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Pawnikar S, Magenheimer BS, Joshi K, Nevarez-Munoz E, Haldane A, Maser RL, Miao Y. Activation of polycystin-1 signaling by binding of stalk-derived peptide agonists. eLife 2024; 13:RP95992. [PMID: 39373641 PMCID: PMC11458180 DOI: 10.7554/elife.95992] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/08/2024] Open
Abstract
Polycystin-1 (PC1) is the protein product of the PKD1 gene whose mutation causes autosomal dominant Polycystic Kidney Disease (ADPKD). PC1 is an atypical G protein-coupled receptor (GPCR) with an autocatalytic GAIN domain that cleaves PC1 into extracellular N-terminal and membrane-embedded C-terminal (CTF) fragments. Recently, activation of PC1 CTF signaling was shown to be regulated by a stalk tethered agonist (TA), resembling the mechanism observed for adhesion GPCRs. Here, synthetic peptides of the first 9- (p9), 17- (p17), and 21-residues (p21) of the PC1 stalk TA were shown to re-activate signaling by a stalkless CTF mutant in human cell culture assays. Novel Peptide Gaussian accelerated molecular dynamics (Pep-GaMD) simulations elucidated binding conformations of p9, p17, and p21 and revealed multiple specific binding regions to the stalkless CTF. Peptide agonists binding to the TOP domain of PC1 induced close TOP-putative pore loop interactions, a characteristic feature of stalk TA-mediated PC1 CTF activation. Additional sequence coevolution analyses showed the peptide binding regions were consistent with covarying residue pairs identified between the TOP domain and the stalk TA. These insights into the structural dynamic mechanism of PC1 activation by TA peptide agonists provide an in-depth understanding that will facilitate the development of therapeutics targeting PC1 for ADPKD treatment.
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Affiliation(s)
- Shristi Pawnikar
- Center for Computational Biology and Department of Molecular Biosciences, University of KansasLawrenceUnited States
| | - Brenda S Magenheimer
- Clinical Laboratory Sciences, University of Kansas Medical CenterKansas CityUnited States
- The Jared Grantham Kidney Institute, University of Kansas Medical CenterKansas CityUnited States
| | - Keya Joshi
- Department of Pharmacology and Computational Medicine Program, University of North CarolinaChapel HillUnited States
| | - Ericka Nevarez-Munoz
- Clinical Laboratory Sciences, University of Kansas Medical CenterKansas CityUnited States
| | - Allan Haldane
- Department of Physics, and Center for Biophysics and Computational Biology, Temple UniversityPhiladelphiaUnited States
| | - Robin L Maser
- Clinical Laboratory Sciences, University of Kansas Medical CenterKansas CityUnited States
- The Jared Grantham Kidney Institute, University of Kansas Medical CenterKansas CityUnited States
- Department of Biochemistry and Molecular Biology, University of Kansas Medical CenterKansas CityUnited States
| | - Yinglong Miao
- Department of Pharmacology and Computational Medicine Program, University of North CarolinaChapel HillUnited States
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2
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Huang M, Zhou J, Li X, Liu R, Jiang Y, Chen K, Jiao Y, Yin X, Liu L, Sun Y, Wang W, Xiao Y, Su T, Guo Q, Huang Y, Yang M, Wei J, Darryl Quarles L, Xiao Z, Zeng C, Luo X, Lei G, Li C. Mechanical protein polycystin-1 directly regulates osteoclastogenesis and bone resorption. Sci Bull (Beijing) 2024; 69:1964-1979. [PMID: 38760248 PMCID: PMC11462616 DOI: 10.1016/j.scib.2024.04.044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Revised: 03/25/2024] [Accepted: 03/26/2024] [Indexed: 05/19/2024]
Abstract
Mechanical loading is required for bone homeostasis, but the underlying mechanism is still unclear. Our previous studies revealed that the mechanical protein polycystin-1 (PC1, encoded by Pkd1) is critical for bone formation. However, the role of PC1 in bone resorption is unknown. Here, we found that PC1 directly regulates osteoclastogenesis and bone resorption. The conditional deletion of Pkd1 in the osteoclast lineage resulted in a reduced number of osteoclasts, decreased bone resorption, and increased bone mass. A cohort study of 32,500 patients further revealed that autosomal dominant polycystic kidney disease, which is mainly caused by loss-of-function mutation of the PKD1 gene, is associated with a lower risk of hip fracture than those with other chronic kidney diseases. Moreover, mice with osteoclast-specific knockout of Pkd1 showed complete resistance to unloading-induced bone loss. A mechanistic study revealed that PC1 facilitated TAZ nuclear translocation via the C-terminal tail-TAZ complex and that conditional deletion of Taz in the osteoclast lineage resulted in reduced osteoclastogenesis and increased bone mass. Pharmacological regulation of the PC1-TAZ axis alleviated unloading- and estrogen deficiency- induced bone loss. Thus, the PC1-TAZ axis may be a potential therapeutic target for osteoclast-related osteoporosis.
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Affiliation(s)
- Mei Huang
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Jingxuan Zhou
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Xiaoxiao Li
- Hunan Key Laboratory of Joint Degeneration and Injury, Changsha 410008, China; Key Laboratory of Aging-related Bone and Joint Diseases Prevention and Treatment, Ministry of Education, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Ran Liu
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Yangzi Jiang
- School of Biomedical Sciences, Institute for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong 999077, China; Key Laboratory for Regenerative Medicine, Ministry of Education, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong 999077, China; Center for Neuromusculoskeletal Restorative Medicine (CNRM), The Chinese University of Hong Kong, Hong Kong 999077, China
| | - Kaixuan Chen
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Yurui Jiao
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Xin Yin
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Ling Liu
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Yuchen Sun
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Weishan Wang
- Department of Orthopaedics, The First Affiliated Hospital of Shihezi University, Shihezi 832061, China
| | - Ye Xiao
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Tian Su
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Qi Guo
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Yan Huang
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Mi Yang
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Jie Wei
- Hunan Key Laboratory of Joint Degeneration and Injury, Changsha 410008, China; Key Laboratory of Aging-related Bone and Joint Diseases Prevention and Treatment, Ministry of Education, Xiangya Hospital, Central South University, Changsha 410008, China; Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha 410008, China; Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Changsha 410008, China
| | - L Darryl Quarles
- Department of Medicine, University of Tennessee Health Science Center, Memphis 38163, USA
| | - Zhousheng Xiao
- Department of Medicine, University of Tennessee Health Science Center, Memphis 38163, USA
| | - Chao Zeng
- Hunan Key Laboratory of Joint Degeneration and Injury, Changsha 410008, China; Key Laboratory of Aging-related Bone and Joint Diseases Prevention and Treatment, Ministry of Education, Xiangya Hospital, Central South University, Changsha 410008, China; Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China.
| | - Xianghang Luo
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital, Central South University, Changsha 410008, China; Key Laboratory of Aging-related Bone and Joint Diseases Prevention and Treatment, Ministry of Education, Xiangya Hospital, Central South University, Changsha 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China.
| | - Guanghua Lei
- Hunan Key Laboratory of Joint Degeneration and Injury, Changsha 410008, China; Key Laboratory of Aging-related Bone and Joint Diseases Prevention and Treatment, Ministry of Education, Xiangya Hospital, Central South University, Changsha 410008, China; Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China.
| | - Changjun Li
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital, Central South University, Changsha 410008, China; Key Laboratory of Aging-related Bone and Joint Diseases Prevention and Treatment, Ministry of Education, Xiangya Hospital, Central South University, Changsha 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China; Laboratory Animal Center, Xiangya Hospital, Central South University, Changsha 410008, China.
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3
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Gargalionis AN, Adamopoulos C, Vottis CT, Papavassiliou AG, Basdra EK. Runx2 and Polycystins in Bone Mechanotransduction: Challenges for Therapeutic Opportunities. Int J Mol Sci 2024; 25:5291. [PMID: 38791330 PMCID: PMC11121608 DOI: 10.3390/ijms25105291] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Revised: 05/04/2024] [Accepted: 05/12/2024] [Indexed: 05/26/2024] Open
Abstract
Bone mechanotransduction is a critical process during skeletal development in embryogenesis and organogenesis. At the same time, the type and level of mechanical loading regulates bone remodeling throughout the adult life. The aberrant mechanosensing of bone cells has been implicated in the development and progression of bone loss disorders, but also in the bone-specific aspect of other clinical entities, such as the tumorigenesis of solid organs. Novel treatment options have come into sight that exploit the mechanosensitivity of osteoblasts, osteocytes, and chondrocytes to achieve efficient bone regeneration. In this regard, runt-related transcription factor 2 (Runx2) has emerged as a chief skeletal-specific molecule of differentiation, which is prominent to induction by mechanical stimuli. Polycystins represent a family of mechanosensitive proteins that interact with Runx2 in mechano-induced signaling cascades and foster the regulation of alternative effectors of mechanotransuction. In the present narrative review, we employed a PubMed search to extract the literature concerning Runx2, polycystins, and their association from 2000 to March 2024. The keywords stated below were used for the article search. We discuss recent advances regarding the implication of Runx2 and polycystins in bone remodeling and regeneration and elaborate on the targeting strategies that may potentially be applied for the treatment of patients with bone loss diseases.
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Affiliation(s)
- Antonios N. Gargalionis
- Laboratory of Clinical Biochemistry, Medical School, National and Kapodistrian University of Athens, ‘Attikon’ University General Hospital, 12462 Athens, Greece;
| | - Christos Adamopoulos
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (C.A.); (A.G.P.)
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Christos T. Vottis
- First Department of Orthopedics, Medical School, National and Kapodistrian University of Athens, ‘Attikon’ University General Hospital, 12462 Athens, Greece;
| | - Athanasios G. Papavassiliou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (C.A.); (A.G.P.)
| | - Efthimia K. Basdra
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (C.A.); (A.G.P.)
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4
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Chang X, Xu S, Zhang H. Regulation of bone health through physical exercise: Mechanisms and types. Front Endocrinol (Lausanne) 2022; 13:1029475. [PMID: 36568096 PMCID: PMC9768366 DOI: 10.3389/fendo.2022.1029475] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2022] [Accepted: 11/15/2022] [Indexed: 12/12/2022] Open
Abstract
Osteoporosis, characterized by bone mineral density reduction, bone mass loss, increased bone fragility, and propensity to fractures, is a common disease in older individuals and one of the most serious health problems worldwide. The imbalance between osteoblasts and osteoclasts results in the predominance of bone resorption and decreased bone formation. In recent years, it has been found that regular and proper exercise not only helps prevent the occurrence of osteoporosis but also adds benefits to osteoporosis therapy; accordingly, bone homeostasis is closely associated with mechanical stress and the intricate crosstalk between osteoblasts and osteoclasts. In this review, we summarize the mechanisms of exercise on osteoporosis and provide new proposals for the prevention and treatment of osteoporosis.
