 24559508 DOI: 10.2319/082313-620.1] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
OBJECTIVE To test the hypothesis that polycystin-1 (PC1) is involved in orthodontic tooth movement as a mechanical sensor. MATERIALS AND METHODS The response to force application was compared between three mutant and four wild-type 7-week-old mice. The mutant mice were PC1/Wnt1-cre, lacking PC1 in the craniofacial region. An orthodontic closed coil spring was bonded between the incisor and the left first molar, applying 20 g of force for 4 days. Micro-computed tomography, hematoxylin and eosin staining, and tartrate-resistent acid phosphatase (TRAP) staining were used to study the differences in tooth movement among the groups. RESULTS In the wild-type mice the bonded molar moved mesially, and the periodontal ligament (PDL) was compressed in the compression side. The compression side showed a hyalinized zone, and osteoclasts were identified there using TRAP staining. In the mutant mice, the molar did not move, the incisor tipped palatally, and there was slight widening of the PDL in the tension area. Osteoclasts were not seen on the bone surface or on the compression side. Osteoclasts were only observed on the other side of the bone-in the bone marrow. CONCLUSIONS These results suggest a difference in tooth movement and osteoclast activity between PC1 mutant mice and wild-type mice in response to orthodontic force. The impaired tooth movement and the lack of osteoclasts on the bone surface in the mutant working side may be related to lack of signal from the PDL due to PC1 deficiency.
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Affiliation(s)
- Miriam Shalish
- a Director of Postgraduate Program, Department of Orthodontics, Hebrew University-Hadassah School of Dental Medicine, Jerusalem, Israel
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20
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Xu H, Guan Y, Wu J, Zhang J, Duan J, An L, Shang P. Polycystin 2 is involved in the nitric oxide production in responding to oscillating fluid shear in MLO-Y4 cells. J Biomech 2013; 47:387-91. [PMID: 24268313 DOI: 10.1016/j.jbiomech.2013.11.018] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2013] [Revised: 10/07/2013] [Accepted: 11/06/2013] [Indexed: 02/03/2023]
Abstract
As a mechano-calcium channel, polycystin2 (PC2) play an important role in the response of renal epithelial cells to fluid flow shear stress. In bone tissue, osteocytes are well known as the main mechanosensory cells, and sensitive to fluid flow stimulus in vitro. In the study, we investigated the effects of oscillating fluid flow (OFF, 2 h, 1 Hz, 1.0 Pa) on the release of Nitric Oxide (NO) and ProstaglandinE2 (PGE2), and the role of PC2 on the release. Our findings demonstrate that PC2 expression increases after 2 h of OFF, and silencing PC2 by RNAi inhibits downstream NO production and iNOS expression, but does not affect the response of PGE2 to OFF.
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Affiliation(s)
- Huiyun Xu
- Key Laboratory for Space Biosciences & Biotechnology, School of Life Sciences, Northwestern Polytechnical University, 127 Youyi Xilu, Xi'an 710072, Shaanxi Province, People's Republic of China
| | - Ying Guan
- Key Laboratory for Space Biosciences & Biotechnology, School of Life Sciences, Northwestern Polytechnical University, 127 Youyi Xilu, Xi'an 710072, Shaanxi Province, People's Republic of China
| | - Jiawei Wu
- Key Laboratory for Space Biosciences & Biotechnology, School of Life Sciences, Northwestern Polytechnical University, 127 Youyi Xilu, Xi'an 710072, Shaanxi Province, People's Republic of China
| | - Jian Zhang
- Key Laboratory for Space Biosciences & Biotechnology, School of Life Sciences, Northwestern Polytechnical University, 127 Youyi Xilu, Xi'an 710072, Shaanxi Province, People's Republic of China
| | - Jin Duan
- Key Laboratory for Space Biosciences & Biotechnology, School of Life Sciences, Northwestern Polytechnical University, 127 Youyi Xilu, Xi'an 710072, Shaanxi Province, People's Republic of China
| | - Long An
- Key Laboratory for Space Biosciences & Biotechnology, School of Life Sciences, Northwestern Polytechnical University, 127 Youyi Xilu, Xi'an 710072, Shaanxi Province, People's Republic of China
| | - Peng Shang
- Key Laboratory for Space Biosciences & Biotechnology, School of Life Sciences, Northwestern Polytechnical University, 127 Youyi Xilu, Xi'an 710072, Shaanxi Province, People's Republic of China.
