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Gil N, Leurs N, Martinand-Mari C, Debiais-Thibaud M. The vertebrate small leucine-rich proteoglycans: amplification of a clustered gene family and evolution of their transcriptional profile in jawed vertebrates. G3 (BETHESDA, MD.) 2025; 15:jkaf003. [PMID: 39774651 PMCID: PMC11917481 DOI: 10.1093/g3journal/jkaf003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Accepted: 12/18/2024] [Indexed: 01/11/2025]
Abstract
Small Leucine-Rich Proteoglycans (SLRPs) are a major family of vertebrate proteoglycans. In bony vertebrates, SLRPs have a variety of functions from structural to signaling and are found in extracellular matrices, notably in skeletal tissues. However, there is little or no data on the diversity, function and expression patterns of SLRPs in cartilaginous fishes, which hinders our understanding of how these genes evolved with the diversification of vertebrates, in particular regarding the early events of whole-genome duplications that shaped gnathostome and cyclostome genomes. We used a selection of chromosome-level assemblies of cartilaginous fish and other vertebrate genomes for phylogeny and synteny reconstructions, allowing better resolution and understanding of the evolution of this gene family in vertebrates. Novel SLRP members were uncovered together with specific loss events in different lineages. Our reconstructions support that the canonical SLRPs have originated from different series of tandem duplications that preceded the extant vertebrate last common ancestor, one of them even preceding the extant chordate last common ancestor. They then further expanded with additional tandem and whole-genome duplications during the diversification of extant vertebrates. Finally, we characterized the expression of several SLRP members in the small-spotted catshark Scyliorhinus canicula and from this, inferred conserved and derived SLRP expression in several skeletal and connective tissues in jawed vertebrates.
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Affiliation(s)
- Nathan Gil
- Institut des Sciences de l’Evolution de Montpellier, Université de Montpellier, CNRS, IRD, 34090 Montpellier, France
| | - Nicolas Leurs
- Institut des Sciences de l’Evolution de Montpellier, Université de Montpellier, CNRS, IRD, 34090 Montpellier, France
| | - Camille Martinand-Mari
- Institut des Sciences de l’Evolution de Montpellier, Université de Montpellier, CNRS, IRD, 34090 Montpellier, France
| | - Mélanie Debiais-Thibaud
- Institut des Sciences de l’Evolution de Montpellier, Université de Montpellier, CNRS, IRD, 34090 Montpellier, France
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2
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Saoud C, Agaimy A, Stoehr R, Michal M, Wang SKW, Mandavilli S, Charville GW, Linos K. Nodular fasciitis: a case series unveiling novel and rare gene fusions, including two cases with aggressive clinical behavior. Virchows Arch 2025:10.1007/s00428-025-04040-6. [PMID: 39912885 DOI: 10.1007/s00428-025-04040-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Revised: 12/23/2024] [Accepted: 01/23/2025] [Indexed: 02/07/2025]
Abstract
Nodular fasciitis is a benign myofibroblastic tumor characterized by rapid growth and spontaneous regression. While nodular fasciitis is typically an indolent process, rare cases with benign morphologic features have developed metastases. Conversely, nodular fasciitis with malignant histologic features and benign clinical course have also been reported. In this study, we present seven nodular fasciitis cases with novel USP6 gene fusion partners, in addition to two cases with rare fusions that displayed aggressive clinical behavior. The cohort comprised five females and four males with a median age of 36 years (range 13-59). Tumors were located in the forearm (n = 3), thigh (n = 2), and shoulder, abdominal wall, chest wall, and oral cavity (one each), ranging from 1.4 to 24.0 cm in size (median, 2.2 cm). Except for the clinically aggressive cases, patients presented with painless masses of varying onset from days to months. Of the clinically aggressive cases, one patient presented with a slowly growing subfascial thigh/hip mass over nine years, leading to erosion of the femur and pelvis; the other presented with a painful subfascial thigh mass of several months' duration. Histologically, all cases, including the clinically aggressive ones, showed conventional nodular fasciitis features without nuclear pleomorphism or atypical mitotic figures; one case with aggressive clinical behavior exhibited focal infarction-type necrosis. Break-apart FISH analysis using USP6 flanking probes failed to detect USP6 rearrangement in two cases (false negatives) and was inconclusive in one case. Next-generation RNA sequencing identified USP6 fusions in all cases. The clinically aggressive cases showed fusions with COL1A1 (exon 1) and PPP6R3 (exon 1), while novel fusions were identified in the remaining cases including EIF4A1 (exon 1), FILIP1L (exon 2), NF1 (exon 33), OMD (exon 1), PFN1 (exon 1), RLIM (exon 1), and SETD5 (exon 1). Six patients underwent surgical resection; three were managed conservatively, with two experiencing spontaneous tumor resolution. Of the clinically aggressive cases, one patient had progression of the tumor with erosion of the underlying bone, and the second patient developed local recurrence at 14 months and lung metastasis at 19 months, ultimately dying of disease at 22 months. The remaining patients showed no recurrence or metastasis. Our findings expand the spectrum of USP6 gene fusion partners in nodular fasciitis and, for the first time, report cases with conventional morphology exhibiting aggressive behavior, including death. These observations raise the question of whether a subset of deep lesions with conventional nodular fasciitis histology but unusual clinical features, such as large tumor size, represents malignant nodular fasciitis or alternatively a nodular fasciitis-like myofibroblastic sarcoma.
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Affiliation(s)
- Carla Saoud
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA
| | - Abbas Agaimy
- Institute of Pathology, Erlangen University Hospital, Comprehensive Cancer Center, European Metropolitan Area Erlangen-Nuremberg, Friedrich Alexander University of Erlangen-Nuremberg, Erlangen, Germany
| | - Robert Stoehr
- Institute of Pathology, Erlangen University Hospital, Comprehensive Cancer Center, European Metropolitan Area Erlangen-Nuremberg, Friedrich Alexander University of Erlangen-Nuremberg, Erlangen, Germany
| | - Michael Michal
- Department of Pathology, Charles University Faculty of Medicine in Pilsen, Pilsen, Czech Republic
- Bioptical Laboratory, Ltd., Pilsen, Czech Republic
| | - Scott Kuan-Wen Wang
- Department of Pathology and Laboratory Medicine, Hartford Hospital, Hartford, CT, USA
| | - Srinivas Mandavilli
- Department of Pathology and Laboratory Medicine, Hartford Hospital, Hartford, CT, USA
| | - Gregory W Charville
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA
| | - Konstantinos Linos
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
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Buraschi S, Pascal G, Liberatore F, Iozzo RV. Comprehensive investigation of proteoglycan gene expression in breast cancer: Discovery of a unique proteoglycan gene signature linked to the malignant phenotype. PROTEOGLYCAN RESEARCH 2025; 3:e70014. [PMID: 40066261 PMCID: PMC11893098 DOI: 10.1002/pgr2.70014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Accepted: 12/06/2024] [Indexed: 03/14/2025]
Abstract
Solid tumors present a formidable challenge in oncology, necessitating innovative approaches to improve therapeutic outcomes. Proteoglycans, multifaceted molecules within the tumor microenvironment, have garnered attention due to their diverse roles in cancer progression. Their unique ability to interact with specific membrane receptors, growth factors, and cytokines provides a promising avenue for the development of recombinant proteoglycan-based therapies that could enhance the precision and efficacy of cancer treatment. In this study, we performed a comprehensive analysis of the proteoglycan gene landscape in human breast carcinomas. Leveraging the available wealth of genomic and clinical data regarding gene expression in breast carcinoma and using a machine learning model, we identified a unique gene expression signature composed of five proteoglycans differentially modulated in the tumor tissue: Syndecan-1 and asporin (upregulated) and decorin, PRELP and podocan (downregulated). Additional query of the breast carcinoma data revealed that serglycin, previously shown to be increased in breast carcinoma patients and mouse models and to correlate with a poor prognosis, was indeed decreased in the vast majority of breast cancer patients and its levels inversely correlated with tumor progression and invasion. This proteoglycan gene signature could provide novel diagnostic capabilities in breast cancer biology and highlights the need for further utilization of publicly available datasets for the clinical validation of preclinical experimental results.