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Affiliation(s)
- Xinyu Chang
- Department of Traumatic Orthopedics, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Sheng Xu
- National Key Laboratory of Medical Immunology and Institute of Immunology, Institute of Immunology, Naval Medical University, Shanghai, China
| | - Hao Zhang
- Department of Traumatic Orthopedics, the First Affiliated Hospital of Naval Medical University, Naval Medical University, Shanghai, China
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5
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Fang X, Ni K, Guo J, Li Y, Zhou Y, Sheng H, Bu B, Luo M, Ouyang M, Deng L. FRET Visualization of Cyclic Stretch-Activated ERK via Calcium Channels Mechanosensation While Not Integrin β1 in Airway Smooth Muscle Cells. Front Cell Dev Biol 2022; 10:847852. [PMID: 35663392 PMCID: PMC9162487 DOI: 10.3389/fcell.2022.847852] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Accepted: 04/05/2022] [Indexed: 12/19/2022] Open
Abstract
Mechanical stretch is one type of common physiological activities such as during heart beating, lung breathing, blood flow through the vessels, and physical exercise. The mechanical stimulations regulate cellular functions and maintain body homeostasis. It still remains to further characterize the mechanical-biomechanical coupling mechanism. Here we applied fluorescence resonance energy transfer (FRET) technology to visualize ERK activity in airway smooth muscle (ASM) cells under cyclic stretch stimulation in airway smooth muscle (ASM) cells, and studied the mechanosensing pathway. FRET measurements showed apparent ERK activation by mechanical stretch, which was abolished by ERK inhibitor PD98059 pretreatment. Inhibition of extracellular Ca2+ influx reduced ERK activation, and selective inhibition of inositol 1,4,5-trisphosphate receptor (IP3R) Ca2+ channel or SERCA Ca2+ pump on endoplasmic reticulum (ER) blocked the activation. Chemical inhibition of the L-type or store-operated Ca2+ channels on plasma membrane, or inhibition of integrin β1 with siRNA had little effect on ERK activation. Disruption of actin cytoskeleton but not microtubule one inhibited the stretch-induced ERK activation. Furthermore, the ER IP3R-dependent ERK activation was not dependent on phospholipase C-IP3 signal, indicating possibly more mechanical mechanism for IP3R activation. It is concluded from our study that the mechanical stretch activated intracellular ERK signal in ASM cells through membrane Ca2+ channels mechanosensation but not integrin β1, which was mediated by actin cytoskeleton.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - Linhong Deng
- *Correspondence: Mingxing Ouyang, ; Linhong Deng,
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6
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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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7
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Liu C, Gao X, Li Y, Sun W, Xu Y, Tan Y, Du R, Zhong G, Zhao D, Liu Z, Jin X, Zhao Y, Wang Y, Yuan X, Pan J, Yuan G, Li Y, Xing W, Kan G, Wang Y, Li Q, Han X, Li J, Ling S, Li Y. The mechanosensitive lncRNA Neat1 promotes osteoblast function through paraspeckle-dependent Smurf1 mRNA retention. Bone Res 2022; 10:18. [PMID: 35210394 PMCID: PMC8873336 DOI: 10.1038/s41413-022-00191-3] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 11/01/2021] [Accepted: 12/14/2021] [Indexed: 12/21/2022] Open
Abstract
Mechanical stimulation plays an important role in bone remodeling. Exercise-induced mechanical loading enhances bone strength, whereas mechanical unloading leads to bone loss. Increasing evidence has demonstrated that long noncoding RNAs (lncRNAs) play key roles in diverse biological, physiological and pathological contexts. However, the roles of lncRNAs in mechanotransduction and their relationships with bone formation remain unknown. In this study, we screened mechanosensing lncRNAs in osteoblasts and identified Neat1, the most clearly decreased lncRNA under simulated microgravity. Of note, not only Neat1 expression but also the specific paraspeckle structure formed by Neat1 was sensitive to different mechanical stimulations, which were closely associated with osteoblast function. Paraspeckles exhibited small punctate aggregates under simulated microgravity and elongated prolate or larger irregular structures under mechanical loading. Neat1 knockout mice displayed disrupted bone formation, impaired bone structure and strength, and reduced bone mass. Neat1 deficiency in osteoblasts reduced the response of osteoblasts to mechanical stimulation. In vivo, Neat1 knockout in mice weakened the bone phenotypes in response to mechanical loading and hindlimb unloading stimulation. Mechanistically, paraspeckles promoted nuclear retention of E3 ubiquitin ligase Smurf1 mRNA and downregulation of their translation, thus inhibiting ubiquitination-mediated degradation of the osteoblast master transcription factor Runx2, a Smurf1 target. Our study revealed that Neat1 plays an essential role in osteoblast function under mechanical stimulation, which provides a paradigm for the function of the lncRNA-assembled structure in response to mechanical stimulation and offers a therapeutic strategy for long-term spaceflight- or bedrest-induced bone loss and age-related osteoporosis.
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Affiliation(s)
- Caizhi Liu
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Xingcheng Gao
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Yuheng Li
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China.,The Key Laboratory of Aerospace Medicine, Ministry of Education, The Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Weijia Sun
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Youjia Xu
- The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Yingjun Tan
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Ruikai Du
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Guohui Zhong
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China.,The Key Laboratory of Aerospace Medicine, Ministry of Education, The Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Dingsheng Zhao
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Zizhong Liu
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Xiaoyan Jin
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Yinlong Zhao
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China.,College of Life Sciences, Hebei Normal University, Shijiazhuang, Hebei, China
| | - Yinbo Wang
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China.,The Key Laboratory of Aerospace Medicine, Ministry of Education, The Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Xinxin Yuan
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Junjie Pan
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China.,Medical College of Soochow University, Suzhou, Jiangsu, China
| | - Guodong Yuan
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China.,Medical School of Southeast University, Nanjing, Jiangsu, China
| | - Youyou Li
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China.,The Key Laboratory of Aerospace Medicine, Ministry of Education, The Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Wenjuan Xing
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China.,The Key Laboratory of Aerospace Medicine, Ministry of Education, The Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Guanghan Kan
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Yanqing Wang
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Qi Li
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Xuan Han
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Jianwei Li
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China.
| | - Shukuan Ling
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China.
| | - Yingxian Li
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China.
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8
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Chen T, Wang H, Jiang C, Lu Y. PKD1 alleviates oxidative stress-inhibited osteogenesis of rat bone marrow-derived mesenchymal stem cells through TAZ activation. J Cell Biochem 2021; 122:1715-1725. [PMID: 34407229 PMCID: PMC9292359 DOI: 10.1002/jcb.30124] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 06/07/2021] [Accepted: 07/22/2021] [Indexed: 01/03/2023]
Abstract
Oxidative stress is known to inhibit osteogenesis and PKD1 is implicated in bone remodeling and skeletogenesis. In the present study, we explored the role of PKD1 in osteogenesis under oxidative stress. H2 O2 was used to induce oxidative stress in rat bone marrow (BM)-mesenchymal stem cells (MSCs) during osteoblast differentiation. Alkaline phosphatase (ALP) activity, calcium deposits, and the RUNX2 marker were assayed to determine osteogenic differentiation. The correlation of PKD1, Sirt1, c-MYC, and TAZ was further confirmed by chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assay. We found that H2 O2 induced the downregulation of PKD1 expression and the upregulation of c-MYC, and Sirt1 was accompanied by decreasing cell viability in BM-MSCs. During osteogenic differentiation, the expression of PKD1 was upregulated significantly whereas Sirt1 tended to be upregulated mildly under normal conditions. Both PKD1 and Sirt1 were upregulated upon oxidative stress. The positive correlation of PKD1 expression with osteogenic differentiation under normal conditions might be hindered by oxidative stress and PKD1 could interact with TAZ under oxidative stress to regulate osteogenic differentiation. Our results suggest that PKD1 may alleviate oxidative stress-inhibited osteogenesis of rat BM-MSCs through TAZ activation.
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Affiliation(s)
- Tongtong Chen
- Department of Radiology, Ruijin Hospital, School of MedicineShanghai Jiaotong UniversityShanghaiChina
| | - Hanqi Wang
- Department of Radiology, Ruijin Hospital, School of MedicineShanghai Jiaotong UniversityShanghaiChina
| | - Chaoyin Jiang
- Department of Orthopedic SurgeryShanghai Jiaotong University Affiliated Sixth People's HospitalShanghaiChina
- Department of Orthopedic SurgeryHaikou Orthopedic and Diabetes Hospital of Shanghai Sixth People's HospitalHainanChina
| | - Yong Lu
- Department of Radiology, Ruijin Hospital, School of MedicineShanghai Jiaotong UniversityShanghaiChina
- Department of Radiology, Ruijin Hospital Luwan Branch, School of MedicineShanghai Jiaotong UniversityShanghaiChina
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9
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The mechanosensory and mechanotransductive processes mediated by ion channels and the impact on bone metabolism: A systematic review. Arch Biochem Biophys 2021; 711:109020. [PMID: 34461086 DOI: 10.1016/j.abb.2021.109020] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 08/25/2021] [Accepted: 08/26/2021] [Indexed: 02/06/2023]
Abstract
Mechanical environments were associated with alterations in bone metabolism. Ion channels present on bone cells are indispensable for bone metabolism and can be directly or indirectly activated by mechanical stimulation. This review aimed to discuss the literature reporting the mechanical regulatory effects of ion channels on bone cells and bone tissue. An electronic search was conducted in PubMed, Embase and Web of Science. Studies about mechanically induced alteration of bone cells and bone tissue by ion channels were included. Ion channels including TRP family channels, Ca2+ release-activated Ca2+ channels (CRACs), Piezo1/2 channels, purinergic receptors, NMDA receptors, voltage-sensitive calcium channels (VSCCs), TREK2 potassium channels, calcium- and voltage-dependent big conductance potassium (BKCa) channels, small conductance, calcium-activated potassium (SKCa) channels and epithelial sodium channels (ENaCs) present on bone cells and bone tissue participate in the mechanical regulation of bone development in addition to contributing to direct or indirect mechanotransduction such as altered membrane potential and ionic flux. Physiological (beneficial) mechanical stimulation could induce the anabolism of bone cells and bone tissue through ion channels, but abnormal (harmful) mechanical stimulation could also induce the catabolism of bone cells and bone tissue through ion channels. Functional expression of ion channels is vital for the mechanotransduction of bone cells. Mechanical activation (opening) of ion channels triggers ion influx and induces the activation of intracellular modulators that can influence bone metabolism. Therefore, mechanosensitive ion channels provide new insights into therapeutic targets for the treatment of bone-related diseases such as osteopenia and aseptic implant loosening.
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Nokhbatolfoghahaei H, Rad MR, Paknejad Z, Ardeshirylajimi A, Khojasteh A. Identification osteogenic signaling pathways following mechanical stimulation: A systematic review. Curr Stem Cell Res Ther 2021; 17:772-792. [PMID: 34615453 DOI: 10.2174/1574888x16666211006105915] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2021] [Revised: 07/17/2021] [Accepted: 07/26/2021] [Indexed: 11/22/2022]
Abstract
INTRODUCTION It has been shown that mechanical forces can induce or promote osteogenic differentiation as well as remodeling of the new created bone tissues. To apply this characteristic in bone tissue engineering, it is important to know which mechanical stimuli through which signaling pathway has a more significant impact on osteogenesis. METHODS In this systematic study, an electronic search was conducted using PubMed and Google Scholar databases. This study has been prepared and organized according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. Included studies were first categorized according to the in vivo and in vitro studies. RESULTS Six types of mechanical stresses were used in these articles and the most commonly used mechanical force and cell source were tension and bone marrow-derived mesenchymal stem cells (BMMSCs), respectively. These forces were able to trigger twelve signaling pathways in which Wnt pathway was so prominent. CONCLUSION 1) Although specific signaling pathways are induced through specific mechanical forces, Wnt signaling pathways are predominantly activated by almost all types of force/stimulation, 2) All signaling pathways regulate expression of RUNX2, which is known as a master regulator of osteogenesis, 3) In Tension force, the mode of force administration, i.e, continuous or non-continuous tension is more important than the percentage of elongation.
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Affiliation(s)
- Hanieh Nokhbatolfoghahaei
- Dental Research Center, Research Institute of Dental Sciences, Shahid Beheshti University of Medical Sciences, Tehran. Iran
| | - Maryam Rezai Rad
- Dental Research Center, Research Institute of Dental Sciences, Shahid Beheshti University of Medical Sciences, Tehran. Iran
| | - Zahrasadat Paknejad
- Medical nanotechnology and tissue engineering research Center, Shahid Beheshti University of Medical Sciences, Tehran. Iran
| | - Abdolreza Ardeshirylajimi
- Department of Tissue Engineering, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran. Iran
| | - Arash Khojasteh
- Department of Tissue Engineering, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran. Iran
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Chalazias A, Plemmenos G, Evangeliou E, Piperi C. Pivotal role of Transient Receptor Potential Channels in oral physiology. Curr Med Chem 2021; 29:1408-1425. [PMID: 34365940 DOI: 10.2174/0929867328666210806113132] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Revised: 06/08/2021] [Accepted: 06/11/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND Transient Receptor Potential (TRP) Channels constitute a large family of non-selective permeable ion channels involved in the perception of environmental stimuli with a central and continuously expanding role in oral tissue homeostasis. Recent studies indicate the regulatory role of TRPs in pulp physiology, oral mucosa sensation, dental pain nociception and salivary gland secretion. This review provides an update on the diverse functions of TRP channels in the physiology of oral cavity, with emphasis on their cellular location, the underlying molecular mechanisms and clinical significance. METHODS A structured search of bibliographic databases (PubMed and MEDLINE) was performed for peer reviewed studies on TRP channels function on oral cavity physiology the last ten years. A qualitative content analysis was performed in screened papers and a critical discussion of main findings is provided. RESULTS TRPs expression has been detected in major cell types of the oral cavity, including odontoblasts, periodontal ligament, oral epithelial, salivary gland cells, and chondrocytes of temporomandibular joints, where they mediate signal perception and transduction of mechanical, thermal, and osmotic stimuli. They contribute to pulp physiology through dentin formation, mineralization, and periodontal ligament formation along with alveolar bone remodeling in dental pulp and periodontal ligament cells. TRPs are also involved in oral mucosa sensation, dental pain nociception, saliva secretion, swallowing reflex and temporomandibular joints' development. CONCLUSION Various TRP channels regulate oral cavity homeostasis, playing an important role in the transduction of external stimuli to intracellular signals in a cell type-specific manner and presenting promising drug targets for the development of pharmacological strategies to manage oral diseases.