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21
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Huang C, Holfeld J, Schaden W, Orgill D, Ogawa R. Mechanotherapy: revisiting physical therapy and recruiting mechanobiology for a new era in medicine. Trends Mol Med 2013; 19:555-64. [DOI: 10.1016/j.molmed.2013.05.005] [Citation(s) in RCA: 123] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2013] [Revised: 05/02/2013] [Accepted: 05/22/2013] [Indexed: 01/13/2023]
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Khonsari RH, Ohazama A, Raouf R, Kawasaki M, Kawasaki K, Porntaveetus T, Ghafoor S, Hammond P, Suttie M, Odri GA, Sandford RN, Wood JN, Sharpe PT. Multiple postnatal craniofacial anomalies are characterized by conditional loss of polycystic kidney disease 2 (Pkd2). Hum Mol Genet 2013; 22:1873-85. [PMID: 23390131 DOI: 10.1093/hmg/ddt041] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
Polycystin 2 (Pkd2), which belongs to the transient receptor potential family, plays a critical role in development. Pkd2 is mainly localized in the primary cilia, which also function as mechanoreceptors in many cells that influence multiple biological processes including Ca(2+) influx, chemical activity and signalling pathways. Mutations in many cilia proteins result in craniofacial abnormalities. Orofacial tissues constantly receive mechanical forces and are known to develop and grow through intricate signalling pathways. Here we investigate the role of Pkd2, whose role remains unclear in craniofacial development and growth. In order to determine the role of Pkd2 in craniofacial development, we located expression in craniofacial tissues and analysed mice with conditional deletion of Pkd2 in neural crest-derived cells, using Wnt1Cre mice. Pkd2 mutants showed many signs of mechanical trauma such as fractured molar roots, distorted incisors, alveolar bone loss and compressed temporomandibular joints, in addition to abnormal skull shapes. Significantly, mutants showed no indication of any of these phenotypes at embryonic stages when heads perceive no significant mechanical stress in utero. The results suggest that Pkd2 is likely to play a critical role in craniofacial growth as a mechanoreceptor. Pkd2 is also identified as one of the genes responsible for autosomal dominant polycystic kidney disease (ADPKD). Since facial anomalies have never been identified in ADPKD patients, we carried out three-dimensional photography of patient faces and analysed these using dense surface modelling. This analysis revealed specific characteristics of ADPKD patient faces, some of which correlated with those of the mutant mice.
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Affiliation(s)
- Roman H Khonsari
- Department of Craniofacial Development and Stem Cell Research, and Comprehensive Biomedical Research Centre, Dental Institute, King’s College London, London, UK
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23
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Nauli SM, Jin X, AbouAlaiwi WA, El-Jouni W, Su X, Zhou J. Non-motile primary cilia as fluid shear stress mechanosensors. Methods Enzymol 2013; 525:1-20. [PMID: 23522462 PMCID: PMC4096622 DOI: 10.1016/b978-0-12-397944-5.00001-8] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Primary cilia are sensory organelles that transmit extracellular signals into intracellular biochemical responses. Structural and functional defects in primary cilia are associated with a group of human diseases, known as ciliopathies, with phenotypes ranging from cystic kidney and obesity to blindness and mental retardation. Primary cilia mediate mechano- and chemosensation in many cell types. The mechanosensory function of the primary cilia requires the atypical G-protein-coupled receptor polycystin-1 and the calcium-permeable nonselective cation channel polycystin-2. Mechanical stimulations such as fluid-shear stress of the primary cilia initiate intracellular calcium rise, nitric oxide release, and protein modifications. In this review, we describe a set of protocols for cell culture to promote ciliation, mechanical stimulations of the primary cilia, and measurements of calcium rise and nitric oxide release induced by fluid shear stress.