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Affiliation(s)
- Simone Buraschi
- Department of Pathology and Genomic Medicine, and the Translational Cellular Oncology Program, Sidney Kimmel Cancer Center, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Gabriel Pascal
- Department of Pathology and Genomic Medicine, and the Translational Cellular Oncology Program, Sidney Kimmel Cancer Center, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Federico Liberatore
- School of Computer Science and Informatics, Cardiff University, Cardiff CF24 4AG, UK
| | - Renato V Iozzo
- Department of Pathology and Genomic Medicine, and the Translational Cellular Oncology Program, Sidney Kimmel Cancer Center, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA 19107, USA
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Hosen S, Ikeda-Yorifuji I, Yamashita T. Asporin and CD109, expressed in the injured neonatal spinal cord, attenuate axonal re-growth in vitro. Neurosci Lett 2024; 833:137832. [PMID: 38796094 DOI: 10.1016/j.neulet.2024.137832] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Revised: 05/17/2024] [Accepted: 05/22/2024] [Indexed: 05/28/2024]
Abstract
Axonal regeneration is restricted in adults and causes irreversible motor dysfunction following spinal cord injury (SCI). In contrast, neonates have prominent regenerative potential and can restore their neural function. Although the distinct cellular responses in neonates have been studied, how they contribute to neural recovery remains unclear. To assess whether the secreted molecules in neonatal SCI can enhance neural regeneration, we re-analyzed the previously performed single-nucleus RNA-seq (snRNA-seq) and focused on Asporin and Cd109, the highly expressed genes in the injured neonatal spinal cord. In the present study, we showed that both these molecules were expressed in the injured spinal cords of adults and neonates. We treated the cortical neurons with recombinant Asporin or CD109 to observe their direct effects on neurons in vitro. We demonstrated that these molecules enhance neurite outgrowth in neurons. However, these molecules did not enhance re-growth of severed axons. Our results suggest that Asporin and CD109 influence neurites at the lesion site, rather than promoting axon regeneration, to restore neural function in neonates after SCI.
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Affiliation(s)
- Sakura Hosen
- Department of Molecular Neuroscience, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Iyo Ikeda-Yorifuji
- Department of Molecular Neuroscience, Graduate School of Medicine, Osaka University, Osaka, Japan.
| | - Toshihide Yamashita
- Department of Molecular Neuroscience, Graduate School of Medicine, Osaka University, Osaka, Japan; WPI Immunology Frontier Research Center, Osaka University, Suita, Japan; Department of Molecular Neuroscience, Graduate School of Frontier Biosciences, Osaka University, Suita, Japan; Department of Neuro-Medical Science, Graduate School of Medicine, Osaka University, Suita, Japan.
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Liu S, Yan X, Guo J, An H, Li X, Yang L, Yu X, Li S. Periodontal ligament-associated protein-1 knockout mice regulate the differentiation of osteoclasts and osteoblasts through TGF-β1/Smad signaling pathway. J Cell Physiol 2024; 239:e31062. [PMID: 37357387 DOI: 10.1002/jcp.31062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Revised: 05/16/2023] [Accepted: 05/30/2023] [Indexed: 06/27/2023]
Abstract
It has been known that periodontal ligament-associated protein-1 (PLAP-1/Asporin) not only inhibits cartilage formation in osteoarthritis, but it also influences the healing of skull defect. However, the effect and mechanism of PLAP-1/Asporin on the mutual regulation of osteoclasts and osteoblasts in periodontitis are not clear. In this study, we utilized a PLAP-1/Asporin gene knockout (KO) mouse model to research this unknown issue. We cultured mouse bone marrow mesenchymal stem cells with Porphyromonas gingivalis lipopolysaccharide (P.g. LPS) for osteogenic induction in vitro. The molecular mechanism of PLAP-1/Asporin in the regulation of osteoblasts was detected by immunoprecipitation, immunofluorescence, and inhibitors of signaling pathways. The results showed that the KO of PLAP-1/Asporin promoted osteogenic differentiation through transforming growth factor beta 1 (TGF-β1)/Smad3 in inflammatory environments. We further found the KO of PLAP-1/Asporin inhibited osteoclast differentiation and promoted osteogenic differentiation through the TGF-β1/Smad signaling pathway in an inflammatory coculture system. The experimental periodontitis model was established by silk ligation and the alveolar bone formation in PLAP-1/Asporin KO mice was promoted through TGF-β1/Smad3 signaling pathway. The subcutaneous osteogenesis model in nude mice also confirmed that the KO of PLAP-1/Asporin promoted bone formation by the histochemical staining. In conclusion, PLAP-1/Asporin regulated the differentiation of osteoclasts and osteoblasts through TGF-β1/Smad signaling pathway. The results of this study lay a theoretical foundation for the further study of the pathological mechanism underlying alveolar bone resorption, and the prevention and treatment of periodontitis.
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Affiliation(s)
- Shuang Liu
- Department of Periodontology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, Shandong, China
| | - Xiao Yan
- Department of Periodontology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, Shandong, China
- Department of Stomatology, the Second Hospital of Shandong University, Jinan, Shandong, China
| | - Jing Guo
- Department of Periodontology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, Shandong, China
| | - Hong An
- Department of Periodontology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, Shandong, China
| | - Xingrui Li
- Department of Periodontology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, Shandong, China
| | - Liying Yang
- Department of Periodontology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, Shandong, China
| | - Xijiao Yu
- Department of Endodontics, Central Laboratory, Jinan Stamotological Hospital, Jinan Key Laboratory of oral tissue regeneration, Shandong Provincial Health Commission Key Laboratory of Oral Diseases and Tissue Regeneration, Jinan, Shandong, China
| | - Shu Li
- Department of Periodontology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, Shandong, China
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6
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Lall SP, Alsafwani ZW, Batra SK, Seshacharyulu P. ASPORIN: A root of the matter in tumors and their host environment. Biochim Biophys Acta Rev Cancer 2024; 1879:189029. [PMID: 38008263 PMCID: PMC10872503 DOI: 10.1016/j.bbcan.2023.189029] [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: 09/10/2023] [Revised: 11/16/2023] [Accepted: 11/19/2023] [Indexed: 11/28/2023]
Abstract
Asporin (ASPN) has been identified as one of the members of the class I small leucine-rich proteoglycans (SLRPs) family in the extracellular matrix (ECM). It is involved in classic ensigns of cancers such as self-dependent growth, resistance to growth inhibitors, restricting apoptosis, cancer metastasis, and bone-related disorders. ASPN is different from other members of SLRPs, such as decorin (DCN) and biglycan (BGN), in a way that it contains a distinctive length of aspartate (D) residues in the amino (N) -terminal region. These D-repeats residues possess germline polymorphisms and are identified to be linked with cancer progression and osteoarthritis (OA). The polyaspartate stretch in the N-terminal region of the protein and its resemblance to DCN are the reasons it is called asporin. In this review, we comprehensively summarized and updated the dual role of ASPN in various malignancies, its structure in mice and humans, variants, mutations, cancer-associated signalings and functions, the relationship between ASPN and cancer-epithelial, stromal fibroblast crosstalk, immune cells and immunosuppression in cancer and other diseases. In cancer and other bone-related diseases, ASPN is identified to be regulating various signaling pathways such as TGFβ, Wnt/β-catenin, notch, hedgehog, EGFR, HER2, and CD44-mediated Rac1. These pathways promote cancer cell invasion, proliferation, and migration by mediating the epithelial-to-mesenchymal transition (EMT) process. Finally, we discussed mouse models mimicking ASPN in vivo function in cancers and the probability of therapeutic targeting of ASPN in cancer cells, fibrosis, and other bone-related diseases.
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Affiliation(s)
- Shobhit P Lall
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
| | - Zahraa W Alsafwani
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA; Eppley Institute for Research in Cancer and Allied Diseases, USA; Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA.
| | - Parthasarathy Seshacharyulu
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA; Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA.