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Affiliation(s)
- Andreas Chalazias
- School of Dentistry, National and Kapodistrian University of Athens, 2 Thivon Str, Goudi, 115 27 Athens. Greece
| | - Grigorios Plemmenos
- School of Dentistry, National and Kapodistrian University of Athens, 2 Thivon Str, Goudi, 115 27 Athens. Greece
| | - Evangelos Evangeliou
- School of Dentistry, National and Kapodistrian University of Athens, 2 Thivon Str, Goudi, 115 27 Athens. Greece
| | - Christina Piperi
- School of Dentistry, National and Kapodistrian University of Athens, 2 Thivon Str, Goudi, 115 27 Athens. Greece
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12
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Simakou T, Freeburn R, Henriquez FL. Gene expression during THP-1 differentiation is influenced by vitamin D3 and not vibrational mechanostimulation. PeerJ 2021; 9:e11773. [PMID: 34316406 PMCID: PMC8286059 DOI: 10.7717/peerj.11773] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Accepted: 06/23/2021] [Indexed: 11/20/2022] Open
Abstract
Background In injury or infection, monocytes migrate into the affected tissues from circulation and differentiate into macrophages which are subsequently involved in the inflammatory responses. Macrophage differentiation and activation have been studied in response to multiple chemokines and cytokines. However, mechanical, and physical stimuli can also influence macrophage differentiation, activation, cytokine production, and phagocytic activity. Methods In this study the macrophage differentiation from THP-1 monocytes was assessed upon the stimulation with 1,25-dihydroxyvitamin D3 and 1,000 Hz vibrations, using qPCR for quantification of transcript expression. Vitamin D binds the vitamin D receptor (VDR) and subsequently modulates the expression of a variety of genes in monocytes. The effects of the 1,000 Hz vibrational stimulation, and the combined treatment of vitamin D3 and 1000 Hz vibrations were unknown. The differentiation of macrophages was assessed by looking at transcription of macrophage markers (e.g., CD14, CD36), antigen presenting molecules (e.g., HLA-DRA), transcription factors (e.g., LEF-1, TCF7L2), and mechanosensors (e.g., PIEZO1 and PKD2). Results The results showed that vitamin D3 induced THP-1 macrophage differentiation, which was characterized by upregulation of CD14 and CD36, downregulation of HLA-DRA, upregulation of the PKD2 (TRPP2), and an inverse relationship between TCF7L2 and LEF-1, which were upregulated and downregulated respectively. The 1,000 Hz vibrations were sensed from the cells which upregulated PIEZO1 and TCF3, but they did not induce expression of genes that would indicate macrophage differentiation. The mRNA transcription profile in the cells stimulated with the combined treatment was comparable to that of the cells stimulated by the vitamin only. The 1,000 Hz vibrations slightly weakened the effect of the vitamin for the regulation of CD36 and HLA-DMB in the suspension cells, but without causing changes in the regulation patterns. The only exception was the upregulation of TCF3 in the suspension cells, which was influenced by the vibrations. In the adherent cells, the vitamin D3 cancelled the upregulating effect of the 1,000 Hz vibrations and downregulated TCF3. The vitamin also cancelled the upregulation of PIEZO1 gene by the 1,000 Hz vibrations in the combined treatment. Conclusion The mechanical stimulation with 1,000 Hz vibrations resulted in upregulation of PIEZO1 in THP-1 cells, but it did not affect the differentiation process which was investigated in this study. Vitamin D3 induced THP-1 macrophage differentiation and could potentially influence M2 polarization as observed by upregulation of CD36 and downregulation of HLA-DRA. In addition, in THP-1 cells undergoing the combined stimulation, the gene expression patterns were influenced by vitamin D3, which also ablated the effect of the mechanical stimulus on PIEZO1 upregulation.
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Affiliation(s)
- Theodoros Simakou
- School of Health and Life Sciences, University of West of Scotland, Paisley, United Kingdom.,Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom
| | - Robin Freeburn
- School of Health and Life Sciences, University of West of Scotland, Paisley, United Kingdom
| | - Fiona L Henriquez
- School of Health and Life Sciences, University of West of Scotland, Paisley, United Kingdom
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Ciliary Signalling and Mechanotransduction in the Pathophysiology of Craniosynostosis. Genes (Basel) 2021; 12:genes12071073. [PMID: 34356089 PMCID: PMC8306115 DOI: 10.3390/genes12071073] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Revised: 07/10/2021] [Accepted: 07/13/2021] [Indexed: 12/25/2022] Open
Abstract
Craniosynostosis (CS) is the second most prevalent inborn craniofacial malformation; it results from the premature fusion of cranial sutures and leads to dimorphisms of variable severity. CS is clinically heterogeneous, as it can be either a sporadic isolated defect, more frequently, or part of a syndromic phenotype with mendelian inheritance. The genetic basis of CS is also extremely heterogeneous, with nearly a hundred genes associated so far, mostly mutated in syndromic forms. Several genes can be categorised within partially overlapping pathways, including those causing defects of the primary cilium. The primary cilium is a cellular antenna serving as a signalling hub implicated in mechanotransduction, housing key molecular signals expressed on the ciliary membrane and in the cilioplasm. This mechanical property mediated by the primary cilium may also represent a cue to understand the pathophysiology of non-syndromic CS. In this review, we aimed to highlight the implication of the primary cilium components and active signalling in CS pathophysiology, dissecting their biological functions in craniofacial development and in suture biomechanics. Through an in-depth revision of the literature and computational annotation of disease-associated genes we categorised 18 ciliary genes involved in CS aetiology. Interestingly, a prevalent implication of midline sutures is observed in CS ciliopathies, possibly explained by the specific neural crest origin of the frontal bone.
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Xu X, Liu S, Liu H, Ru K, Jia Y, Wu Z, Liang S, Khan Z, Chen Z, Qian A, Hu L. Piezo Channels: Awesome Mechanosensitive Structures in Cellular Mechanotransduction and Their Role in Bone. Int J Mol Sci 2021; 22:ijms22126429. [PMID: 34208464 PMCID: PMC8234635 DOI: 10.3390/ijms22126429] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 06/10/2021] [Accepted: 06/12/2021] [Indexed: 12/13/2022] Open
Abstract
Piezo channels are mechanosensitive ion channels located in the cell membrane and function as key cellular mechanotransducers for converting mechanical stimuli into electrochemical signals. Emerged as key molecular detectors of mechanical forces, Piezo channels' functions in bone have attracted more and more attention. Here, we summarize the current knowledge of Piezo channels and review the research advances of Piezo channels' function in bone by highlighting Piezo1's role in bone cells, including osteocyte, bone marrow mesenchymal stem cell (BM-MSC), osteoblast, osteoclast, and chondrocyte. Moreover, the role of Piezo channels in bone diseases is summarized.
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Affiliation(s)
- Xia Xu
- Lab for Bone Metabolism, Key Lab for Space Biosciences and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi’an 710072, China; (X.X.); (S.L.); (H.L.); (K.R.); (Y.J.); (Z.W.); (S.L.); (Z.K.); (Z.C.)
- Xi’an Key Laboratory of Special Medicine and Health Engineering, School of Life Sciences, Northwestern Polytechnical University, Xi’an 710072, China
- Research Center for Special Medicine and Health Systems Engineering, School of Life Sciences, Northwestern Polytechnical University, Xi’an 710072, China
- NPU-UAB Joint Laboratory for Bone Metabolism, School of Life Sciences, Northwestern Polytechnical University, Xi’an 710072, China
| | - Shuyu Liu
- Lab for Bone Metabolism, Key Lab for Space Biosciences and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi’an 710072, China; (X.X.); (S.L.); (H.L.); (K.R.); (Y.J.); (Z.W.); (S.L.); (Z.K.); (Z.C.)
- Xi’an Key Laboratory of Special Medicine and Health Engineering, School of Life Sciences, Northwestern Polytechnical University, Xi’an 710072, China
- Research Center for Special Medicine and Health Systems Engineering, School of Life Sciences, Northwestern Polytechnical University, Xi’an 710072, China
- NPU-UAB Joint Laboratory for Bone Metabolism, School of Life Sciences, Northwestern Polytechnical University, Xi’an 710072, China
| | - Hua Liu
- Lab for Bone Metabolism, Key Lab for Space Biosciences and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi’an 710072, China; (X.X.); (S.L.); (H.L.); (K.R.); (Y.J.); (Z.W.); (S.L.); (Z.K.); (Z.C.)
- Xi’an Key Laboratory of Special Medicine and Health Engineering, School of Life Sciences, Northwestern Polytechnical University, Xi’an 710072, China
- Research Center for Special Medicine and Health Systems Engineering, School of Life Sciences, Northwestern Polytechnical University, Xi’an 710072, China
- NPU-UAB Joint Laboratory for Bone Metabolism, School of Life Sciences, Northwestern Polytechnical University, Xi’an 710072, China
| | - Kang Ru
- Lab for Bone Metabolism, Key Lab for Space Biosciences and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi’an 710072, China; (X.X.); (S.L.); (H.L.); (K.R.); (Y.J.); (Z.W.); (S.L.); (Z.K.); (Z.C.)
- Xi’an Key Laboratory of Special Medicine and Health Engineering, School of Life Sciences, Northwestern Polytechnical University, Xi’an 710072, China
- Research Center for Special Medicine and Health Systems Engineering, School of Life Sciences, Northwestern Polytechnical University, Xi’an 710072, China
- NPU-UAB Joint Laboratory for Bone Metabolism, School of Life Sciences, Northwestern Polytechnical University, Xi’an 710072, China
| | - Yunxian Jia
- Lab for Bone Metabolism, Key Lab for Space Biosciences and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi’an 710072, China; (X.X.); (S.L.); (H.L.); (K.R.); (Y.J.); (Z.W.); (S.L.); (Z.K.); (Z.C.)
- Xi’an Key Laboratory of Special Medicine and Health Engineering, School of Life Sciences, Northwestern Polytechnical University, Xi’an 710072, China
- Research Center for Special Medicine and Health Systems Engineering, School of Life Sciences, Northwestern Polytechnical University, Xi’an 710072, China
- NPU-UAB Joint Laboratory for Bone Metabolism, School of Life Sciences, Northwestern Polytechnical University, Xi’an 710072, China
| | - Zixiang Wu
- Lab for Bone Metabolism, Key Lab for Space Biosciences and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi’an 710072, China; (X.X.); (S.L.); (H.L.); (K.R.); (Y.J.); (Z.W.); (S.L.); (Z.K.); (Z.C.)
- Xi’an Key Laboratory of Special Medicine and Health Engineering, School of Life Sciences, Northwestern Polytechnical University, Xi’an 710072, China
- Research Center for Special Medicine and Health Systems Engineering, School of Life Sciences, Northwestern Polytechnical University, Xi’an 710072, China
- NPU-UAB Joint Laboratory for Bone Metabolism, School of Life Sciences, Northwestern Polytechnical University, Xi’an 710072, China
| | - Shujing Liang
- Lab for Bone Metabolism, Key Lab for Space Biosciences and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi’an 710072, China; (X.X.); (S.L.); (H.L.); (K.R.); (Y.J.); (Z.W.); (S.L.); (Z.K.); (Z.C.)
- Xi’an Key Laboratory of Special Medicine and Health Engineering, School of Life Sciences, Northwestern Polytechnical University, Xi’an 710072, China
- Research Center for Special Medicine and Health Systems Engineering, School of Life Sciences, Northwestern Polytechnical University, Xi’an 710072, China
- NPU-UAB Joint Laboratory for Bone Metabolism, School of Life Sciences, Northwestern Polytechnical University, Xi’an 710072, China
| | - Zarnaz Khan
- Lab for Bone Metabolism, Key Lab for Space Biosciences and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi’an 710072, China; (X.X.); (S.L.); (H.L.); (K.R.); (Y.J.); (Z.W.); (S.L.); (Z.K.); (Z.C.)
- Xi’an Key Laboratory of Special Medicine and Health Engineering, School of Life Sciences, Northwestern Polytechnical University, Xi’an 710072, China
- Research Center for Special Medicine and Health Systems Engineering, School of Life Sciences, Northwestern Polytechnical University, Xi’an 710072, China
- NPU-UAB Joint Laboratory for Bone Metabolism, School of Life Sciences, Northwestern Polytechnical University, Xi’an 710072, China
| | - Zhihao Chen
- Lab for Bone Metabolism, Key Lab for Space Biosciences and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi’an 710072, China; (X.X.); (S.L.); (H.L.); (K.R.); (Y.J.); (Z.W.); (S.L.); (Z.K.); (Z.C.)