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Affiliation(s)
- Surya M. Nauli
- Department of Pharmacology, The University of Toledo, Toledo, Ohio, USA
| | - Xingjian Jin
- Department of Pharmacology, The University of Toledo, Toledo, Ohio, USA
| | | | - Wassim El-Jouni
- Renal Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Xuefeng Su
- Renal Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Jing Zhou
- Renal Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
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24
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Henry SP, Liang S, Akdemir KC, de Crombrugghe B. The postnatal role of Sox9 in cartilage. J Bone Miner Res 2012; 27:2511-25. [PMID: 22777888 PMCID: PMC3502666 DOI: 10.1002/jbmr.1696] [Citation(s) in RCA: 122] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2012] [Revised: 06/05/2012] [Accepted: 06/22/2012] [Indexed: 11/09/2022]
Abstract
Sox9 is an essential transcription factor for the differentiation of the chondrocytic lineage during embryonic development. To test whether Sox9 continues to play a critical role in cartilaginous tissues in the adult mice, we used an inducible, genetic strategy to disrupt the Sox9 gene postnatally in these tissues. The postnatal inactivation of Sox9 led to stunted growth characterized by decreased proliferation, increased cell death, and dedifferentiation of growth plate chondrocytes. Upon postnatal Sox9 inactivation in the articular cartilage, the sulfated proteoglycan and aggrecan content of the uncalcified cartilage were rapidly depleted and the degradation of aggrecan was accompanied by higher ADAMTS5 immunostaining and increased detection of the aggrecan neoepitope, NITEGE. In spite of the severe loss of Collagen 2a1 mRNA, the Collagen II protein persisted in the articular cartilage, and no histopathological signs of osteoarthritis were observed. The homeostasis of the intervertebral disk (IVD) was dramatically altered upon Sox9 depletion, resulting in disk compression and subsequent degeneration. Inactivation of Sox9 in the IVD markedly reduced the expression of several genes encoding extracellular matrix proteins, as well as some of the enzymes responsible for their posttranslational modification. Furthermore, the loss of Sox9 in the IVD decreased the expression of cytokines, cell-surface receptors, and ion channels, suggesting that Sox9 coordinates a large genetic program that is instrumental for the proper homeostasis of the cells contained in the IVD postnatally. Our results indicate that Sox9 has an essential role in the physiological control of cartilaginous tissues in adult mice. © 2012 American Society for Bone and Mineral Research.
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Affiliation(s)
- Stephen P Henry
- Department of Genetics, The University of Texas M.D. Anderson Cancer Center; Houston, TX, USA.
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25
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Dalagiorgou G, Piperi C, Georgopoulou U, Adamopoulos C, Basdra EK, Papavassiliou AG. Mechanical stimulation of polycystin-1 induces human osteoblastic gene expression via potentiation of the calcineurin/NFAT signaling axis. Cell Mol Life Sci 2012; 70:167-180. [PMID: 23014991 DOI: 10.1007/s00018-012-1164-5] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2012] [Revised: 09/03/2012] [Accepted: 09/06/2012] [Indexed: 01/12/2023]
Abstract
Mechanical forces trigger biological responses in bone cells that ultimately control osteoblastogenesis and bone program. Although several mechanosensors have been postulated, the precise mechanotransduction pathway remains obscure as the initial mechanosensing event has not yet been identified. Studies in kidney cells have shown that polycystin-1 (PC1), via its extracellular N-terminal part, may function as an "antenna-like" protein providing a linkage between environmental cues and their conversion into biochemical responses that regulate various cellular processes via the calcineurin/NFAT pathway. Here we explored the involvement of PC1 in mechanical load (stretching)-induced signaling cascades that control osteoblastogenesis/bone formation. FACS and TransAM Transcription Factor ELISA analyses employing extracts from primary human osteoblast-like, PC1 expressing cells subjected to mechanical stretching (0-6 h) revealed that unphosphorylated/DNA-binding competent NFATc1 increased at 0.5-1 h and returned to normal at 6 h. In accordance with the activation mechanism of NFATc1, stretching of cultured cells pre-treated with cyclosporin A (CsA, a specific inhibitor of the calcineurin/NFAT pathway) abrogated the observed decrease in the abundance of the cytoplasmic pNFATc1 (phosphorylated/inactive) species. Furthermore, stretching of osteoblastic cells pre-treated with an antibody against the mechanosensing N-terminal part of PC1 also abrogated the observed decrease in the cytoplasmic levels of the inactive pNFATc1 species. Importantly, under similar conditions (pre-incubation of stretched cells with the inhibitory anti-PC1 antibody), the expression of the key osteoblastic, NFATc1-target gene runx2 decreased compared to untreated cells. Therefore, PC1 acts as chief mechanosensing molecule that modulates osteoblastic gene transcription and hence bone-cell differentiation through the calcineurin/NFAT signaling cascade.