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7
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Kinoshita M, Yamada S, Sasaki J, Suzuki S, Kajikawa T, Iwayama T, Fujihara C, Imazato S, Murakami S. Mice Lacking PLAP-1/Asporin Show Alteration of Periodontal Ligament Structures and Acceleration of Bone Loss in Periodontitis. Int J Mol Sci 2023; 24:15989. [PMID: 37958972 PMCID: PMC10649079 DOI: 10.3390/ijms242115989] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 10/24/2023] [Accepted: 11/03/2023] [Indexed: 11/15/2023] Open
Abstract
Periodontal ligament-associated protein 1 (PLAP-1), also known as Asporin, is an extracellular matrix protein expressed in the periodontal ligament and plays a crucial role in periodontal tissue homeostasis. Our previous research demonstrated that PLAP-1 may inhibit TLR2/4-mediated inflammatory responses, thereby exerting a protective function against periodontitis. However, the precise roles of PLAP-1 in the periodontal ligament (PDL) and its relationship to periodontitis have not been fully explored. In this study, we employed PLAP-1 knockout mice to investigate its roles and contributions to PDL tissue and function in a ligature-induced periodontitis model. Mandibular bone samples were collected from 10-week-old male C57BL/6 (WT) and PLAP-1 knockout (KO) mice. These samples were analyzed through micro-computed tomography (μCT) scanning, hematoxylin and eosin (HE) staining, picrosirius red staining, and fluorescence immunostaining using antibodies targeting extracellular matrix proteins. Additionally, the structure of the PDL collagen fibrils was examined using transmission electron microscopy (TEM). We also conducted tooth extraction and ligature-induced periodontitis models using both wild-type and PLAP-1 KO mice. PLAP-1 KO mice did not exhibit any changes in alveolar bone resorption up to the age of 10 weeks, but they did display an enlarged PDL space, as confirmed by μCT and histological analyses. Fluorescence immunostaining revealed increased expression of extracellular matrix proteins, including Col3, BGN, and DCN, in the PDL tissues of PLAP-1 KO mice. TEM analysis demonstrated an increase in collagen diameter within the PDL of PLAP-1 KO mice. In line with these findings, the maximum stress required for tooth extraction was significantly lower in PLAP-1 KO mice in the tooth extraction model compared to WT mice (13.89 N ± 1.34 and 16.51 N ± 1.31, respectively). In the ligature-induced periodontitis model, PLAP-1 knockout resulted in highly severe alveolar bone resorption, with a higher number of collagen fiber bundle tears and significantly more osteoclasts in the periodontium. Our results demonstrate that mice lacking PLAP-1/Asporin show alteration of periodontal ligament structures and acceleration of bone loss in periodontitis. This underscores the significant role of PLAP-1 in maintaining collagen fibrils in the PDL and suggests the potential of PLAP-1 as a therapeutic target for periodontal diseases.
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Affiliation(s)
- Masaki Kinoshita
- Department of Periodontology and Regenerative Dentistry, Osaka University Graduate School of Dentistry, Suita 565-0871, Osaka, Japan; (M.K.); (T.I.); (C.F.); (S.M.)
| | - Satoru Yamada
- Department of Periodontology and Endodontolgy, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Miyagi, Japan; (S.S.); (T.K.)
| | - Junichi Sasaki
- Department of Dental Biomaterials, Osaka University Graduate School of Dentistry, Suita 565-0871, Osaka, Japan; (J.S.); (S.I.)
| | - Shigeki Suzuki
- Department of Periodontology and Endodontolgy, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Miyagi, Japan; (S.S.); (T.K.)
| | - Tetsuhiro Kajikawa
- Department of Periodontology and Endodontolgy, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Miyagi, Japan; (S.S.); (T.K.)
| | - Tomoaki Iwayama
- Department of Periodontology and Regenerative Dentistry, Osaka University Graduate School of Dentistry, Suita 565-0871, Osaka, Japan; (M.K.); (T.I.); (C.F.); (S.M.)
| | - Chiharu Fujihara
- Department of Periodontology and Regenerative Dentistry, Osaka University Graduate School of Dentistry, Suita 565-0871, Osaka, Japan; (M.K.); (T.I.); (C.F.); (S.M.)
| | - Satoshi Imazato
- Department of Dental Biomaterials, Osaka University Graduate School of Dentistry, Suita 565-0871, Osaka, Japan; (J.S.); (S.I.)
| | - Shinya Murakami
- Department of Periodontology and Regenerative Dentistry, Osaka University Graduate School of Dentistry, Suita 565-0871, Osaka, Japan; (M.K.); (T.I.); (C.F.); (S.M.)
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Berdiaki A, Giatagana EM, Tzanakakis G, Nikitovic D. The Landscape of Small Leucine-Rich Proteoglycan Impact on Cancer Pathogenesis with a Focus on Biglycan and Lumican. Cancers (Basel) 2023; 15:3549. [PMID: 37509212 PMCID: PMC10377491 DOI: 10.3390/cancers15143549] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 06/30/2023] [Accepted: 07/07/2023] [Indexed: 07/30/2023] Open
Abstract
Cancer development is a multifactorial procedure that involves changes in the cell microenvironment and specific modulations in cell functions. A tumor microenvironment contains tumor cells, non-malignant cells, blood vessels, cells of the immune system, stromal cells, and the extracellular matrix (ECM). The small leucine-rich proteoglycans (SLRPs) are a family of nineteen proteoglycans, which are ubiquitously expressed among mammalian tissues and especially abundant in the ECM. SLRPs are divided into five canonical classes (classes I-III, containing fourteen members) and non-canonical classes (classes IV-V, including five members) based on their amino-acid structural sequence, chromosomal organization, and functional properties. Variations in both the protein core structure and glycosylation status lead to SLRP-specific interactions with cell membrane receptors, cytokines, growth factors, and structural ECM molecules. SLRPs have been implicated in the regulation of cancer growth, motility, and invasion, as well as in cancer-associated inflammation and autophagy, highlighting their crucial role in the processes of carcinogenesis. Except for the class I SLRP decorin, to which an anti-tumorigenic role has been attributed, other SLPRs' roles have not been fully clarified. This review will focus on the functions of the class I and II SLRP members biglycan and lumican, which are correlated to various aspects of cancer development.
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Affiliation(s)
- Aikaterini Berdiaki
- Laboratory of Histology-Embryology, Medical School, University of Crete, 71003 Heraklion, Greece
| | - Eirini-Maria Giatagana
- Laboratory of Histology-Embryology, Medical School, University of Crete, 71003 Heraklion, Greece
| | - George Tzanakakis
- Laboratory of Histology-Embryology, Medical School, University of Crete, 71003 Heraklion, Greece
| | - Dragana Nikitovic
- Laboratory of Histology-Embryology, Medical School, University of Crete, 71003 Heraklion, Greece
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Gesteira TF, Verma S, Coulson-Thomas VJ. Small leucine rich proteoglycans: Biology, function and their therapeutic potential in the ocular surface. Ocul Surf 2023; 29:521-536. [PMID: 37355022 PMCID: PMC11092928 DOI: 10.1016/j.jtos.2023.06.013] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 06/13/2023] [Accepted: 06/21/2023] [Indexed: 06/26/2023]
Abstract
Small leucine rich proteoglycans (SLRPs) are the largest family of proteoglycans, with 18 members that are subdivided into five classes. SLRPs are small in size and can be present in tissues as glycosylated and non-glycosylated proteins, and the most studied SLRPs include decorin, biglycan, lumican, keratocan and fibromodulin. SLRPs specifically bind to collagen fibrils, regulating collagen fibrillogenesis and the biomechanical properties of tissues, and are expressed at particularly high levels in fibrous tissues, such as the cornea. However, SLRPs are also very active components of the ECM, interacting with numerous growth factors, cytokines and cell surface receptors. Therefore, SLRPs regulate major cellular processes and have a central role in major fundamental biological processes, such as maintaining corneal homeostasis and transparency and regulating corneal wound healing. Over the years, mutations and/or altered expression of SLRPs have been associated with various corneal diseases, such as congenital stromal corneal dystrophy and cornea plana. Recently, there has been great interest in harnessing the various functions of SLRPs for therapeutic purposes. In this comprehensive review, we describe the structural features and the related functions of SLRPs, and how these affect the therapeutic potential of SLRPs, with special emphasis on the use of SLRPs for treating ocular surface pathologies.