- Xi’an Key Laboratory of Special Medicine and Health Engineering, School of Life Sciences, Northwestern Polytechnical University, Xi’an 710072, China
- Research Center for Special Medicine and Health Systems Engineering, School of Life Sciences, Northwestern Polytechnical University, Xi’an 710072, China
- NPU-UAB Joint Laboratory for Bone Metabolism, School of Life Sciences, Northwestern Polytechnical University, Xi’an 710072, China
| | - Airong Qian
- Lab for Bone Metabolism, Key Lab for Space Biosciences and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi’an 710072, China; (X.X.); (S.L.); (H.L.); (K.R.); (Y.J.); (Z.W.); (S.L.); (Z.K.); (Z.C.)
- Xi’an Key Laboratory of Special Medicine and Health Engineering, School of Life Sciences, Northwestern Polytechnical University, Xi’an 710072, China
- Research Center for Special Medicine and Health Systems Engineering, School of Life Sciences, Northwestern Polytechnical University, Xi’an 710072, China
- NPU-UAB Joint Laboratory for Bone Metabolism, School of Life Sciences, Northwestern Polytechnical University, Xi’an 710072, China
- Correspondence: (A.Q.); (L.H.)
| | - Lifang Hu
- Lab for Bone Metabolism, Key Lab for Space Biosciences and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi’an 710072, China; (X.X.); (S.L.); (H.L.); (K.R.); (Y.J.); (Z.W.); (S.L.); (Z.K.); (Z.C.)
- Xi’an Key Laboratory of Special Medicine and Health Engineering, School of Life Sciences, Northwestern Polytechnical University, Xi’an 710072, China
- Research Center for Special Medicine and Health Systems Engineering, School of Life Sciences, Northwestern Polytechnical University, Xi’an 710072, China
- NPU-UAB Joint Laboratory for Bone Metabolism, School of Life Sciences, Northwestern Polytechnical University, Xi’an 710072, China
- Correspondence: (A.Q.); (L.H.)
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Thompson CL, McFie M, Chapple JP, Beales P, Knight MM. Polycystin-2 Is Required for Chondrocyte Mechanotransduction and Traffics to the Primary Cilium in Response to Mechanical Stimulation. Int J Mol Sci 2021; 22:4313. [PMID: 33919210 PMCID: PMC8122406 DOI: 10.3390/ijms22094313] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 04/10/2021] [Accepted: 04/13/2021] [Indexed: 12/12/2022] Open
Abstract
Primary cilia and associated intraflagellar transport are essential for skeletal development, joint homeostasis, and the response to mechanical stimuli, although the mechanisms remain unclear. Polycystin-2 (PC2) is a member of the transient receptor potential polycystic (TRPP) family of cation channels, and together with Polycystin-1 (PC1), it has been implicated in cilia-mediated mechanotransduction in epithelial cells. The current study investigates the effect of mechanical stimulation on the localization of ciliary polycystins in chondrocytes and tests the hypothesis that they are required in chondrocyte mechanosignaling. Isolated chondrocytes were subjected to mechanical stimulation in the form of uniaxial cyclic tensile strain (CTS) in order to examine the effects on PC2 ciliary localization and matrix gene expression. In the absence of strain, PC2 localizes to the chondrocyte ciliary membrane and neither PC1 nor PC2 are required for ciliogenesis. Cartilage matrix gene expression (Acan, Col2a) is increased in response to 10% CTS. This response is inhibited by siRNA-mediated loss of PC1 or PC2 expression. PC2 ciliary localization requires PC1 and is increased in response to CTS. Increased PC2 cilia trafficking is dependent on the activation of transient receptor potential cation channel subfamily V member 4 (TRPV4) activation. Together, these findings demonstrate for the first time that polycystins are required for chondrocyte mechanotransduction and highlight the mechanosensitive cilia trafficking of PC2 as an important component of cilia-mediated mechanotransduction.
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Affiliation(s)
- Clare L. Thompson
- Centre for Predictive In Vitro Models, School of Engineering and Materials Science, Queen Mary University of London, London E1 4NS, UK; (M.M.); (M.M.K.)
| | - Megan McFie
- Centre for Predictive In Vitro Models, School of Engineering and Materials Science, Queen Mary University of London, London E1 4NS, UK; (M.M.); (M.M.K.)
| | - J. Paul Chapple
- Centre for Endocrinology, William Harvey Research Institute, School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK;
| | - Philip Beales
- Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, London WC1N 1EH, UK;
| | - Martin M. Knight
- Centre for Predictive In Vitro Models, School of Engineering and Materials Science, Queen Mary University of London, London E1 4NS, UK; (M.M.); (M.M.K.)
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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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Nigro EA, Boletta A. Role of the polycystins as mechanosensors of extracellular stiffness. Am J Physiol Renal Physiol 2021; 320:F693-F705. [PMID: 33615892 DOI: 10.1152/ajprenal.00545.2020] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Polycystin-1 (PC-1) is a transmembrane protein, encoded by the PKD1 gene, mutated in autosomal dominant polycystic kidney disease (ADPKD). This common genetic disorder, characterized by cyst formation in both kidneys, ultimately leading to renal failure, is still waiting for a definitive treatment. The overall function of PC-1 and the molecular mechanism responsible for cyst formation are slowly coming to light, but they are both still intensively studied. In particular, PC-1 has been proposed to act as a mechanosensor, although the precise signal that activates the mechanical properties of this protein has been long debated and questioned. In this review, we report studies and evidence of PC-1 function as a mechanosensor, starting from the peculiarity of its structure, through the long journey that progressively shed new light on the potential initiating events of cystogenesis, concluding with the description of PC-1 recently shown ability to sense the mechanical stimuli provided by the stiffness of the extracellular environment. These new findings have potentially important implications for the understanding of ADPKD pathophysiology and potentially for designing new therapies.NEW & NOTEWORTHY Polycystin-1 has recently emerged as a possible receptor able to sense extracellular stiffness and to negatively control the cellular actomyosin contraction machinery. Here, we revisit a large body of literature on autosomal dominant polycystic kidney disease providing a new possible mechanistic view on the topic.
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Affiliation(s)
- Elisa A Nigro
- Molecular Basis of Cystic Kidney Diseases, Division of Genetics and Cell Biology, Istituto di Ricovero e Cura a Carattere Scientifico, San Raffaele Scientific Institute, Milan, Italy
| | - Alessandra Boletta
- Molecular Basis of Cystic Kidney Diseases, Division of Genetics and Cell Biology, Istituto di Ricovero e Cura a Carattere Scientifico, San Raffaele Scientific Institute, Milan, Italy
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Wang P, Hao L, Wang Z, Wang Y, Guo M, Zhang P. Gadolinium-Doped BTO-Functionalized Nanocomposites with Enhanced MRI and X-ray Dual Imaging to Simulate the Electrical Properties of Bone. ACS APPLIED MATERIALS & INTERFACES 2020; 12:49464-49479. [PMID: 33090759 DOI: 10.1021/acsami.0c15837] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
Physicochemical properties of biomaterials play a regulatory role in osteoblast proliferation and differentiation. Inspired by the electrical properties of natural bone, the electroactive composites applied to osteogenesis have gradually become the hotspot of research. In this work, an electroactive biocomposite of poly(lactic-co-glycolic acid) mixed with gadolinium-doped barium titanate nanoparticles (Gd-BTO NPs) was investigated to establish the structure-activity relationship between electrical property, especially surface potential, and osteogenic activity. Furthermore, the potential mechanism was also explored. The results showed that the introduction of Gd-BTO NPs was more conducive to improve the elastic modulus and beneficial to utilize MRI and X-ray dual imaging. The electrical characteristics of composites indicate that the introduction of Gd-BTO NPs can effectively improve the electrical properties of materials including dielectricity, piezoelectricity, and surface potential. Moreover, adjusting the amount of gadolinium doping could optimize electrical activity and enhance MRI compatibility. The surface potential of 0.2Gd-BTO/PLGA could reach -58.2 to -60.9 mV at pH values from 7 to 9. Functional studies on cells revealed that the negative surface potential of poled Gd-BTO/PLGA enhanced cell attachment and osteogenic differentiation significantly. Furthermore, the negative surface potential could induce intracellular Ca2+ ion concentration oscillation and improve osteogenic differentiation via the calcineurin/NFAT signal pathway. These findings suggest that electroactive Gd-BTO/PLGA nanocomposites may have huge potential for bone regeneration and be expected to have wide applications in the field of bone tissue engineering.
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Affiliation(s)
- Peng Wang
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun 130022, P. R. China
- School of Applied Chemistry and Engineering, University of Science and Technology of China, 96 Jinzhai Road, Hefei, Anhui 230026, P. R. China
| | - Lili Hao
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun 130022, P. R. China
- School of Applied Chemistry and Engineering, University of Science and Technology of China, 96 Jinzhai Road, Hefei, Anhui 230026, P. R. China
| | - Zongliang Wang
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun 130022, P. R. China
| | - Yu Wang
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun 130022, P. R. China
| | - Min Guo
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun 130022, P. R. China
| | - Peibiao Zhang
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun 130022, P. R. China
- School of Applied Chemistry and Engineering, University of Science and Technology of China, 96 Jinzhai Road, Hefei, Anhui 230026, P. R. China
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19
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Gitomer B, Pereira R, Salusky IB, Stoneback JW, Isakova T, Cai X, Dalrymple LS, Ofsthun N, You Z, Malluche HH, Maddux F, George D, Torres V, Chapman A, Steinman TI, Wolf M, Chonchol M. Mineral bone disease in autosomal dominant polycystic kidney disease. Kidney Int 2020; 99:977-985. [PMID: 32926884 DOI: 10.1016/j.kint.2020.07.041] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 06/23/2020] [Accepted: 07/16/2020] [Indexed: 01/09/2023]
Abstract
Mice with disruption of Pkd1 in osteoblasts demonstrate reduced bone mineral density, trabecular bone volume and cortical thickness. To date, the bone phenotype in adult patients with autosomal dominant polycystic kidney disease (ADPKD) with stage I and II chronic kidney disease has not been investigated. To examine this, we characterized biochemical markers of mineral metabolism, examined bone turnover and biology, and estimated risk of fracture in patients with ADPKD. Markers of mineral metabolism were measured in 944 patients with ADPKD and other causes of kidney disease. Histomorphometry and immunohistochemistry were compared on bone biopsies from 20 patients with ADPKD with a mean eGFR of 97 ml/min/1.73m2 and 17 healthy individuals. Furthermore, adults with end stage kidney disease (ESKD) initiating hemodialysis between 2002-2013 and estimated the risk of bone fracture associated with ADPKD as compared to other etiologies of kidney disease were examined. Intact fibroblast growth factor 23 was higher and total alkaline phosphatase lower in patients with compared to patients without ADPKD with chronic kidney disease. Compared to healthy individuals, patients with ADPKD demonstrated significantly lower osteoid volume/bone volume (0.61 vs. 1.21%) and bone formation rate/bone surface (0.012 vs. 0.026 μm3/μm2/day). ESKD due to ADPKD was not associated with a higher risk of fracture as compared to ESKD due to diabetes (age adjusted incidence rate ratio: 0.53 (95% confidence interval 0.31, 0.74) or compared to other etiologies of kidney disease. Thus, individuals with ADPKD have lower alkaline phosphatase, higher circulating intact fibroblast growth factor 23 and decreased bone formation rate. However, ADPKD is not associated with higher rates of bone fracture in ESKD.
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Affiliation(s)
- Berenice Gitomer
- Division of Renal Diseases and Hypertension, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado, USA
| | - Renata Pereira
- Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Isidro B Salusky
- Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Jason W Stoneback
- Department of Orthopedics, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado, USA
| | - Tamara Isakova
- Division of Nephrology and Hypertension, Department of Medicine, Center for Translational Metabolism and Health, Institute for Public Health and Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Xuan Cai
- Division of Nephrology and Hypertension, Department of Medicine, Center for Translational Metabolism and Health, Institute for Public Health and Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | | | - Norma Ofsthun
- Fresenius Medical Care North America, Waltham, Massachusetts, USA
| | - Zhiying You
- Division of Renal Diseases and Hypertension, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado, USA
| | - Harmut H Malluche
- Division of Nephrology, Bone and Mineral Metabolism, Department of Medicine, University of Kentucky Chandler Medical Center, Lexington, Kentucky, USA
| | | | - Diana George
- Division of Renal Diseases and Hypertension, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado, USA
| | - Vicente Torres
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA
| | - Arlene Chapman
- Section of Nephrology, University of Chicago, Chicago, Illinois, USA
| | - Theodore I Steinman
- Department of Medicine and Renal Division, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
| | - Myles Wolf
- Division of Nephrology, Department of Medicine, Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina, USA
| | - Michel Chonchol
- Division of Renal Diseases and Hypertension, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado, USA.