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Affiliation(s)
- Georgia Dalagiorgou
- Department of Biological Chemistry, University of Athens Medical School, 11527 Athens, Greece
| | - Christina Piperi
- Department of Biological Chemistry, University of Athens Medical School, 11527 Athens, Greece
| | - Urania Georgopoulou
- Molecular Virology Laboratory, Hellenic Pasteur Institute, 11527 Athens, Greece
| | - Christos Adamopoulos
- Department of Biological Chemistry, University of Athens Medical School, 11527 Athens, Greece
| | - Efthimia K Basdra
- Department of Biological Chemistry, University of Athens Medical School, 11527 Athens, Greece
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26
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Qiu N, Xiao Z, Cao L, David V, Quarles LD. Conditional mesenchymal disruption of pkd1 results in osteopenia and polycystic kidney disease. PLoS One 2012; 7:e46038. [PMID: 23029375 PMCID: PMC3448720 DOI: 10.1371/journal.pone.0046038] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2012] [Accepted: 08/28/2012] [Indexed: 01/13/2023] Open
Abstract
Conditional deletion of Pkd1 in osteoblasts using either Osteocalcin(Oc)-Cre or Dmp1-Cre results in defective osteoblast-mediated postnatal bone formation and osteopenia. Pkd1 is also expressed in undifferentiated mesenchyme that gives rise to the osteoblast lineage. To examine the effects of Pkd1 on prenatal osteoblast development, we crossed Pkd1flox/flox and Col1a1(3.6)-Cre mice, which has been used to achieve selective inactivation of Pkd1 earlier in the osteoblast lineage. Control Pkd1flox/flox and Pkd1flox/+, heterozygous Col1a1(3.6)-Cre;Pkd1flox/+ and Pkd1flox/null, and homozygous Col1a1(3.6)-Cre;Pkd1flox/flox and Col1a1(3.6)-Cre;Pkd1flox/null mice were analyzed at ages ranging from E14.5 to 8-weeks-old. Newborn Col1a1(3.6)-Cre;Pkd1flox/null mice exhibited defective skeletogenesis in association with a greater reduction in Pkd1 expression in bone. Conditional Col1a1(3.6)-Cre;Pkd1flox/+ and Col1a1(3.6)-Cre;Pkd1flox/flox mice displayed a gene dose-dependent decrease in bone formation and increase in marrow fat at 6 weeks of age. Bone marrow stromal cell and primary osteoblast cultures from homozygous Col1a1(3.6)-Cre;Pkd1flox/flox mice showed increased proliferation, impaired osteoblast development and enhanced adipogenesis ex vivo. Unexpectedly, we found evidence for Col1a1(3.6)-Cre mediated deletion of Pkd1 in extraskeletal tissues in Col1a1(3.6)-Cre;Pkd1flox/flox mice. Deletion of Pkd1 in mesenchymal precursors resulted in pancreatic and renal, but not hepatic, cyst formation. The non-lethality of Col1a1(3.6)-Cre;Pkd1flox/flox mice establishes a new model to study abnormalities in bone development and cyst formation in pancreas and kidney caused by Pkd1 gene inactivation.