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Affiliation(s)
| | - Sudhir Verma
- College of Optometry, University of Houston, USA; Department of Zoology, Deen Dayal Upadhyaya College, University of Delhi, Delhi, India
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10
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Lin Y, Lai X, Huang S, Pu L, Zeng Q, Wang Z, Huang W. Identification of diagnostic hub genes related to neutrophils and infiltrating immune cell alterations in idiopathic pulmonary fibrosis. Front Immunol 2023; 14:1078055. [PMID: 37334348 PMCID: PMC10272521 DOI: 10.3389/fimmu.2023.1078055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Accepted: 05/18/2023] [Indexed: 06/20/2023] Open
Abstract
Background There is still a lack of specific indicators to diagnose idiopathic pulmonary fibrosis (IPF). And the role of immune responses in IPF is elusive. In this study, we aimed to identify hub genes for diagnosing IPF and to explore the immune microenvironment in IPF. Methods We identified differentially expressed genes (DEGs) between IPF and control lung samples using the GEO database. Combining LASSO regression and SVM-RFE machine learning algorithms, we identified hub genes. Their differential expression were further validated in bleomycin-induced pulmonary fibrosis model mice and a meta-GEO cohort consisting of five merged GEO datasets. Then, we used the hub genes to construct a diagnostic model. All GEO datasets met the inclusion criteria, and verification methods, including ROC curve analysis, calibration curve (CC) analysis, decision curve analysis (DCA) and clinical impact curve (CIC) analysis, were performed to validate the reliability of the model. Through the Cell Type Identification by Estimating Relative Subsets of RNA Transcripts algorithm (CIBERSORT), we analyzed the correlations between infiltrating immune cells and hub genes and the changes in diverse infiltrating immune cells in IPF. Results A total of 412 DEGs were identified between IPF and healthy control samples, of which 283 were upregulated and 129 were downregulated. Through machine learning, three hub genes (ASPN, SFRP2, SLCO4A1) were screened. We confirmed their differential expression using pulmonary fibrosis model mice evaluated by qPCR, western blotting and immunofluorescence staining and analysis of the meta-GEO cohort. There was a strong correlation between the expression of the three hub genes and neutrophils. Then, we constructed a diagnostic model for diagnosing IPF. The areas under the curve were 1.000 and 0.962 for the training and validation cohorts, respectively. The analysis of other external validation cohorts, as well as the CC analysis, DCA, and CIC analysis, also demonstrated strong agreement. There was also a significant correlation between IPF and infiltrating immune cells. The frequencies of most infiltrating immune cells involved in activating adaptive immune responses were increased in IPF, and a majority of innate immune cells showed reduced frequencies. Conclusion Our study demonstrated that three hub genes (ASPN, SFRP2, SLCO4A1) were associated with neutrophils, and the model constructed with these genes showed good diagnostic value in IPF. There was a significant correlation between IPF and infiltrating immune cells, indicating the potential role of immune regulation in the pathological process of IPF.
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Affiliation(s)
- Yingying Lin
- Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xiaofan Lai
- Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Shaojie Huang
- Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Lvya Pu
- Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Qihao Zeng
- Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Zhongxing Wang
- Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Wenqi Huang
- Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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11
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Chen Y, Luo M, Xie Y, Xing L, Han X, Tian Y. Periodontal ligament-associated protein-1 engages in teeth overeruption and periodontal fiber disorder following occlusal hypofunction. J Periodontal Res 2023; 58:131-142. [PMID: 36445954 DOI: 10.1111/jre.13075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 09/28/2022] [Accepted: 11/08/2022] [Indexed: 12/03/2022]
Abstract
BACKGROUND AND OBJECTIVE Teeth overeruption is a problem of clinical significance, but the underlying mechanism how changes in external occlusal force convert to the periodontium remodeling signals has been a largely under explored domain. And recently, periodontal ligament-associated protein-1 (PLAP-1)/asporin was found to play a pivotal role in maintaining periodontal homeostasis. The aim of this study was to explore the function of PLAP-1 in the periodontally hypofunctional tissue turnover. METHODS After extracting left maxillary molars in mice, the left and right mandibular molars were distributed into hypofunction group (HG) and control group (CG), respectively. Mice were sacrificed for radiographic, histological, and molecular biological analyses after 1, 4 and 12 weeks. In vitro, dynamic compression was applied using Flexcell FX-5000 Compression System to simulate intermittent occlusal force. The expression of PLAP1 in loaded and unloaded human periodontal ligament cells (hPDLCs) was compared, and its molecular biological effects were further explored by small interfering RNA (siRNA) targeting PLAP1. RESULTS In vivo, fiber disorder in periodontal ligament (PDL), bone apposition at furcation regions, and bone resorption in alveolar bone were illustrated in the HG compared with the CG. In addition, PLAP-1 positive area decreased significantly in PDL following occlusal unloading. In vitro, the loss of compressive loading relatively downregulated PLAP1 expression, which was essential to promote collagen I but inhibit osterix and osteocalcin expression in hPDLCs. CONCLUSIONS PLAP-1 presumably plays a pivotal role in occlusal force-regulated periodontal homeostasis by facilitating collagen fiber synthesis in hPDLCs and suppressing excessive osteoblast differentiation, further preventing teeth from overeruption. Further evidence in PLAP-1 conditional knockout mice is needed.
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Affiliation(s)
- Yilin Chen
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.,Department of Orthodontics and Pediatric Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Mengqi Luo
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.,Department of Orthodontics and Pediatric Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Yaxin Xie
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.,Department of Orthodontics and Pediatric Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Lu Xing
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.,Department of Orthodontics and Pediatric Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Xianglong Han
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.,Department of Orthodontics and Pediatric Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Ye Tian
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.,Department of Orthodontics and Pediatric Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu, China
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12
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Fan R, Yan X, Zhang W. Relationship between asporin and extracellular matrix behavior: A literature review. Medicine (Baltimore) 2022; 101:e32490. [PMID: 36595867 PMCID: PMC9794316 DOI: 10.1097/md.0000000000032490] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Asporin (ASPN), as a member of the small leucine-rich repeat proteoglycan family, is a type of protein that is found in the extracellular matrix. Collagen deposition or transformation is involved in a variety of pathological processes. ASPN is identified in cancerous tissue, pathological cardiac tissue, articular cartilage, keloid, and fibrotic lung tissue, and it has a role in the development of cancer, cardiovascular, bone and joint, keloid, and pulmonary fibrosis by interfering with collagen metabolism. This review article summarizes the data on ASPN expressions in mouse and human and highlights that overexpress of ASPN might play a role in a variety of diseases. Although our knowledge of ASPN is currently limited, these instances may help us better understand how it interacts with diseases.
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Affiliation(s)
- Rui Fan
- First School of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Shandong, China
| | - Xiaoyan Yan
- Department of Geriatrics, Shandong University of Traditional Chinese Medicine Affiliated Hospital, Shandong, China
| | - Wei Zhang
- Department of Respiratory and Critical Care Medicine, Shandong University of Traditional Chinese Medicine Affiliated Hospital, Shandong, China
- * Correspondence: Wei Zhang, Department of Respiratory and Critical Care Medicine, Shandong University of Traditional Chinese Medicine Affiliated Hospital, Shandong 250014, China (e-mail: )
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13
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Investigation of Transcriptome Patterns in Endometrial Cancers from Obese and Lean Women. Int J Mol Sci 2022; 23:ijms231911471. [PMID: 36232772 PMCID: PMC9569830 DOI: 10.3390/ijms231911471] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 09/16/2022] [Accepted: 09/20/2022] [Indexed: 12/04/2022] Open
Abstract
Endometrial cancer is the most common gynaecological malignancy in developed countries. One of the largest risk factors for endometrial cancer is obesity. The aim of this study was to determine whether there are differences in the transcriptome of endometrial cancers from obese vs. lean women. Here we investigate the transcriptome of endometrial cancer between obese and lean postmenopausal women using rRNA-depleted RNA-Seq data from endometrial cancer tissues and matched adjacent non-cancerous endometrial tissues. Differential expression analysis identified 12,484 genes (6370 up-regulated and 6114 down-regulated) in endometrial cancer tissues from obese women, and 6219 genes (3196 up-regulated and 3023 down-regulated) in endometrial cancer tissues from lean women (adjusted p-value < 0.1). A gene ontology enrichment analysis revealed that the top 1000 up-regulated genes (by adjusted p-value) were enriched for growth and proliferation pathways while the top 1000 down-regulated genes were enriched for cytoskeleton restructure networks in both obese and lean endometrial cancer tissues. In this study, we also show perturbations in the expression of protein coding genes (HIST1H2BL, HIST1H3F, HIST1H2BH, HIST1H1B, TTK, PTCHD1, ASPN, PRELP, and CDH13) and the lncRNA MBNL1-AS1 in endometrial cancer tissues. Overall, this study has identified gene expression changes that are similar and also unique to endometrial cancers from obese vs. lean women. Furthermore, some of these genes may serve as prognostic biomarkers or, possibly, therapeutic targets for endometrial cancer.