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20
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Song J, Liu L, Lv L, Hu S, Tariq A, Wang W, Dang X. Fluid shear stress induces Runx-2 expression via upregulation of PIEZO1 in MC3T3-E1 cells. Cell Biol Int 2020; 44:1491-1502. [PMID: 32181967 DOI: 10.1002/cbin.11344] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Accepted: 03/14/2020] [Indexed: 01/14/2023]
Abstract
Mechanically induced biological responses in bone cells involve a complex biophysical process. Although various mechanosensors have been identified, the precise mechanotransduction pathway remains poorly understood. PIEZO1 is a newly discovered mechanically activated ion channel in bone cells. This study aimed to explore the involvement of PIEZO1 in mechanical loading (fluid shear stress)-induced signaling cascades that control osteogenesis. The results showed that fluid shear stress increased PIEZO1 expression in MC3T3-E1 cells. The fluid shear stress elicited the key osteoblastic gene Runx-2 expression; however, PIEZO1 silencing using small interference RNA blocked these effects. The AKT/GSK-3β/β-catenin pathway was activated in this process. PIEZO1 silencing impaired mechanically induced activation of the AKT/GSK-3β/β-catenin pathway. Therefore, the results demonstrated that MC3T3-E1 osteoblasts required PIEZO1 to adapt to the external mechanical fluid shear stress, thereby inducing osteoblastic Runx-2 gene expression, partly through the AKT/GSK-3β/β-catenin pathway.
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Affiliation(s)
- Jidong Song
- The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an Jiaotong University, Xi'an, 710004, Shaanxi, China
| | - Liying Liu
- The Center Laboratory for Biomedical Research, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, Shaanxi, China
| | - Leifeng Lv
- The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an Jiaotong University, Xi'an, 710004, Shaanxi, China
| | - Shugang Hu
- The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an Jiaotong University, Xi'an, 710004, Shaanxi, China
| | - Alkhatatbeh Tariq
- The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an Jiaotong University, Xi'an, 710004, Shaanxi, China
| | - Wei Wang
- The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an Jiaotong University, Xi'an, 710004, Shaanxi, China
| | - Xiaoqian Dang
- The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an Jiaotong University, Xi'an, 710004, Shaanxi, China
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21
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Papavassiliou KA, Zoi I, Gargalionis AN, Koutsilieris M. Polycystin-1 affects cancer cell behaviour and interacts with mTOR and Jak signalling pathways in cancer cell lines. J Cell Mol Med 2019; 23:6215-6227. [PMID: 31251475 PMCID: PMC6714176 DOI: 10.1111/jcmm.14506] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2019] [Revised: 06/03/2019] [Accepted: 06/04/2019] [Indexed: 01/28/2023] Open
Abstract
Polycystic Kidney Disease (PKD), which is attributable to mutations in the PKD1 and PKD2 genes encoding polycystin‐1 (PC1) and polycystin‐2 (PC2) respectively, shares common cellular defects with cancer, such as uncontrolled cell proliferation, abnormal differentiation and increased apoptosis. Interestingly, PC1 regulates many signalling pathways including Jak/STAT, mTOR, Wnt, AP‐1 and calcineurin‐NFAT which are also used by cancer cells for sending signals that will allow them to acquire and maintain malignant phenotypes. Nevertheless, the molecular relationship between polycystins and cancer is unknown. In this study, we investigated the role of PC1 in cancer biology using glioblastoma (GOS3), prostate (PC3), breast (MCF7), lung (A549) and colorectal (HT29) cancer cell lines. Our in vitro results propose that PC1 promotes cell migration in GOS3 cells and suppresses cell migration in A549 cells. In addition, PC1 enhances cell proliferation in GOS3 cells but inhibits it in MCF7, A549 and HT29 cells. We also found that PC1 up‐regulates mTOR signalling and down‐regulates Jak signalling in GOS3 cells, while it up‐regulates mTOR signalling in PC3 and HT29 cells. Together, our study suggests that PC1 modulates cell proliferation and migration and interacts with mTOR and Jak signalling pathways in different cancer cell lines. Understanding the molecular details of how polycystins are associated with cancer may lead to the identification of new players in this devastating disease.
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Affiliation(s)
- Kostas A Papavassiliou
- Department of Physiology, 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 Biopathology, Aeginition Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Michael Koutsilieris
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
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22
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Gargalionis AN, Basdra EK, Papavassiliou AG. Polycystins and Mechanotransduction in Human Disease. Int J Mol Sci 2019; 20:2182. [PMID: 31052533 PMCID: PMC6539061 DOI: 10.3390/ijms20092182] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Revised: 04/30/2019] [Accepted: 05/01/2019] [Indexed: 12/20/2022] Open
Abstract
Alterations in the process of mechanotransduction have been implicated in the pathogenesis of several diseases such as genetic diseases, osteoporosis, cardiovascular anomalies, and cancer. Several studies over the past twenty years have demonstrated that polycystins (polycystin-1, PC1; and polycystin-2, PC2) respond to changes of extracellular mechanical cues, and mediate pathogenic mechanotransduction and cyst formation in kidney cells. However, recent reports reveal the emergence of polycystins as key proteins that facilitate the transduction of mechano-induced signals in various clinical entities besides polycystic kidney disease, such as cancer, cardiovascular defects, bone loss, and deformations, as well as inflammatory processes like psoriasis. Herewith, we discuss data from recent studies that establish this role with potential clinical utility.
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Affiliation(s)
- Antonios N Gargalionis
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece.
| | - Efthimia K Basdra
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece.
| | - Athanasios G Papavassiliou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece.
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23
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Gargalionis AN, Basdra EK, Papavassiliou AG. Polycystins in disease mechanobiology. J Cell Biochem 2019; 120:6894-6898. [PMID: 30461048 DOI: 10.1002/jcb.28127] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Revised: 10/29/2018] [Indexed: 01/24/2023]
Abstract
Distorted mechanotransduction represents the molecular hallmark of disease mechanobiology and is displayed with common features during the development of various pathophysiologies. Polycystins constitute a family of mechanosensitive proteins that facilitate pathogenic signal transduction mechanisms. The main representatives of the family are polycystin-1 (PC1) and polycystin-2 (PC2), which function as a mechano-induced membrane receptor and a calcium-permeable ion channel, respectively. PC1 and PC2 mediate extracellular mechanical stimulation, induce intracellular molecular signaling and evoke corresponding gene transcription. Recent reports reveal that polycystin-mediated signaling does not occur in polycystic kidney disease only, where it is most prominently studied. It is also present during the development of clinical entities such as endothelial dysfunction and atheromatosis, deregulation of osteoblast differentiation, cancer development, and psoriasis. In this study, we highlight emerging data that support the overall contribution of polycystins to disease mechanobiology and suggest further exploration of this protein family in diseases generated from force-bearing tissue structures.
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Affiliation(s)
- Antonios N Gargalionis
- 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
| | - Athanasios G Papavassiliou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
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24
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The expression profile of genes involved in osteoclastogenesis detected in whole blood of Arabian horses during 3 years of competing at race track. Res Vet Sci 2018; 123:59-64. [PMID: 30586653 DOI: 10.1016/j.rvsc.2018.12.013] [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: 06/14/2018] [Revised: 11/09/2018] [Accepted: 12/17/2018] [Indexed: 11/24/2022]
Abstract
One of the most significant reason of economic loss on race track performance is lame in performed horses. Primarily, due to the failure within proper bone maintenance during conditioning in young horses. The training overload causes bone turnover disturbances in homeostasis between bone resorption and bone formation which promote the bone loss. Within our study we investigated training induced changes in transcript abundance of genes (NFATc1, CTSK, DAP12, CLEC5A, IL6ST, VAV3) involved in osteoclastogenesis hence bone resorption, in whole blood of Arabian horses. The expression pattern of all analysed genes varied depend of exercise intense activity. All training stages generate similar response to training whatever season was. The initial training had greater effect on expression pattern than increased, prolonged, established conditioning. Notwithstanding, the significant increase of transcript abundance of all investigated genes was observed during period of starts with racing competition. There is no biomarker known with highly significant accuracy according to degree of articular cartilage or bone disease in a single joint. Thus, the markers presented in our report, poses the potential to be further investigate as useful tool for bone turnover.
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25
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Gargalionis AN, Malakou LS, Adamopoulos C, Piperi C, Theohari I, Nokhbehsaim M, Deschner J, Kokkalis G, Korkolopoulou P, Papadavid E, Papavassiliou AG, Basdra EK. Polycystin-1 downregulation induces ERK-dependent mTOR pathway activation in a cellular model of psoriasis. Biochim Biophys Acta Mol Basis Dis 2018; 1864:3468-3476. [PMID: 30077613 DOI: 10.1016/j.bbadis.2018.07.036] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2018] [Revised: 07/31/2018] [Accepted: 07/31/2018] [Indexed: 10/28/2022]
Abstract
Psoriatic plaques tend to localize to the knees and elbows, areas that are particularly subject to mechanical stress resulting from bending and friction. Moreover, plaques often develop at sites of mechanical trauma or injury (Koebner phenomenon). Nevertheless, mechanotransduction has never been linked to psoriasis. Polycystins (polycystin-1, PC1; polycystin-2, PC2) are mechanosensitive molecules that function as key regulators of cellular mechanosensitivity and mechanotransduction. The aim of this in vitro study was to investigate the role of polycystins in the development of psoriasis. We showed that PC1 knockdown in HaCaT cells led to an elevated mRNA expression of psoriasis-related biomarkers Ki-67, IL-6, TNF-α, VEGF and Bcl-2, while PC1 functional inhibition was accompanied by increased cell proliferation and migration of HaCaT cells. In addition, PC1 knockdown via siRNA in HaCaT cells was followed by activation of critical molecules of the mTOR and MAPK pathways and this mTOR pathway activation was ERK-dependent. Furthermore, loss of PC1 protein expression and elevated levels of activated mTOR substrates were also observed in human samples of psoriatic plaques. Overall, our study suggests that the PC1/ERK/mTOR signaling axis represents a novel potential mechanism in psoriasis pathogenesis.
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Affiliation(s)
- Antonios N Gargalionis
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Lina S Malakou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Christos Adamopoulos
- 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
| | - Irene Theohari
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 'Laikon' General Hospital, Athens, Greece
| | - Marjan Nokhbehsaim
- Section of Experimental Dento-Maxillo-Facial Medicine, Center of Dento-Maxillo-Facial Medicine, University of Bonn, Bonn, Germany
| | - James Deschner
- Department of Periodontology and Operative Dentistry, University Medical Center of the Johannes Gutenberg University, Mainz, Germany
| | - Georgios Kokkalis
- Second Department of Dermatology, Medical School, National and Kapodistrian University of Athens, '?ttikon' General University Hospital, Athens, Greece
| | - Penelope Korkolopoulou
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 'Laikon' General Hospital, Athens, Greece
| | - Evangelia Papadavid
- Second Department of Dermatology, Medical School, National and Kapodistrian University of Athens, '?ttikon' General University Hospital, 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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26
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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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27
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Malakou LS, Gargalionis AN, Piperi C, Papadavid E, Papavassiliou AG, Basdra EK. Molecular mechanisms of mechanotransduction in psoriasis. ANNALS OF TRANSLATIONAL MEDICINE 2018; 6:245. [PMID: 30069447 DOI: 10.21037/atm.2018.04.09] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Psoriasis is an immune disease of the skin that frequently develops upon triggering events of mechanical nature and leads to increased proliferation and damaged differentiation of keratinocytes of the epidermis. Mechanical forces are mediated through mechanotransduction, which is the process that translates physical cues into biochemical signaling networks. Latest updates underline the role of mechanotransduction during the acquisition of aberrant properties by the keratinocytes of the skin, therefore implying a potential contribution that promotes psoriasis pathogenesis. The present review discusses the mechano-induced signaling pathways and individual molecules that become activated in psoriasis and in keratinocytes, along with mechano-based putative treatment strategies. We also suggest emerging mechanosensitive molecules for further investigation with potential diagnostic and therapeutic utility in psoriasis.