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Affiliation(s)
- Ni Qiu
- Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America
| | - Zhousheng Xiao
- Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America
| | - Li Cao
- Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America
| | - Valentin David
- Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America
| | - Leigh Darryl Quarles
- Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America
- * E-mail:
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27
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Katebi N, Kolpakova-Hart E, Lin CY, Olsen BR. The mouse palate and its cellular responses to midpalatal suture expansion forces. Orthod Craniofac Res 2012; 15:148-58. [PMID: 22812437 DOI: 10.1111/j.1601-6343.2012.01547.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
OBJECTIVES To investigate the anatomy of the mouse palate, the midpalatal suture, and the cellular characteristics in the sutures before and immediately after midpalatal suture expansion. MATERIALS AND METHODS Wild-type C57BL/6 male mice, aged between 6 weeks and 12 months, were chosen for all the experiments. The complete palate of the non-operated group and the midpalatal suture-expanded group at different ages was used for histological, micro-CT, immunohistochemistry, and sutural cell analyses. RESULTS This study documents precise morphological and histological characteristics of the mouse palatal sutures. In addition to the opening of the midpalatal suture caused by expansion, both transverse and interpalatine sutures were also seen to be affected. Cellular density was decreased in different types of sutures following the application of mechanical force. CONCLUSIONS The detailed morphology and histology of the mouse palate and the cellular changes that occur following midpalatal suture expansion, as described here, will be helpful as a basis for further investigations of palatal suture tissue responses to mechanical force.
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Affiliation(s)
- N Katebi
- Department of Developmental Biology, Harvard School of Dental Medicine, 188 Longwood Avenue, Boston, MA 02115, USA
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28
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Mechanosensing by the primary cilium: deletion of Kif3A reduces bone formation due to loading. PLoS One 2012; 7:e33368. [PMID: 22428034 PMCID: PMC3299788 DOI: 10.1371/journal.pone.0033368] [Citation(s) in RCA: 82] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2010] [Accepted: 02/13/2012] [Indexed: 11/19/2022] Open
Abstract
Primary cilia, solitary microtubule-based structures that grow from the centriole and extend into the extracellular space, have increasingly been implicated as sensors of a variety of biochemical and biophysical signals. Mutations in primary cilium-related genes have been linked to a number of rare developmental disorders as well as dysregulation of cell proliferation. We propose that primary cilia are also important in mechanically regulated bone formation in adults and that their malfunction could play a role in complex multi-factorial bone diseases, such as osteoporosis. In this study, we generated mice with an osteoblast- and osteocyte-specific knockout of Kif3a, a subunit of the kinesin II intraflagellar transport (IFT) protein; IFT is required for primary cilia formation, maintenance, and function. These Colα1(I) 2.3-Cre;Kif3a(fl/fl) mice exhibited no obvious morphological skeletal abnormalities. Skeletally mature Colα1(I) 2.3-Cre;Kif3a(fl/fl) and control mice were exposed to 3 consecutive days of cyclic axial ulna loading, which resulted in a significant increase in bone formation in both the conditional knockouts and controls. However, Colα1(I) 2.3-Cre;Kif3a(fl/fl) mice did exhibit decreased formation of new bone in response to mechanical ulnar loading compared to control mice. These results suggest that primary cilia act as cellular mechanosensors in bone and that their function may be critical for the regulation of bone physiology due to mechanical loading in adults.