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14
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Yang Y, Liu P, Teng R, Liu F, Zhang C, Lu X, Ding Y. Integrative bioinformatics analysis of potential therapeutic targets and immune infiltration characteristics in dilated cardiomyopathy. ANNALS OF TRANSLATIONAL MEDICINE 2022; 10:348. [PMID: 35433958 PMCID: PMC9011224 DOI: 10.21037/atm-22-732] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 03/21/2022] [Indexed: 11/15/2022]
Abstract
Background Dilated cardiomyopathy (DCM) is currently the major cause of systolic heart failure. This study explored potential therapeutic targets and investigated the role of immune cell infiltration in DCM. Methods Three DCM datasets (GSE3585, GSE9800, and GSE84796) from the Gene Expression Omnibus (GEO) database were merged into an integrated dataset, and batch effects were removed. Differentially expressed genes (DEGs) were screened and the associations between gene co-expression modules and clinical traits were assessed by weighted gene co-expression network analysis (WGCNA) in R software. Any DEGs from the integrated dataset overlapped with the significant module genes were defined as common genes (CGs). Enrichment analysis of the CGs was performed. The protein-protein interaction (PPI) network of the CGs was visualized and the hub gene was identified by using Cytoscape 3.8.2 software. The miRNA-transcription factor-mRNA (miRNA-TF-mRNA) network was constructed using Cytoscape to unveil the regulatory relationships in DCM. Finally, the CIBERSORT method (https://cibersort.stanford.edu/) was used to investigate immune cell infiltration in DCM. Results A total of 53 DEGs were identified, and 5 gene co-expression modules were detected by WGCNA of the DCM and control group samples of cardiac tissue. Genes such as FRZB, ASPN, and PHLDA1 were significantly upregulated, whereas IDH2 and ENDOG were significantly downregulated. Functional enrichment analysis showed that CGs were mainly enriched in the extracellular matrix (ECM) signaling pathway. ASPN was the hub gene in the PPI network. The miRNA-TF-mRNA network revealed that FRZB and ASPN were targeted by paired related homeobox 2 (Prrx2). We also found that miR-129-5p could regulate ASPN, PHLDA1, and IDH2 simultaneously. The immune infiltration analysis revealed higher levels of M1 macrophages in DCM samples than in the control samples. Conclusions In conclusion, we speculate that miR-129-5p might target ASPN in regulating DCM via the ECM signaling pathway. Macrophage infiltration may be involved in ECM remodeling and eventually lead to DCM.
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Affiliation(s)
- Yujiao Yang
- Department of Geriatrics, Sir Run Run Hospital of Nanjing Medical University, Nanjing, China.,Department of Geriatrics, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Ping Liu
- Department of Geriatrics, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Ruoling Teng
- Department of Geriatrics, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Fenfen Liu
- Department of Geriatrics, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Cuiping Zhang
- Department of Geriatrics, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Xiang Lu
- Department of Geriatrics, Sir Run Run Hospital of Nanjing Medical University, Nanjing, China
| | - Yi Ding
- Department of Geriatrics, The Third Affiliated Hospital of Soochow University, Changzhou, China
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15
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Huang S, Lai X, Yang L, Ye F, Huang C, Qiu Y, Lin S, Pu L, Wang Z, Huang W. Asporin Promotes TGF-β-induced Lung Myofibroblast Differentiation by Facilitating Rab11-dependent Recycling of TβRI. Am J Respir Cell Mol Biol 2021; 66:158-170. [PMID: 34705621 DOI: 10.1165/rcmb.2021-0257oc] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive fibrotic lung disease with high mortality and morbidity. Asporin (ASPN), a member of the small leucine-rich proteoglycan (SLRP) family, plays crucial roles in tissue injury and regeneration. However, the precise pathophysiological role of ASPN and its molecular mechanisms in IPF remain unknown. We sought to investigate the role of ASPN during the development of pulmonary fibrosis and the therapeutic potential of targeting ASPN-related signaling pathways. In our study, three microarray datasets were downloaded from the Gene Expression Omnibus (GEO) database, and differentially expressed genes (DEGs) were screened out by bioinformatic analysis. Hub genes were selected from the protein-protein interaction network. ASPN was examined in lung tissues from pulmonary fibrosis mouse models and the role of ASPN in TGF-β/Smad signaling was determined by transfection with ASPN shRNA vectors in vitro. Biotinylation assays were conducted to measure plasma membrane TβRI and TβRI recycling after ASPN knockdown. The results showed ASPN expression was increased in the lungs of pulmonary fibrosis mouse models, and ASPN was primarily localized in α-SMA+ myofibroblasts. In vitro experiments proved that ASPN knockdown inhibited TGF-β/Smad signaling and myofibroblast differentiation by regulating the stability of TβRI. Further molecular mechanisms revealed that ASPN knockdown inhibited TGF-β/Smad signaling by suppressing recycling of TβRI to the cell surface in a Rab11-dependent manner and facilitated lysosome-mediated degradation of TβRI. In conclusion, our findings provide important evidence for the use of ASPN as a novel pharmacological target for treating pulmonary fibrosis.
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Affiliation(s)
- Shaojie Huang
- Sun Yat-sen University First Affiliated Hospital, 71068, Department of Cardiac Surgery, Guangzhou, China
| | - Xiaofan Lai
- Sun Yat-sen University First Affiliated Hospital, 71068, Department of Anesthesiology, Guangzhou, China
| | - Lu Yang
- Sun Yat-sen University First Affiliated Hospital, 71068, Department of Anesthesiology, Guangzhou, China
| | - Fang Ye
- Sun Yat-sen University First Affiliated Hospital, 71068, Department of Anesthesiology, Guangzhou, China
| | - Chanyan Huang
- Sun Yat-sen University First Affiliated Hospital, 71068, Department of Anesthesiology, Guangzhou, China
| | - Yuan Qiu
- Sun Yat-Sen University, 26469, Center for stem cell biology and tissue engineering, Guangzhou, China
| | - Sijia Lin
- Sun Yat-Sen University, 26469, Guangzhou, China
| | - Lvya Pu
- Sun Yat-Sen University, 26469, Guangzhou, China
| | - Zhongxing Wang
- Sun Yat-sen University First Affiliated Hospital, 71068, Department of Anesthesiology, Guangzhou, China
| | - Wenqi Huang
- Sun Yat-sen University First Affiliated Hospital, 71068, Department of Anesthesiology, Guangzhou, China;
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16
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Roles of Two Small Leucine-Rich Proteoglycans Decorin and Biglycan in Pregnancy and Pregnancy-Associated Diseases. Int J Mol Sci 2021; 22:ijms221910584. [PMID: 34638928 PMCID: PMC8509074 DOI: 10.3390/ijms221910584] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Revised: 09/21/2021] [Accepted: 09/22/2021] [Indexed: 11/18/2022] Open
Abstract
Two small leucine-rich proteoglycans (SLRP), decorin and biglycan, play important roles in structural–functional integrity of the placenta and fetal membranes, and their alterations can result in several pregnancy-associated diseases. In this review, we briefly discuss normal placental structure and functions, define and classify SLRPs, and then focus on two SLRPs, decorin (DCN) and biglycan (BGN). We discuss the consequences of deletions/mutations of DCN and BGN. We then summarize DCN and BGN expression in the pregnant uterus, myometrium, decidua, placenta, and fetal membranes. Actions of these SLRPs as ligands are then discussed in the context of multiple binding partners in the extracellular matrix and cell surface (receptors), as well as their alterations in pathological pregnancies, such as preeclampsia, fetal growth restriction, and preterm premature rupture of membranes. Lastly, we raise some unanswered questions as food for thought.