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Affiliation(s)
- Lina S Malakou
- 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
| | - Evangelia Papadavid
- Second Department of Dermatology, Medical School, National and Kapodistrian University of Athens, 'Attikon' General University Hospital, Athens, Greece
| | - Athanasios G Papavassiliou
- 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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28
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Stevenson NL, Bergen DJM, Xu A, Wyatt E, Henry F, McCaughey J, Vuolo L, Hammond CL, Stephens DJ. Regulator of calcineurin-2 is a centriolar protein with a role in cilia length control. J Cell Sci 2018; 131:jcs.212258. [PMID: 29643119 DOI: 10.1242/jcs.212258] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2017] [Accepted: 04/04/2018] [Indexed: 02/03/2023] Open
Abstract
Almost every cell in the human body extends a primary cilium. Defective cilia function leads to a set of disorders known as ciliopathies, which are characterised by debilitating developmental defects that affect many tissues. Here, we report a new role for regulator of calcineurin 2 (RCAN2) in primary cilia function. It localises to centrioles and the basal body and is required to maintain normal cilia length. RCAN2 was identified as the most strongly upregulated gene from a comparative RNAseq analysis of cells in which expression of the Golgi matrix protein giantin had been abolished by gene editing. In contrast to previous work where we showed that depletion of giantin by RNAi results in defects in ciliogenesis and in cilia length control, giantin knockout cells generate normal cilia after serum withdrawal. Furthermore, giantin knockout zebrafish show increased expression of RCAN2. Importantly, suppression of RCAN2 expression in giantin knockout cells results in the same defects in the control of cilia length that are seen upon RNAi of giantin itself. Together, these data define RCAN2 as a regulator of cilia function that can compensate for the loss of giantin function.
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Affiliation(s)
- Nicola L Stevenson
- Cell Biology Laboratories, School of Biochemistry, University of Bristol, Biomedical Sciences Building, University Walk, Bristol, UK, BS8 1TD
| | - Dylan J M Bergen
- Cell Biology Laboratories, School of Biochemistry, University of Bristol, Biomedical Sciences Building, University Walk, Bristol, UK, BS8 1TD
| | - Amadeus Xu
- Cell Biology Laboratories, School of Biochemistry, University of Bristol, Biomedical Sciences Building, University Walk, Bristol, UK, BS8 1TD
| | - Emily Wyatt
- Cell Biology Laboratories, School of Biochemistry, University of Bristol, Biomedical Sciences Building, University Walk, Bristol, UK, BS8 1TD
| | - Freya Henry
- Cell Biology Laboratories, School of Biochemistry, University of Bristol, Biomedical Sciences Building, University Walk, Bristol, UK, BS8 1TD
| | - Janine McCaughey
- Cell Biology Laboratories, School of Biochemistry, University of Bristol, Biomedical Sciences Building, University Walk, Bristol, UK, BS8 1TD
| | - Laura Vuolo
- Cell Biology Laboratories, School of Biochemistry, University of Bristol, Biomedical Sciences Building, University Walk, Bristol, UK, BS8 1TD
| | - Chrissy L Hammond
- School of Physiology and Pharmacology, University of Bristol, Biomedical Sciences Building, University Walk, Bristol, UK, BS8 1TD
| | - David J Stephens
- Cell Biology Laboratories, School of Biochemistry, University of Bristol, Biomedical Sciences Building, University Walk, Bristol, UK, BS8 1TD
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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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30
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Gargalionis AN, Basdra EK, Papavassiliou AG. Polycystins and mechanotransduction in bone. Oncotarget 2017; 8:106159-106160. [PMID: 29290931 PMCID: PMC5739716 DOI: 10.18632/oncotarget.22421] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2017] [Accepted: 11/10/2017] [Indexed: 11/25/2022] Open
Affiliation(s)
- Antonios N Gargalionis
- Athanasios G. Papavassiliou: Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Efthimia K Basdra
- Athanasios G. Papavassiliou: Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Athanasios G Papavassiliou
- Athanasios G. Papavassiliou: Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
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31
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Xiao Z, Baudry J, Cao L, Huang J, Chen H, Yates CR, Li W, Dong B, Waters CM, Smith JC, Quarles LD. Polycystin-1 interacts with TAZ to stimulate osteoblastogenesis and inhibit adipogenesis. J Clin Invest 2017; 128:157-174. [PMID: 29202470 DOI: 10.1172/jci93725] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2017] [Accepted: 10/17/2017] [Indexed: 01/15/2023] Open
Abstract
The molecular mechanisms that transduce the osteoblast response to physical forces in the bone microenvironment are poorly understood. Here, we used genetic and pharmacological experiments to determine whether the polycystins PC1 and PC2 (encoded by Pkd1 and Pkd2) and the transcriptional coactivator TAZ form a mechanosensing complex in osteoblasts. Compound-heterozygous mice lacking 1 copy of Pkd1 and Taz exhibited additive decrements in bone mass, impaired osteoblast-mediated bone formation, and enhanced bone marrow fat accumulation. Bone marrow stromal cells and osteoblasts derived from these mice showed impaired osteoblastogenesis and enhanced adipogenesis. Increased extracellular matrix stiffness and application of mechanical stretch to multipotent mesenchymal cells stimulated the nuclear translocation of the PC1 C-terminal tail/TAZ (PC1-CTT/TAZ) complex, leading to increased runt-related transcription factor 2-mediated (Runx2-mediated) osteogenic and decreased PPARγ-dependent adipogenic gene expression. Using structure-based virtual screening, we identified a compound predicted to bind to PC2 in the PC1:PC2 C-terminal tail region with helix:helix interaction. This molecule stimulated polycystin- and TAZ-dependent osteoblastogenesis and inhibited adipogenesis. Thus, we show that polycystins and TAZ integrate at the molecular level to reciprocally regulate osteoblast and adipocyte differentiation, indicating that the polycystins/TAZ complex may be a potential therapeutic target to increase bone mass.
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Affiliation(s)
- Zhousheng Xiao
- Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | - Jerome Baudry
- UT/ORNL Center for Molecular Biophysics, Oak Ridge National Laboratory, Oak Ridge, Tennessee, USA.,Department of Biochemistry and Cellular and Molecular Biology, University of Tennessee, Knoxville, Tennessee, USA
| | - Li Cao
- Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | - Jinsong Huang
- Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | - Hao Chen
- Department of Pharmaceutical Sciences and
| | | | - Wei Li
- Department of Pharmaceutical Sciences and
| | - Brittany Dong
- Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | - Christopher M Waters
- Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | - Jeremy C Smith
- UT/ORNL Center for Molecular Biophysics, Oak Ridge National Laboratory, Oak Ridge, Tennessee, USA.,Department of Biochemistry and Cellular and Molecular Biology, University of Tennessee, Knoxville, Tennessee, USA
| | - L Darryl Quarles
- Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA
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32
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Li F, Song R, Ao L, Reece TB, Cleveland JC, Dong N, Fullerton DA, Meng X. ADAMTS5 Deficiency in Calcified Aortic Valves Is Associated With Elevated Pro-Osteogenic Activity in Valvular Interstitial Cells. Arterioscler Thromb Vasc Biol 2017; 37:1339-1351. [PMID: 28546218 DOI: 10.1161/atvbaha.117.309021] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2016] [Accepted: 05/09/2017] [Indexed: 12/20/2022]
Abstract
OBJECTIVE Extracellular matrix proteinases are implicated in the pathogenesis of calcific aortic valve disease. The ADAMTS5 (a disintegrin and metalloproteinase with thrombospondin motifs 5) enzyme is secreted, matrix-associated metalloendopeptidase, capable of degrading extracellular matrix proteins, particularly matrilin 2. We sought to determine the role of the ADAMTS5/matrilin 2 axis in mediating the phenotype transition of valvular interstitial cells (VICs) associated with calcific aortic valve disease. APPROACH AND RESULTS Levels of ADAMTS5, matrilin 2, and α-SMA (α-smooth muscle actin) were evaluated in calcified and normal human aortic valve tissues and VICs. Calcified aortic valves have reduced levels of ADAMTS5 and higher levels of matrilin 2 and α-SMA. Treatment of normal VICs with soluble matrilin 2 caused an increase in α-SMA level through Toll-like receptors 2 and 4, which was accompanied by upregulation of runt-related transcription factor 2 and alkaline phosphatase. In addition, ADAMTS5 knockdown in normal VICs enhanced the effect of matrilin 2. Matrilin 2 activated nuclear factor (NF) κB and NF of activated T cells complex 1 and induced the interaction of these 2 NFs. Inhibition of either NF-κB or NF of activated T cells complex 1 suppressed matrilin 2's effect on VIC phenotype change. Knockdown of α-SMA reduced and overexpression of α-SMA enhanced the expression of pro-osteogenic factors and calcium deposit formation in human VICs. CONCLUSIONS Matrilin 2 induces myofibroblastic transition and elevates pro-osteogenic activity in human VICs via activation of NF-κB and NF of activated T cells complex 1. Myofibroblastic transition in human VICs is an important mechanism of elevating the pro-osteogenic activity. Matrilin 2 accumulation associated with relative ADAMTS5 deficiency may contribute to the mechanism underlying calcific aortic valve disease progression.
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Affiliation(s)
- Fei Li
- From the Department of Surgery, University of Colorado Denver, Aurora (F.L., R.S., L.A., T.B.R., J.C.C., D.A.F., X.M.); and Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (F.L., N.D.)
| | - Rui Song
- From the Department of Surgery, University of Colorado Denver, Aurora (F.L., R.S., L.A., T.B.R., J.C.C., D.A.F., X.M.); and Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (F.L., N.D.)
| | - Lihua Ao
- From the Department of Surgery, University of Colorado Denver, Aurora (F.L., R.S., L.A., T.B.R., J.C.C., D.A.F., X.M.); and Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (F.L., N.D.)
| | - T Brett Reece
- From the Department of Surgery, University of Colorado Denver, Aurora (F.L., R.S., L.A., T.B.R., J.C.C., D.A.F., X.M.); and Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (F.L., N.D.)
| | - Joseph C Cleveland
- From the Department of Surgery, University of Colorado Denver, Aurora (F.L., R.S., L.A., T.B.R., J.C.C., D.A.F., X.M.); and Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (F.L., N.D.)
| | - Nianguo Dong
- From the Department of Surgery, University of Colorado Denver, Aurora (F.L., R.S., L.A., T.B.R., J.C.C., D.A.F., X.M.); and Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (F.L., N.D.)
| | - David A Fullerton
- From the Department of Surgery, University of Colorado Denver, Aurora (F.L., R.S., L.A., T.B.R., J.C.C., D.A.F., X.M.); and Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (F.L., N.D.)
| | - Xianzhong Meng
- From the Department of Surgery, University of Colorado Denver, Aurora (F.L., R.S., L.A., T.B.R., J.C.C., D.A.F., X.M.); and Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (F.L., N.D.).
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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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34
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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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Pesce M, Messina E, Chimenti I, Beltrami AP. Cardiac Mechanoperception: A Life-Long Story from Early Beats to Aging and Failure. Stem Cells Dev 2016; 26:77-90. [PMID: 27736363 DOI: 10.1089/scd.2016.0206] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
The life-long story of the heart starts concomitantly with primary differentiation events occurring in multipotent progenitors located in the so-called heart tube. This initially tubular structure starts a looping process, which leads to formation of the final four-chambered heart with a primary contribution of geometric and position-associated cell sensing. While this establishes the correct patterning of the final cardiac structure, it also provides feedbacks to fundamental cellular machineries controlling proliferation and differentiation, thus ensuring a coordinated restriction of cell growth and a myocyte terminal differentiation. Novel evidences provided by embryological and cell engineering studies have clarified the relevance of mechanics-supported position sensing for the correct recognition of cell fate inside developing embryos and multicellular aggregates. One of the main components of this pathway, the Hippo-dependent signal transduction machinery, is responsible for cell mechanics intracellular transduction with important consequences for gene transcription and cell growth control. Being the Hippo pathway also directly connected to stress responses and altered metabolism, it is tempting to speculate that permanent alterations of mechanosensing may account for modifying self-renewal control in tissue homeostasis. In the present contribution, we translate these concepts to the aging process and the failing of the human heart, two pathophysiologic conditions that are strongly affected by stress responses and altered metabolism.