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29
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Xiao Z, Dallas M, Qiu N, Nicolella D, Cao L, Johnson M, Bonewald L, Quarles LD. Conditional deletion of Pkd1 in osteocytes disrupts skeletal mechanosensing in mice. FASEB J 2011; 25:2418-32. [PMID: 21454365 DOI: 10.1096/fj.10-180299] [Citation(s) in RCA: 92] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
We investigated whether polycystin-1 is a bone mechanosensor. We conditionally deleted Pkd1 in mature osteoblasts/osteocytes by crossing Dmp1-Cre with Pkd1(flox/m1Bei) mice, in which the m1Bei allele is nonfunctional. We assessed in wild-type and Pkd1-deficient mice the response to mechanical loading in vivo by ulna loading and ex vivo by measuring the response of isolated osteoblasts to fluid shear stress. We found that conditional Pkd1 heterozygotes (Dmp1-Cre;Pkd1(flox/+)) and null mice (Pkd1(Dmp1-cKO)) exhibited a ∼ 40 and ∼ 90% decrease, respectively, in functional Pkd1 transcripts in bone. Femoral bone mineral density (12 vs. 27%), trabecular bone volume (32 vs. 48%), and cortical thickness (6 vs. 17%) were reduced proportionate to the reduction of Pkd1 gene dose, as were mineral apposition rate (MAR) and expression of Runx2-II, Osteocalcin, Dmp1, and Phex. Anabolic load-induced periosteal lamellar MAR (0.58 ± 0.14; Pkd1(Dmp1-cKO) vs. 1.68 ± 0.34 μm/d; control) and increases in Cox-2, c-Jun, Wnt10b, Axin2, and Runx2-II gene expression were significantly attenuated in Pkd1(Dmp1-cKO) mice compared with controls. Application of fluid shear stress to immortalized osteoblasts from Pkd1(null/null) and Pkd1(m1Bei/m1Bei)-derived osteoblasts failed to elicit the increments in cytosolic calcium observed in wild-type controls. These data indicate that polycystin-1 is essential for the anabolic response to skeletal loading in osteoblasts/osteocytes.
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Affiliation(s)
- Zhousheng Xiao
- Department of Medicine, The University of Tennessee Health Science Center, Memphis, TN 38165, USA.
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30
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Patients with autosomal dominant polycystic kidney disease have elevated fibroblast growth factor 23 levels and a renal leak of phosphate. Kidney Int 2010; 79:234-40. [PMID: 20944552 DOI: 10.1038/ki.2010.375] [Citation(s) in RCA: 66] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Fibroblast growth factor 23 (FGF23) and parathyroid hormone blood levels rise following progressive loss of renal function. Here we measured parameters of phosphate metabolism in 100 patients with autosomal dominant polycystic kidney disease (ADPKD) in stage 1 or 2 of chronic kidney disease, 20 patients with non-diabetic chronic kidney disease, and 26 with type 2 diabetes. Twenty healthy volunteers served as controls. The mean levels of FGF23 were significantly (4-fold) higher in ADPKD compared to non-diabetic and diabetic patients, and healthy volunteers. Mean serum phosphate levels were significantly lower in ADPKD patients compared to non-diabetic and diabetic patients, and the healthy volunteers. The prevalence of hypophosphatemia was 38, 25, 27, and 5% in ADPKD, non-diabetic and diabetic patients, and healthy volunteers, respectively. The tubular maximum of phosphate reabsorption per glomerular filtration rate was lowest in ADPKD patients with a significantly high positive correlation with serum phosphate levels. Estimated glomerular filtration rates were approximately 100 ml/min per 1.73 m² in all groups and parathyroid hormone and vitamin D metabolite levels were in the normal range. Thus, FGF23 was substantially elevated in ADPKD patients compared to other CKD patients matched for glomerular filtration rate, and was associated with increased renal phosphate excretion. The mechanism for this anomaly will require further study.
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31
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Abdul-Majeed S, Nauli SM. Calcium-mediated mechanisms of cystic expansion. Biochim Biophys Acta Mol Basis Dis 2010; 1812:1281-90. [PMID: 20932898 DOI: 10.1016/j.bbadis.2010.09.016] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2010] [Revised: 09/13/2010] [Accepted: 09/30/2010] [Indexed: 01/23/2023]
Abstract
In this review, we will discuss several well-accepted signaling pathways toward calcium-mediated mechanisms of cystic expansion. The second messenger calcium ion has contributed to a vast diversity of signal transduction pathways. We will dissect calcium signaling as a possible mechanism that contributes to renal cyst formation. Because cytosolic calcium also regulates an array of signaling pathways, we will first discuss cilia-induced calcium fluxes, followed by Wnt signaling that has attributed to much-discussed planar cell polarity. We will then look at the relationship between cytosolic calcium and cAMP as one of the most important aspects of cyst progression. The signaling of cAMP on MAPK and mTOR will also be discussed. We infer that while cilia-induced calcium fluxes may be the initial signaling messenger for various cellular pathways, no single signaling mediator or pathway is implicated exclusively in the progression of the cystic expansion. This article is part of a Special Issue entitled: Polycystic Kidney Disease.