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17
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Liu L, Zhao C, Zhang H, Lu Y, Luo B, Yao Z, Shao Y, Zeng H, Zeng C, Zhang R, Fang H, Pan J, Bai X, Cai D. Asporin regulated by miR-26b-5p mediates chondrocyte senescence and exacerbates osteoarthritis progression via TGF-β1/Smad2 pathway. Rheumatology (Oxford) 2021; 61:2631-2643. [PMID: 34559207 DOI: 10.1093/rheumatology/keab725] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 09/07/2021] [Indexed: 11/12/2022] Open
Abstract
OBJECTIVES This study aimed to investigate the role and mechanism of asporin in modulating chondrocyte senescence in osteoarthritis (OA) pathology. METHODS Asporin and senescence-related hallmark expression were examined in human and experimental OA mouse cartilage samples. Twelve-week-old male C57 mice were administered with recombinant protein (rm-asporin)- or asporin-siRNA-expressing lentiviruses via intra-articular injection once a week after destabilization of the medial meniscus (DMM) surgery to induce OA. Cartilage damage was measured using the Osteoarthritis Research Society International score. Senescence-associated β-galactosidase (SA-βGal) staining, γH2AX, p21, and p16INK4a were analyzed by immunofluorescence staining and western blot to assess the specific role of asporin in chondrocyte senescence. The TGF-β1/Smad2 signaling pathway and miR-26b-5p were further evaluated to explore the mechanism of asporin in OA. RESULTS Asporin was upregulated in articular chondrocytes of OA patients and DMM mice and accompanied by accumulation of senescent cells. Asporin overexpression exaggerated OA progression, whereas silencing asporin restored chondrocyte homeostasis and deferred chondrocyte senescence, leading to markedly attenuated DMM-induced OA. Cellular and molecular analyses showed that asporin can be inhibited by miR-26b-5p, which was significantly downregulated in OA cartilage, leading to exacerbation of experimental OA partially through inhibition of TGF-β1/Smad2 signaling in chondrocytes. CONCLUSIONS Our findings indicate that asporin plays an essential role in chondrocyte senescence and OA pathogenesis. Upregulated by miR-26b-5p, asporin inhibits the TGF-β1/Smad2 pathway to accelerate chondrocyte senescence and exacerbate cartilage degeneration. Targeting the miR-26b-5p/asporin/Smad2 axis may serve as a practical therapeutic strategy to delay chondrocyte senescence and OA development.
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Affiliation(s)
- Liangliang Liu
- Orthopedic Hospital of Guangdong Province, Academy of Orthopedics•Guangdong Province, Department of Orthopedics, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China.,The Third School of Clinical Medicine, Southern Medical University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, Guangzhou, China
| | - Chang Zhao
- Orthopedic Hospital of Guangdong Province, Academy of Orthopedics•Guangdong Province, Department of Orthopedics, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China.,The Third School of Clinical Medicine, Southern Medical University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, Guangzhou, China
| | - Haiyan Zhang
- Orthopedic Hospital of Guangdong Province, Academy of Orthopedics•Guangdong Province, Department of Orthopedics, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China.,The Third School of Clinical Medicine, Southern Medical University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, Guangzhou, China
| | - Yuheng Lu
- Orthopedic Hospital of Guangdong Province, Academy of Orthopedics•Guangdong Province, Department of Orthopedics, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China.,The Third School of Clinical Medicine, Southern Medical University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, Guangzhou, China
| | - Bingsheng Luo
- Orthopedic Hospital of Guangdong Province, Academy of Orthopedics•Guangdong Province, Department of Orthopedics, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China.,The Third School of Clinical Medicine, Southern Medical University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, Guangzhou, China
| | - Zihao Yao
- Orthopedic Hospital of Guangdong Province, Academy of Orthopedics•Guangdong Province, Department of Orthopedics, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China.,The Third School of Clinical Medicine, Southern Medical University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, Guangzhou, China
| | - Yan Shao
- Orthopedic Hospital of Guangdong Province, Academy of Orthopedics•Guangdong Province, Department of Orthopedics, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China.,The Third School of Clinical Medicine, Southern Medical University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, Guangzhou, China
| | - Hua Zeng
- Orthopedic Hospital of Guangdong Province, Academy of Orthopedics•Guangdong Province, Department of Orthopedics, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China.,The Third School of Clinical Medicine, Southern Medical University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, Guangzhou, China
| | - Chun Zeng
- Orthopedic Hospital of Guangdong Province, Academy of Orthopedics•Guangdong Province, Department of Orthopedics, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China.,The Third School of Clinical Medicine, Southern Medical University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, Guangzhou, China
| | - Rongkai Zhang
- Orthopedic Hospital of Guangdong Province, Academy of Orthopedics•Guangdong Province, Department of Orthopedics, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China.,The Third School of Clinical Medicine, Southern Medical University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, Guangzhou, China
| | - Hang Fang
- Orthopedic Hospital of Guangdong Province, Academy of Orthopedics•Guangdong Province, Department of Orthopedics, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China.,The Third School of Clinical Medicine, Southern Medical University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, Guangzhou, China
| | - Jianying Pan
- Orthopedic Hospital of Guangdong Province, Academy of Orthopedics•Guangdong Province, Department of Orthopedics, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China.,The Third School of Clinical Medicine, Southern Medical University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, Guangzhou, China
| | - Xiaochun Bai
- Orthopedic Hospital of Guangdong Province, Academy of Orthopedics•Guangdong Province, Department of Orthopedics, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China.,The Third School of Clinical Medicine, Southern Medical University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, Guangzhou, China
| | - Daozhang Cai
- Orthopedic Hospital of Guangdong Province, Academy of Orthopedics•Guangdong Province, Department of Orthopedics, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China.,The Third School of Clinical Medicine, Southern Medical University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, Guangzhou, China
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18
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Ege B, Erdogmus Z, Bozgeyik E, Koparal M, Kurt MY, Gulsun B. Asporin levels in patients with temporomandibular joint disorders. J Oral Rehabil 2021; 48:1109-1117. [PMID: 34309889 DOI: 10.1111/joor.13234] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 06/29/2021] [Accepted: 07/17/2021] [Indexed: 11/30/2022]
Abstract
BACKGROUND Understanding the pathogenesis of temporomandibular joint disorder (TMD) is important for diagnosis and treatment planning. Thus, biochemical analysis is usually used for the detection of tissue damage. OBJECTIVE In this study, we aimed to investigate the serum asporin levels in patients with TMD. METHODS Our study was planned to be performed on 43 healthy individuals (control group) without any joint problems and 43 patients with temporomandibular joint internal derangement (TMJ-ID; patients group) according to the Wilkes classification (stages 3, 4 and 5). Serum asporin levels were determined by the enzyme-linked immunosorbent assay (ELISA) method and compared between groups. Asporin levels were analysed according to the demographic and clinical characteristics of the patients, and the differences between them were demonstrated. RESULTS Asporin levels were found to be significantly increased in the patients group compared to control group (p = .0303). The age and gender distributions of the samples in the control and patients groups were homogeneous, and there was no statistically significant difference between the groups. In addition, while there was no significant change in asporin levels in females in the patients group compared with the control group, the asporin levels were significantly increased in males in the patients group (p = .0403). CONCLUSIONS Consequently, asporin seems to be an important biomarker in the pathobiology of TMJ-ID as it is significantly upregulated in these patients.