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Affiliation(s)
- Maurizio Pesce
- 1 Tissue Engineering Research Unit, Centro Cardiologico Monzino, IRCCS , Milan, Italy
| | - Elisa Messina
- 2 Department of Pediatric Cardiology, "Sapienza" University , Rome, Italy
| | - Isotta Chimenti
- 3 Department of Medical Surgical Science and Biotechnology, "Sapienza" University , Rome, Italy
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Adamopoulos C, Gargalionis AN, Piperi C, Papavassiliou AG. Recent Advances in Mechanobiology of Osteosarcoma. J Cell Biochem 2016; 118:232-236. [PMID: 27463370 DOI: 10.1002/jcb.25660] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2016] [Accepted: 07/26/2016] [Indexed: 02/06/2023]
Affiliation(s)
- Christos Adamopoulos
- Department of Biological Chemistry; Medical School; National and Kapodistrian University of Athens; Athens 11527 Greece
| | - Antonios N. Gargalionis
- Department of Biological Chemistry; Medical School; National and Kapodistrian University of Athens; Athens 11527 Greece
| | - Christina Piperi
- Department of Biological Chemistry; Medical School; National and Kapodistrian University of Athens; Athens 11527 Greece
| | - Athanasios G. Papavassiliou
- Department of Biological Chemistry; Medical School; National and Kapodistrian University of Athens; Athens 11527 Greece
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37
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Adamopoulos C, Gargalionis AN, Basdra EK, Papavassiliou AG. Deciphering signaling networks in osteosarcoma pathobiology. Exp Biol Med (Maywood) 2016; 241:1296-1305. [PMID: 27190271 PMCID: PMC4950271 DOI: 10.1177/1535370216648806] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Osteosarcoma is the most frequent type of primary bone tumors among children and adolescents. During the past years, little progress has been made regarding prognosis of osteosarcoma patients, especially for those with metastatic disease. Genomic instability and gene alterations are common, but current data do not reveal a consistent and repeatable pattern of osteosarcoma development, thus paralleling the tumor's high heterogeneity. Critical signal transduction pathways have been implicated in osteosarcoma pathobiology and are being evaluated as therapeutic targets, including receptor activator for nuclear factor-κB (RANK), Wnt, Notch, phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin, and mechanotransduction pathways. Herein, we recapitulate and discuss recent advances in the context of molecular mechanisms and signaling networks that contribute to osteosarcoma progression and metastasis, towards patient-tailored and novel-targeted treatments.
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Affiliation(s)
- Christos Adamopoulos
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece
| | - Antonios N Gargalionis
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece
| | - Efthimia K Basdra
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece
| | - Athanasios G Papavassiliou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece
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38
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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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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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40
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Pedrozo Z, Criollo A, Battiprolu PK, Morales CR, Contreras-Ferrat A, Fernández C, Jiang N, Luo X, Caplan MJ, Somlo S, Rothermel BA, Gillette TG, Lavandero S, Hill JA. Polycystin-1 Is a Cardiomyocyte Mechanosensor That Governs L-Type Ca2+ Channel Protein Stability. Circulation 2015; 131:2131-42. [PMID: 25888683 PMCID: PMC4470854 DOI: 10.1161/circulationaha.114.013537] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2014] [Accepted: 04/10/2015] [Indexed: 11/16/2022]
Abstract
BACKGROUND L-type calcium channel activity is critical to afterload-induced hypertrophic growth of the heart. However, the mechanisms governing mechanical stress-induced activation of L-type calcium channel activity are obscure. Polycystin-1 (PC-1) is a G protein-coupled receptor-like protein that functions as a mechanosensor in a variety of cell types and is present in cardiomyocytes. METHODS AND RESULTS We subjected neonatal rat ventricular myocytes to mechanical stretch by exposing them to hypo-osmotic medium or cyclic mechanical stretch, triggering cell growth in a manner dependent on L-type calcium channel activity. RNAi-dependent knockdown of PC-1 blocked this hypertrophy. Overexpression of a C-terminal fragment of PC-1 was sufficient to trigger neonatal rat ventricular myocyte hypertrophy. Exposing neonatal rat ventricular myocytes to hypo-osmotic medium resulted in an increase in α1C protein levels, a response that was prevented by PC-1 knockdown. MG132, a proteasomal inhibitor, rescued PC-1 knockdown-dependent declines in α1C protein. To test this in vivo, we engineered mice harboring conditional silencing of PC-1 selectively in cardiomyocytes (PC-1 knockout) and subjected them to mechanical stress in vivo (transverse aortic constriction). At baseline, PC-1 knockout mice manifested decreased cardiac function relative to littermate controls, and α1C L-type calcium channel protein levels were significantly lower in PC-1 knockout hearts. Whereas control mice manifested robust transverse aortic constriction-induced increases in cardiac mass, PC-1 knockout mice showed no significant growth. Likewise, transverse aortic constriction-elicited increases in hypertrophic markers and interstitial fibrosis were blunted in the knockout animals CONCLUSION PC-1 is a cardiomyocyte mechanosensor that is required for cardiac hypertrophy through a mechanism that involves stabilization of α1C protein.
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MESH Headings
- Animals
- Animals, Newborn
- Biomarkers
- Calcium Channels, L-Type/biosynthesis
- Calcium Channels, L-Type/genetics
- Calcium Channels, L-Type/physiology
- Cardiomegaly/etiology
- Cardiomegaly/prevention & control
- Cells, Cultured
- Fibrosis
- Hypertrophy
- Hypotonic Solutions/pharmacology
- Male
- Mechanotransduction, Cellular/physiology
- Mice
- Mice, Knockout
- Myocytes, Cardiac/drug effects
- Myocytes, Cardiac/physiology
- Protein Interaction Mapping
- Protein Stability
- Protein Structure, Tertiary
- RNA Interference
- Rats
- Rats, Sprague-Dawley
- Recombinant Fusion Proteins/metabolism
- Stress, Mechanical
- TRPP Cation Channels/chemistry
- TRPP Cation Channels/genetics
- TRPP Cation Channels/physiology
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Affiliation(s)
- Zully Pedrozo
- From Division of Cardiology, Department of Internal Medicine (Z.P., A.C., P.K.B., C.R.M., N.J., X.L., B.A.R., T.G.G., S.L., J.A.H.) and Department of Molecular Biology (B.A.R., J.A.H.), UT Southwestern Medical Center, Dallas, TX; Advanced Center for Chronic Diseases and Centro de Estudios Moleculares de la Célula, Facultad de Medicina & Facultad de Ciencias Químicas y Farmacéuticas, Santiago, Chile (Z.P., A.C.-F., C.F., S.L.); Instituto de Ciencias Biomédicas, Facultad de Medicina (Z.P., S.L.) and Instituto de Investigación en Ciencias Odontológicas, Facultad de Odontología (A.C.), Universidad de Chile, Santiago; and Departments of Cellular and Molecular Physiology (M.J.C.), Internal Medicine (S.S.), and Genetics (S.S.), Yale University School of Medicine, New Haven, CT
| | - Alfredo Criollo
- From Division of Cardiology, Department of Internal Medicine (Z.P., A.C., P.K.B., C.R.M., N.J., X.L., B.A.R., T.G.G., S.L., J.A.H.) and Department of Molecular Biology (B.A.R., J.A.H.), UT Southwestern Medical Center, Dallas, TX; Advanced Center for Chronic Diseases and Centro de Estudios Moleculares de la Célula, Facultad de Medicina & Facultad de Ciencias Químicas y Farmacéuticas, Santiago, Chile (Z.P., A.C.-F., C.F., S.L.); Instituto de Ciencias Biomédicas, Facultad de Medicina (Z.P., S.L.) and Instituto de Investigación en Ciencias Odontológicas, Facultad de Odontología (A.C.), Universidad de Chile, Santiago; and Departments of Cellular and Molecular Physiology (M.J.C.), Internal Medicine (S.S.), and Genetics (S.S.), Yale University School of Medicine, New Haven, CT
| | - Pavan K Battiprolu
- From Division of Cardiology, Department of Internal Medicine (Z.P., A.C., P.K.B., C.R.M., N.J., X.L., B.A.R., T.G.G., S.L., J.A.H.) and Department of Molecular Biology (B.A.R., J.A.H.), UT Southwestern Medical Center, Dallas, TX; Advanced Center for Chronic Diseases and Centro de Estudios Moleculares de la Célula, Facultad de Medicina & Facultad de Ciencias Químicas y Farmacéuticas, Santiago, Chile (Z.P., A.C.-F., C.F., S.L.); Instituto de Ciencias Biomédicas, Facultad de Medicina (Z.P., S.L.) and Instituto de Investigación en Ciencias Odontológicas, Facultad de Odontología (A.C.), Universidad de Chile, Santiago; and Departments of Cellular and Molecular Physiology (M.J.C.), Internal Medicine (S.S.), and Genetics (S.S.), Yale University School of Medicine, New Haven, CT
| | - Cyndi R Morales
- From Division of Cardiology, Department of Internal Medicine (Z.P., A.C., P.K.B., C.R.M., N.J., X.L., B.A.R., T.G.G., S.L., J.A.H.) and Department of Molecular Biology (B.A.R., J.A.H.), UT Southwestern Medical Center, Dallas, TX; Advanced Center for Chronic Diseases and Centro de Estudios Moleculares de la Célula, Facultad de Medicina & Facultad de Ciencias Químicas y Farmacéuticas, Santiago, Chile (Z.P., A.C.-F., C.F., S.L.); Instituto de Ciencias Biomédicas, Facultad de Medicina (Z.P., S.L.) and Instituto de Investigación en Ciencias Odontológicas, Facultad de Odontología (A.C.), Universidad de Chile, Santiago; and Departments of Cellular and Molecular Physiology (M.J.C.), Internal Medicine (S.S.), and Genetics (S.S.), Yale University School of Medicine, New Haven, CT
| | - Ariel Contreras-Ferrat
- From Division of Cardiology, Department of Internal Medicine (Z.P., A.C., P.K.B., C.R.M., N.J., X.L., B.A.R., T.G.G., S.L., J.A.H.) and Department of Molecular Biology (B.A.R., J.A.H.), UT Southwestern Medical Center, Dallas, TX; Advanced Center for Chronic Diseases and Centro de Estudios Moleculares de la Célula, Facultad de Medicina & Facultad de Ciencias Químicas y Farmacéuticas, Santiago, Chile (Z.P., A.C.-F., C.F., S.L.); Instituto de Ciencias Biomédicas, Facultad de Medicina (Z.P., S.L.) and Instituto de Investigación en Ciencias Odontológicas, Facultad de Odontología (A.C.), Universidad de Chile, Santiago; and Departments of Cellular and Molecular Physiology (M.J.C.), Internal Medicine (S.S.), and Genetics (S.S.), Yale University School of Medicine, New Haven, CT
| | - Carolina Fernández
- From Division of Cardiology, Department of Internal Medicine (Z.P., A.C., P.K.B., C.R.M., N.J., X.L., B.A.R., T.G.G., S.L., J.A.H.) and Department of Molecular Biology (B.A.R., J.A.H.), UT Southwestern Medical Center, Dallas, TX; Advanced Center for Chronic Diseases and Centro de Estudios Moleculares de la Célula, Facultad de Medicina & Facultad de Ciencias Químicas y Farmacéuticas, Santiago, Chile (Z.P., A.C.-F., C.F., S.L.); Instituto de Ciencias Biomédicas, Facultad de Medicina (Z.P., S.L.) and Instituto de Investigación en Ciencias Odontológicas, Facultad de Odontología (A.C.), Universidad de Chile, Santiago; and Departments of Cellular and Molecular Physiology (M.J.C.), Internal Medicine (S.S.), and Genetics (S.S.), Yale University School of Medicine, New Haven, CT
| | - Nan Jiang
- From Division of Cardiology, Department of Internal Medicine (Z.P., A.C., P.K.B., C.R.M., N.J., X.L., B.A.R., T.G.G., S.L., J.A.H.) and Department of Molecular Biology (B.A.R., J.A.H.), UT Southwestern Medical Center, Dallas, TX; Advanced Center for Chronic Diseases and Centro de Estudios Moleculares de la Célula, Facultad de Medicina & Facultad de Ciencias Químicas y Farmacéuticas, Santiago, Chile (Z.P., A.C.-F., C.F., S.L.); Instituto de Ciencias Biomédicas, Facultad de Medicina (Z.P., S.L.) and Instituto de Investigación en Ciencias Odontológicas, Facultad de Odontología (A.C.), Universidad de Chile, Santiago; and Departments of Cellular and Molecular Physiology (M.J.C.), Internal Medicine (S.S.), and Genetics (S.S.), Yale University School of Medicine, New Haven, CT
| | - Xiang Luo
- From Division of Cardiology, Department of Internal Medicine (Z.P., A.C., P.K.B., C.R.M., N.J., X.L., B.A.R., T.G.G., S.L., J.A.H.) and Department of Molecular Biology (B.A.R., J.A.H.), UT Southwestern Medical Center, Dallas, TX; Advanced Center for Chronic Diseases and Centro de Estudios Moleculares de la Célula, Facultad de Medicina & Facultad de Ciencias Químicas y Farmacéuticas, Santiago, Chile (Z.P., A.C.-F., C.F., S.L.); Instituto de Ciencias Biomédicas, Facultad de Medicina (Z.P., S.L.) and Instituto de Investigación en Ciencias Odontológicas, Facultad de Odontología (A.C.), Universidad de Chile, Santiago; and Departments of Cellular and Molecular Physiology (M.J.C.), Internal Medicine (S.S.), and Genetics (S.S.), Yale University School of Medicine, New Haven, CT