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32
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Dalagiorgou G, Basdra EK, Papavassiliou AG. Polycystin-1: function as a mechanosensor. Int J Biochem Cell Biol 2010; 42:1610-3. [PMID: 20601082 DOI: 10.1016/j.biocel.2010.06.017] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2010] [Revised: 06/16/2010] [Accepted: 06/18/2010] [Indexed: 12/31/2022]
Abstract
Polycystin-1 (PC1), encoded by the Pkd1 gene, is a large transmembrane protein whose mutation is involved in autosomal dominant polycystic kidney disease. When expressed, PC1 activates a G-protein signaling pathway that subsequently modulates Ca(2+) channels. PC1 is highly expressed in developing tissue and via its C-terminus tail forms a complex with polycystin-2; this complex, found to be located at the primary cilia, seems to act as a mechanosensor that could affect proliferation, differentiation and apoptosis of cells. Also, loss of polycystins correlates with disruption of flow-dependent and steady-state intracellular Ca(2+) signaling. Despite the lack of clarity on the role of the polycystins as mechanosensor molecules, a new interest in this PCs/primary cilium complex is providing continuously new insights. In this review, some of the known features of PC1 such as structure, function, signaling pathways involved and its role as a possible therapeutic target are being discussed.
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Affiliation(s)
- Georgia Dalagiorgou
- Department of Biological Chemistry, University of Athens Medical School, Athens, Greece
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33
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Xiao ZS, Quarles LD. Role of the polycytin-primary cilia complex in bone development and mechanosensing. Ann N Y Acad Sci 2010; 1192:410-21. [PMID: 20392267 DOI: 10.1111/j.1749-6632.2009.05239.x] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Pkd1 encodes PC1, a transmembrane receptor-like protein, and Pkd2 encodes PC2, a calcium channel, which interact to form functional polycystin complexes that are widely expressed in many tissues and cell types. The study of autosomal dominant polycystic kidney disease (ADPKD), caused by inactivating mutations of PKD1 or PKD2 genes, has elucidated the functions of polycystins and their interdependence on primary cilia in renal epithelial cells. We have found that Pkd1 and Pkd2, as well as primary cilia, are present in osteoblasts and osteocytes. In addition, we have found that loss of polycystin-1 (Pkd1) function in mice results in abnormal bone development and osteopenia due to the impaired differentiation of osteoblasts. It is likely that the polycytin/primary cilia complex responds to a multitude of environmental clues affecting skeletal development and bone formation postnatally. Overall, polycystins in bone may define a new target for developing anabolic agents to treat osteoporotic disorders.
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Affiliation(s)
- Z S Xiao
- The Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas, USA
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34
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Ratnam S, Nauli SM. Hypertension in Autosomal Dominant Polycystic Kidney Disease: A Clinical and Basic Science Perspective. INTERNATIONAL JOURNAL OF NEPHROLOGY & UROLOGY 2010; 2:294-308. [PMID: 25364490 PMCID: PMC4215423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
Cardiovascular complications are major causes of morbidity and mortality in patients with autosomal dominant polycystic kidney disease (ADPKD). In particular, hypertension is insidious and remains a continuous problem that evolves during the course of the disease. Hypertension in ADPKD has been associated with abnormality in the renin-angiotensin-aldosterone system (RAAS). Early vascular changes have also been reported in young ADPKD patients. In addition, the cellular functions of mechanosensory cilia within vascular system have emerged recently. The basic and clinical perspectives of RAAS, vascular remodeling and sensory cilia are reviewed with regard to hypertension in ADPKD.