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Affiliation(s)
- Bilal Ege
- Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, Adıyaman University, Adıyaman, Turkey
| | - Zozan Erdogmus
- Oral and Maxillofacial Surgery Clinic, Diyarbakır Oral and Dental Health Center, Diyarbakır, Turkey
| | - Esra Bozgeyik
- Department of Medical Services and Techniques, Vocational School of Health Services, Adiyaman University, Adiyaman, Turkey
| | - Mahmut Koparal
- Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, Adıyaman University, Adıyaman, Turkey
| | - Muhammed Yusuf Kurt
- Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, Adıyaman University, Adıyaman, Turkey
| | - Belgin Gulsun
- Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, Dicle University, Diyarbakır, Turkey
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Liu L, Yu H, Long Y, You Z, Ogawa R, Du Y, Huang C. Asporin inhibits collagen matrix-mediated intercellular mechanocommunications between fibroblasts during keloid progression. FASEB J 2021; 35:e21705. [PMID: 34105826 DOI: 10.1096/fj.202100111r] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 04/09/2021] [Accepted: 05/17/2021] [Indexed: 01/03/2023]
Abstract
Keloids are fibrotic lesions that grow unceasingly and invasively and are driven by local mechanical stimuli. Unlike other fibrotic diseases and normal wound healing, keloids exhibit little transformation of dermal fibroblasts into α-SMA+ myofibroblasts. This study showed that asporin is the most strongly expressed gene in keloids and its gene-ontology terms relate strongly to ECM metabolism/organization. Experiments with human dermal cells (HDFs) showed that asporin overexpression/treatment abrogated the HDF ability to adopt a perpendicular orientation when subjected to stretching tension. It also induced calcification of the surrounding 3D collagen matrix. Asporin overexpression/treatment also prevented the HDFs from remodeling the surrounding 3D collagen matrix, leading to a disorganized network of thick, wavy collagen fibers that resembled keloid collagen architecture. This in turn impaired the ability of the HDFs to contract the collagen matrix. Asporin treatment also made the fibroblasts impervious to the fibrous collagen contraction of α-SMA+ myofibroblasts, which normally activates fibroblasts. Thus, by calcifying collagen, asporin prevents fibroblasts from linearly rearranging the surrounding collagen; this reduces both their mechanosensitivity and mechanosignaling to each other through the collagen network. This blocks fibroblast activation and differentiation into the mature myofibroblasts that efficiently remodel the extracellular matrix. Consequently, the fibroblasts remain immature, highly proliferative, and continue laying down abundant extracellular matrix, causing keloid growth and invasion. Notably, dermal injection of asporin-overexpressing HDFs into murine wounds recapitulated keloid collagen histopathological characteristics. Thus, disrupted interfibroblast mechanocommunication may promote keloid progression. Asporin may be a new diagnostic biomarker and therapeutic target for keloids.
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Affiliation(s)
- Longwei Liu
- Department of Biomedical Engineering, School of Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, China
| | - Hongsheng Yu
- Department of Biomedical Engineering, School of Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, China
| | - Yi Long
- Department of Biomedical Engineering, School of Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, China
| | - Zhifeng You
- Department of Biomedical Engineering, School of Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, China
| | - Rei Ogawa
- Department of Plastic, Reconstructive and Aesthetic Surgery, Nippon Medical School, Tokyo, Japan
| | - Yanan Du
- Department of Biomedical Engineering, School of Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, China
| | - Chenyu Huang
- Department of Dermatology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
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20
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Yashiro M, Hasegawa T, Yamamoto Y, Tsujio G, Nishimura S, Sera T, Sugimoto A, Kushiyama S, Kasashima H, Fukuoka T, Sakurai K, Toyokawa T, Kubo N, Ohira M. Asporin Expression on Stromal Cells and/or Cancer Cells Might Be A Useful Prognostic Marker in Patients with Diffuse-Type Gastric Cancer. Eur Surg Res 2021; 62:53-60. [PMID: 33882483 DOI: 10.1159/000515458] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Accepted: 02/22/2021] [Indexed: 11/19/2022]
Abstract
BACKGROUND Asporin (ASPN), a member of the proteoglycan family, has been shown to have a close correlation with cancer progression. It is not known whether ASPN is an oncogenic driver or a tumor suppressor in human gastric cancer. We sought herein to determine the relationship between ASPN expression and clinicopathological features of gastric cancer. PATIENTS AND METHODS A total of 296 gastric cancer patients (diffuse type, n = 144; intestinal type, n = 152) were enrolled. The ASPN expression level in each case was analyzed by immunohistochemistry. RESULTS ASPN was mainly found on stromal cells, especially on fibroblasts in tumor stroma, i.e., cancer-associated fibroblasts. The ASPN expression on either cancer cells or stromal cells was significantly high in macroscopic scirrhous-type tumors (p < 0.001) and histologically abundant stroma-type tumors (p < 0.001). Interestingly, a Kaplan-Meier survival curve of the 144 cases of diffuse-type gastric cancer revealed a significantly poorer prognosis in patients with ASPN-positive expression (p = 0.043; log rank) compared to those with ASPN-negative expression, but the prognoses were not significantly different in these subgroups of the 152 cases of intestinal-type gastric cancer. A multivariate analysis with respect to overall survival showed that ASPN expression on stromal cells and/or cancer cells was significantly correlated with overall survival in patients with diffuse-type gastric cancer (p = 0.041). CONCLUSION In gastric cancer, ASPN was expressed mainly on stromal cells and partially on cancer cells. ASPN expression on stromal cells and/or cancer cells might be a useful prognostic marker in patients with diffuse-type gastric cancer.
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Affiliation(s)
- Masakazu Yashiro
- Molecular Oncology and Therapeutics, Osaka City University Graduate School of Medicine, Osaka City, Japan.,Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Osaka City, Japan.,Cancer Center for Translational Research, Osaka City University Graduate School of Medicine, Osaka City, Japan
| | - Tsuyoshi Hasegawa
- Molecular Oncology and Therapeutics, Osaka City University Graduate School of Medicine, Osaka City, Japan.,Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Osaka City, Japan
| | - Yurie Yamamoto
- Molecular Oncology and Therapeutics, Osaka City University Graduate School of Medicine, Osaka City, Japan.,Cancer Center for Translational Research, Osaka City University Graduate School of Medicine, Osaka City, Japan
| | - Gen Tsujio
- Molecular Oncology and Therapeutics, Osaka City University Graduate School of Medicine, Osaka City, Japan.,Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Osaka City, Japan
| | - Sadaaki Nishimura
- Molecular Oncology and Therapeutics, Osaka City University Graduate School of Medicine, Osaka City, Japan.,Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Osaka City, Japan
| | - Tomohiro Sera
- Molecular Oncology and Therapeutics, Osaka City University Graduate School of Medicine, Osaka City, Japan.,Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Osaka City, Japan
| | - Atsushi Sugimoto
- Molecular Oncology and Therapeutics, Osaka City University Graduate School of Medicine, Osaka City, Japan.,Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Osaka City, Japan
| | - Shuhei Kushiyama
- Molecular Oncology and Therapeutics, Osaka City University Graduate School of Medicine, Osaka City, Japan.,Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Osaka City, Japan
| | - Hiroaki Kasashima
- Molecular Oncology and Therapeutics, Osaka City University Graduate School of Medicine, Osaka City, Japan.,Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Osaka City, Japan
| | - Tatsunari Fukuoka
- Molecular Oncology and Therapeutics, Osaka City University Graduate School of Medicine, Osaka City, Japan.,Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Osaka City, Japan.,Cancer Center for Translational Research, Osaka City University Graduate School of Medicine, Osaka City, Japan
| | - Katsunobu Sakurai
- Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Osaka City, Japan
| | - Takahiro Toyokawa
- Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Osaka City, Japan
| | - Naoshi Kubo
- Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Osaka City, Japan
| | - Masaichi Ohira
- Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Osaka City, Japan
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21
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Mice lacking PLAP-1/asporin counteracts high fat diet-induced metabolic disorder and alveolar bone loss by controlling adipose tissue expansion. Sci Rep 2021; 11:4970. [PMID: 33654143 PMCID: PMC7925592 DOI: 10.1038/s41598-021-84512-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Accepted: 02/17/2021] [Indexed: 12/19/2022] Open
Abstract
Adipose tissue fibrosis with chronic inflammation is a hallmark of obesity-related metabolic disorders, and the role of proteoglycans in developing adipose tissue fibrosis is of interest. Periodontal disease is associated with obesity; however, the underlying molecular mechanisms remain unclear. Here we investigated the roles of periodontal ligament associated protein-1 (PLAP-1)/asporin, a proteoglycan preferentially and highly expressed in the periodontal ligament, in obesity-related adipose tissue dysfunction and adipocyte differentiation. It was found that PLAP-1 is also highly expressed in white adipose tissues. Plap-1 knock-out mice counteracted obesity and alveolar bone resorption induced by a high-fat diet. Plap-1 knock-down in 3T3-L1 cells resulted in less lipid accumulation, and recombinant PLAP-1 enhanced lipid accumulation in 3T3-L1 cells. In addition, it was found that primary preadipocytes isolated from Plap-1 knock-out mice showed lesser lipid accumulation than the wild-type (WT) mice. Furthermore, the stromal vascular fraction of Plap-1 knock-out mice showed different extracellular matrix gene expression patterns compared to WT. These findings demonstrate that PLAP-1 enhances adipogenesis and could be a key molecule in understanding the association between periodontal disease and obesity-related metabolic disorders.