| | - Michael J Caplan
- From Division of Cardiology, Department of Internal Medicine (Z.P., A.C., P.K.B., C.R.M., N.J., X.L., B.A.R., T.G.G., S.L., J.A.H.) and Department of Molecular Biology (B.A.R., J.A.H.), UT Southwestern Medical Center, Dallas, TX; Advanced Center for Chronic Diseases and Centro de Estudios Moleculares de la Célula, Facultad de Medicina & Facultad de Ciencias Químicas y Farmacéuticas, Santiago, Chile (Z.P., A.C.-F., C.F., S.L.); Instituto de Ciencias Biomédicas, Facultad de Medicina (Z.P., S.L.) and Instituto de Investigación en Ciencias Odontológicas, Facultad de Odontología (A.C.), Universidad de Chile, Santiago; and Departments of Cellular and Molecular Physiology (M.J.C.), Internal Medicine (S.S.), and Genetics (S.S.), Yale University School of Medicine, New Haven, CT
| | - Stefan Somlo
- From Division of Cardiology, Department of Internal Medicine (Z.P., A.C., P.K.B., C.R.M., N.J., X.L., B.A.R., T.G.G., S.L., J.A.H.) and Department of Molecular Biology (B.A.R., J.A.H.), UT Southwestern Medical Center, Dallas, TX; Advanced Center for Chronic Diseases and Centro de Estudios Moleculares de la Célula, Facultad de Medicina & Facultad de Ciencias Químicas y Farmacéuticas, Santiago, Chile (Z.P., A.C.-F., C.F., S.L.); Instituto de Ciencias Biomédicas, Facultad de Medicina (Z.P., S.L.) and Instituto de Investigación en Ciencias Odontológicas, Facultad de Odontología (A.C.), Universidad de Chile, Santiago; and Departments of Cellular and Molecular Physiology (M.J.C.), Internal Medicine (S.S.), and Genetics (S.S.), Yale University School of Medicine, New Haven, CT
| | - Beverly A Rothermel
- From Division of Cardiology, Department of Internal Medicine (Z.P., A.C., P.K.B., C.R.M., N.J., X.L., B.A.R., T.G.G., S.L., J.A.H.) and Department of Molecular Biology (B.A.R., J.A.H.), UT Southwestern Medical Center, Dallas, TX; Advanced Center for Chronic Diseases and Centro de Estudios Moleculares de la Célula, Facultad de Medicina & Facultad de Ciencias Químicas y Farmacéuticas, Santiago, Chile (Z.P., A.C.-F., C.F., S.L.); Instituto de Ciencias Biomédicas, Facultad de Medicina (Z.P., S.L.) and Instituto de Investigación en Ciencias Odontológicas, Facultad de Odontología (A.C.), Universidad de Chile, Santiago; and Departments of Cellular and Molecular Physiology (M.J.C.), Internal Medicine (S.S.), and Genetics (S.S.), Yale University School of Medicine, New Haven, CT
| | - Thomas G Gillette
- From Division of Cardiology, Department of Internal Medicine (Z.P., A.C., P.K.B., C.R.M., N.J., X.L., B.A.R., T.G.G., S.L., J.A.H.) and Department of Molecular Biology (B.A.R., J.A.H.), UT Southwestern Medical Center, Dallas, TX; Advanced Center for Chronic Diseases and Centro de Estudios Moleculares de la Célula, Facultad de Medicina & Facultad de Ciencias Químicas y Farmacéuticas, Santiago, Chile (Z.P., A.C.-F., C.F., S.L.); Instituto de Ciencias Biomédicas, Facultad de Medicina (Z.P., S.L.) and Instituto de Investigación en Ciencias Odontológicas, Facultad de Odontología (A.C.), Universidad de Chile, Santiago; and Departments of Cellular and Molecular Physiology (M.J.C.), Internal Medicine (S.S.), and Genetics (S.S.), Yale University School of Medicine, New Haven, CT
| | - Sergio Lavandero
- From Division of Cardiology, Department of Internal Medicine (Z.P., A.C., P.K.B., C.R.M., N.J., X.L., B.A.R., T.G.G., S.L., J.A.H.) and Department of Molecular Biology (B.A.R., J.A.H.), UT Southwestern Medical Center, Dallas, TX; Advanced Center for Chronic Diseases and Centro de Estudios Moleculares de la Célula, Facultad de Medicina & Facultad de Ciencias Químicas y Farmacéuticas, Santiago, Chile (Z.P., A.C.-F., C.F., S.L.); Instituto de Ciencias Biomédicas, Facultad de Medicina (Z.P., S.L.) and Instituto de Investigación en Ciencias Odontológicas, Facultad de Odontología (A.C.), Universidad de Chile, Santiago; and Departments of Cellular and Molecular Physiology (M.J.C.), Internal Medicine (S.S.), and Genetics (S.S.), Yale University School of Medicine, New Haven, CT.
| | - Joseph A Hill
- From Division of Cardiology, Department of Internal Medicine (Z.P., A.C., P.K.B., C.R.M., N.J., X.L., B.A.R., T.G.G., S.L., J.A.H.) and Department of Molecular Biology (B.A.R., J.A.H.), UT Southwestern Medical Center, Dallas, TX; Advanced Center for Chronic Diseases and Centro de Estudios Moleculares de la Célula, Facultad de Medicina & Facultad de Ciencias Químicas y Farmacéuticas, Santiago, Chile (Z.P., A.C.-F., C.F., S.L.); Instituto de Ciencias Biomédicas, Facultad de Medicina (Z.P., S.L.) and Instituto de Investigación en Ciencias Odontológicas, Facultad de Odontología (A.C.), Universidad de Chile, Santiago; and Departments of Cellular and Molecular Physiology (M.J.C.), Internal Medicine (S.S.), and Genetics (S.S.), Yale University School of Medicine, New Haven, CT.
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41
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Abstract
Skeletal loading is an important physiological regulator of bone mass. Theoretically, mechanical forces or administration of drugs that activate bone mechanosensors would be a novel treatment for osteoporotic disorders, particularly age-related osteoporosis and other bone loss caused by skeletal unloading. Uncertainty regarding the identity of the molecular targets that sense and transduce mechanical forces in bone, however, has limited the therapeutic exploitation of mechanosesning pathways to control bone mass. Recently, two evolutionally conserved mechanosensing pathways have been shown to function as "physical environment" sensors in cells of the osteoblasts lineage. Indeed, polycystin-1 (Pkd1, or PC1) and polycystin-2 (Pkd2, or PC2' or TRPP2), which form a flow sensing receptor channel complex, and TAZ (transcriptional coactivator with PDZ-binding motif, or WWTR1), which responds to the extracellular matrix microenvironment act in concert to reciprocally regulate osteoblastogenesis and adipogenesis through co-activating Runx2 and a co-repressing PPARγ activities. Interactions of polycystins and TAZ with other putative mechanosensing mechanism, such as primary cilia, integrins and hemichannels, may create multifaceted mechanosensing networks in bone. Moreover, modulation of polycystins and TAZ interactions identify novel molecular targets to develop small molecules that mimic the effects of mechanical loading on bone.
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Affiliation(s)
- Zhousheng Xiao
- Department of Medicine, University of Tennessee Health Science Center, Memphis, TN 38165, USA
| | - Leigh Darryl Quarles
- Department of Medicine, University of Tennessee Health Science Center, Memphis, TN 38165, USA
- Coleman College of Medicine Building, Suite B216, University of Tennessee Health Science Center, 956 Court Avenue, Memphis, TN 38163, USA
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42
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Gargalionis AN, Korkolopoulou P, Farmaki E, Piperi C, Dalagiorgou G, Adamopoulos C, Levidou G, Saetta A, Fragkou P, Tsioli P, Kiaris H, Zizi-Serbetzoglou A, Karavokyros I, Papavassiliou KA, Tsavaris N, Patsouris E, Basdra EK, Papavassiliou AG. Polycystin-1 and polycystin-2 are involved in the acquisition of aggressive phenotypes in colorectal cancer. Int J Cancer 2015; 136:1515-1527. [PMID: 25123959 DOI: 10.1002/ijc.29140] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2014] [Revised: 08/01/2014] [Accepted: 08/07/2014] [Indexed: 01/01/2023]
Abstract
The polycystins PC1 and PC2 are emerging as major players in mechanotransduction, a process that influences all steps of the invasion/metastasis cascade. We hypothesized that PC1 and PC2 facilitate cancer aggressiveness. Immunoblotting, RT-PCR, semi-quantitative and quantitative real-time PCR and FACS analyses were employed to investigate the effect of polycystin overexpression in colorectal cancer (CRC) cells. The impact of PC1 inhibition on cancer-cell proliferation was evaluated through an MTT assay. In vitro data were analyzed by Student's t-test. HT29 human xenografts were treated with anti-PC1 (extracellular domain) inhibitory antibody and analyzed via immunohistochemistry to determine the in vivo role of PC1 in CRC. Clinical significance was assessed by examining PC1 and PC2 protein expression in CRC patients (immunohistochemistry). In vivo and clinical data were analyzed by non-parametric tests, Kaplan-Meier curves, log-rank test and Cox model. All statistical tests were two-sided. PC1 overexpression promotes epithelial-to-mesenchymal transition (EMT) in HCT116 cells, while PC2 overexpression results in upregulation of the mTOR pathway in SW480 cells. PC1 inhibition causes reduced cell proliferation in CRC cells inducing tumor necrosis and suppressing EMT in HT29 tumor xenografts. In clinical study, PC1 and PC2 overexpression associates with adverse pathological parameters, including invasiveness and mucinous carcinomas. Moreover, PC1 overexpression appears as an independent prognostic factor of reduced recurrence-free survival (HR = 1.016, p = 0.03) and lowers overall survival probability, while aberrant PC2 expression predicts poor overall survival (p = 0.0468). These results support, for the first time, a direct link between mechanosensing polycystins (PC1 and PC2) and CRC progression.
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43
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Havill LM, Coan HB, Mahaney MC, Nicolella DP. Characterization of complex, co-adapted skeletal biomechanics phenotypes: a needed paradigm shift in the genetics of bone structure and function. Curr Osteoporos Rep 2014; 12:174-80. [PMID: 24756406 PMCID: PMC4010686 DOI: 10.1007/s11914-014-0211-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
The genetic architecture of skeletal biomechanical performance has tremendous potential to advance our knowledge of the biological mechanisms that drive variation in skeletal fragility and osteoporosis risk. Research using traditional approaches that focus on specific gene pathways is increasing our understanding of how and to what degree those pathways may affect population-level variation in fracture susceptibility, and shows that known pathways may affect bone fragility through unsuspected mechanisms. Non-traditional approaches that incorporate a new appreciation for the degree to which bone traits co-adapt to functional loading environments, using a wide variety of redundant compensatory mechanisms to meet both physiological and mechanical demands, represent a radical departure from the dominant reductionist paradigm and have the potential to rapidly advance our understanding of bone fragility and identification of new targets for therapeutic intervention.
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Affiliation(s)
- L M Havill
- Genetics, Texas Biomedical Research Institute, P.O. Box 760549, San Antonio, TX, 78245, USA,
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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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Spyropoulou A, Basdra EK. Mechanotransduction in bone: Intervening in health and disease. World J Exp Med 2013; 3:74-86. [DOI: 10.5493/wjem.v3.i4.74] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2013] [Revised: 09/06/2013] [Accepted: 11/03/2013] [Indexed: 02/06/2023] Open
Abstract
Mechanotransduction has been proven to be one of the most significant variables in bone remodeling and its alterations have been shown to result in a variety of bone diseases. Osteoporosis, Paget’s disease, orthopedic disorders, osteopetrosis as well as hyperparathyroidism and hyperthyroidism all comprise conditions which have been linked with deregulated bone remodeling. Although the significance of mechanotransduction for bone health and disease is unquestionable, the mechanisms behind this important process have not been fully understood. This review will discuss the molecules that have been found to be implicated in mechanotransduction, as well as the mechanisms underlying bone health and disease, emphasizing on what is already known as well as new molecules potentially taking part in conveying mechanical signals from the cell surface towards the nucleus under physiological or pathologic conditions. It will also focus on the model systems currently used in mechanotransduction studies, like osteoblast-like cells as well as three-dimensional constructs and their applications among others. It will also examine the role of mechanostimulatory techniques in preventing and treating bone degenerative diseases and consider their applications in osteoporosis, craniofacial development, skeletal deregulations, fracture treatment, neurologic injuries following stroke or spinal cord injury, dentistry, hearing problems and bone implant integration in the near future.
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46
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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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