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Affiliation(s)
| | - Surya M. Nauli
- Correspondence: Surya M. Nauli, PhD The University of Toledo 2801 W. Bancroft St; MS 607 Toledo, OH 43606 Tel: 419-530-1910 Fax: 419-530-1909
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35
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Xiao Z, Zhang S, Cao L, Qiu N, David V, Quarles LD. Conditional disruption of Pkd1 in osteoblasts results in osteopenia due to direct impairment of bone formation. J Biol Chem 2009; 285:1177-87. [PMID: 19887454 DOI: 10.1074/jbc.m109.050906] [Citation(s) in RCA: 62] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
PKD1 (polycystin-1), the disease-causing gene for ADPKD, is widely expressed in various cell types, including osteoblasts, where its function is unknown. Although global inactivation of Pkd1 in mice results in abnormal skeletal development, the presence of polycystic kidneys and perinatal lethality confound ascertaining the direct osteoblastic functions of PKD1 in adult bone. To determine the role of PKD1 in osteoblasts, we conditionally inactivated Pkd1 in postnatal mature osteoblasts by crossing Oc (osteocalcin)-Cre mice with floxed Pkd1 (Pkd1(flox/m1Bei)) mice to generate conditional heterozygous (Oc-Cre;Pkd1(flox/+)) and homozygous (Oc-Cre;Pkd1(flox/m1Bei)) Pkd1-deficient mice. Cre-mediated recombination (Pkd1(Delta flox)) occurred exclusively in bone. Compared with control mice, the conditional deletion of Pkd1 from osteoblasts resulted in a gene dose-dependent reduction in bone mineral density, trabecular bone volume, and cortical thickness. In addition, mineral apposition rates and osteoblast-related gene expression, including Runx2-II (Runt-related transcription factor 2), osteocalcin, osteopontin, and bone sialoprotein, were reduced proportionate to the reduction of Pkd1 gene dose in bone of Oc-Cre;Pkd1(flox/+) and Oc-Cre;Pkd1(flox/m1Bei) mice. Primary osteoblasts derived from Oc-Cre;Pkd1(flox/m1Bei) displayed impaired differentiation and suppressed activity of the phosphatidylinositol 3-kinase-Akt-GSK3beta-beta-catenin signaling pathways. The conditional deletion of Pkd1 also resulted in increased adipogenesis in bone marrow and in osteoblast cultures. Thus, PKD1 directly functions in osteoblasts to regulate bone formation.
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Affiliation(s)
- Zhousheng Xiao
- Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas 66160, USA
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36
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Abou Alaiwi WA, Lo ST, Nauli SM. Primary cilia: highly sophisticated biological sensors. SENSORS 2009; 9:7003-20. [PMID: 22423203 PMCID: PMC3290460 DOI: 10.3390/s90907003] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/02/2009] [Revised: 07/31/2009] [Accepted: 09/01/2009] [Indexed: 12/18/2022]
Abstract
Primary cilia, thin hair-like structures protruding from the apical surface of most mammalian cells, have gained the attention of many researchers over the past decade. Primary cilia are microtubule-filled sensory organelles that are enclosed within the ciliary membrane. They originate at the cell surface from the mother centriole that becomes the mature basal body. In this review, we will discuss recent literatures on the roles of cilia as sophisticated sensory organelles. With particular emphasis on vascular endothelia and renal epithelia, the mechanosensory role of cilia in sensing fluid shear stress will be discussed. Also highlighted is the ciliary involvement in cell cycle regulation, development, cell signaling and cancer. Finally, primary cilia-related disorders will be briefly described.
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Affiliation(s)
- Wissam A. Abou Alaiwi
- Author to whom correspondence may be addressed; E-Mails: (W.A.A.); (S.M.N.); Tel.: +1-419-530-1921 (W.A.A); +1-419-530-1910 (S.M.N.); Fax: +1-419-530-1909
| | | | - Surya M. Nauli
- Author to whom correspondence may be addressed; E-Mails: (W.A.A.); (S.M.N.); Tel.: +1-419-530-1921 (W.A.A); +1-419-530-1910 (S.M.N.); Fax: +1-419-530-1909
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