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22
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Siadat SM, Zamboulis DE, Thorpe CT, Ruberti JW, Connizzo BK. Tendon Extracellular Matrix Assembly, Maintenance and Dysregulation Throughout Life. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1348:45-103. [PMID: 34807415 DOI: 10.1007/978-3-030-80614-9_3] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
In his Lissner Award medal lecture in 2000, Stephen Cowin asked the question: "How is a tissue built?" It is not a new question, but it remains as relevant today as it did when it was asked 20 years ago. In fact, research on the organization and development of tissue structure has been a primary focus of tendon and ligament research for over two centuries. The tendon extracellular matrix (ECM) is critical to overall tissue function; it gives the tissue its unique mechanical properties, exhibiting complex non-linear responses, viscoelasticity and flow mechanisms, excellent energy storage and fatigue resistance. This matrix also creates a unique microenvironment for resident cells, allowing cells to maintain their phenotype and translate mechanical and chemical signals into biological responses. Importantly, this architecture is constantly remodeled by local cell populations in response to changing biochemical (systemic and local disease or injury) and mechanical (exercise, disuse, and overuse) stimuli. Here, we review the current understanding of matrix remodeling throughout life, focusing on formation and assembly during the postnatal period, maintenance and homeostasis during adulthood, and changes to homeostasis in natural aging. We also discuss advances in model systems and novel tools for studying collagen and non-collagenous matrix remodeling throughout life, and finally conclude by identifying key questions that have yet to be answered.
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Affiliation(s)
| | - Danae E Zamboulis
- Institute of Life Course and Medical Sciences, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, UK
| | - Chavaunne T Thorpe
- Comparative Biomedical Sciences, The Royal Veterinary College, University of London, London, UK
| | - Jeffrey W Ruberti
- Department of Bioengineering, Northeastern University, Boston, MA, USA
| | - Brianne K Connizzo
- Department of Biomedical Engineering, Boston University, Boston, MA, USA.
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23
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Ding F, Li X. Apigenin Mitigates Intervertebral Disc Degeneration through the Amelioration of Tumor Necrosis Factor α (TNF-α) Signaling Pathway. Med Sci Monit 2020; 26:e924587. [PMID: 32949455 PMCID: PMC7523418 DOI: 10.12659/msm.924587] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Background Intervertebral disc degeneration (IDD) is a common spinal disease affected by environmental and lifestyle factors that has a significant pathological cascade toward inflammation and partial disability. There is currently no therapy that can completely restore the cellular derangement in IDD. Hence, in this study, the therapeutic effects of apigenin on IDD were evaluated using a rat model. Material/Methods Animals were separated into 4 groups: Grp 1, sham-operated control; Grp 2, IDD-induced; Grp 3, IDD-induced+apigenin treatment; Grp 4, apigenin control. The animals were assessed for inflammatory cytokines, chemokines, and prostaglandin signaling. Results There were significant increases in the inflammatory cytokines IL-1β, IL-2, IL-6, IL-8 and IL-17 in the IDD-induced group compared to that of control. Moreover, with increased levels of MMP-3, MMP-9, ADAMTS-4, and syndecan-4, the levels of TNF-α, IFN-γ, prostaglandin E2, and cyclooxygenase 2 were directly increased in the IDD-induced group. In contrast, apigenin protectively restored levels of prostaglandin signaling and reduced cytokine levels. In addition, nucleus pulposus cells cultured separately with either TNF-α inhibitor or apigenin significantly attenuated the levels of extracellular matrix proteins. Conclusions The reduction of cytokine levels under apigenin treatment suggests it may be a promising target drug therapy for the treatment of deleterious IDD conditions.
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Affiliation(s)
- Fan Ding
- Department of Orthopaedic Surgery, The First People's Hospital of Jingmen, Jingmen, Hubei, China (mainland)
| | - Xia Li
- Department of Ophthalmology, The First People's Hospital of Jingmen, Jingmen, Hubei, China (mainland)
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24
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Harsanyi S, Zamborsky R, Kokavec M, Danisovic L. Genetics of developmental dysplasia of the hip. Eur J Med Genet 2020; 63:103990. [PMID: 32540376 DOI: 10.1016/j.ejmg.2020.103990] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Accepted: 06/09/2020] [Indexed: 12/12/2022]
Abstract
In the last decade, the advances in the molecular analyses and sequencing techniques allowed researchers to study developmental dysplasia of the hip (DDH) more thoroughly. Certain chromosomes, genes, loci and polymorphisms are being associated with variable severity of this disorder. The wide range of signs and symptoms is dependent either on isolated or systemic manifestation. Phenotypes of isolated cases range from only a mild ligamental laxity, through subluxation, to a complete dislocation of the femoral head. Systemic manifestation is connected to various forms of skeletal dysplasia and other malformations characterized by significant genetic aberrations. To reveal the background of DDH heredity, multiple studies focused on large sample sizes with an emphasis on the correlation between genotype, phenotype and continuous clinical examination. Etiological risk factors that have been observed and documented in patients include genetic, environmental, and mechanical factors, which significantly contribute to the familial or nonfamilial occurrence and phenotypic variability of this disorder. Still, the multifactorial etiology and pathogenesis of DDH are not yet sufficiently clarified, explained, or understood. Formation of connective tissue, osteogenesis, chondrogenesis, and all other affected pathways and variations in the function of their individual elements contribute to the creation of the pathology in a developing human body. This review article presents an up-to-date list of known DDH associated genes, their products, and functional characteristics.
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Affiliation(s)
- Stefan Harsanyi
- Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University in Bratislava, Sasinkova 4, 811 08, Bratislava, Slovakia.
| | - Radoslav Zamborsky
- Department of Orthopedics, Faculty of Medicine, Comenius University and National Institute of Children's Diseases, Limbova 1, 833 40, Bratislava, Slovakia.
| | - Milan Kokavec
- Department of Orthopedics, Faculty of Medicine, Comenius University and National Institute of Children's Diseases, Limbova 1, 833 40, Bratislava, Slovakia.
| | - Lubos Danisovic
- Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University in Bratislava, Sasinkova 4, 811 08, Bratislava, Slovakia.
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25
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Hummitzsch K, Hatzirodos N, Macpherson AM, Schwartz J, Rodgers RJ, Irving-Rodgers HF. Transcriptome analyses of ovarian stroma: tunica albuginea, interstitium and theca interna. Reproduction 2020; 157:545-565. [PMID: 30925461 DOI: 10.1530/rep-18-0323] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2018] [Accepted: 03/29/2019] [Indexed: 01/15/2023]
Abstract
The ovary has specialised stromal compartments, including the tunica albuginea, interstitial stroma and theca interna, which develops concurrently with the follicular antrum. To characterise the molecular determinants of these compartments, stroma adjacent to preantral follicles (pre-theca), interstitium and tunica albuginea were laser microdissected (n = 4 per group) and theca interna was dissected from bovine antral follicles (n = 6). RNA microarray analysis showed minimal differences between interstitial stroma and pre-theca, and these were combined for some analyses and referred to as stroma. Genes significantly upregulated in theca interna compared to stroma included INSL3, LHCGR, HSD3B1, CYP17A1, ALDH1A1, OGN, POSTN and ASPN. Quantitative RT-PCR showed significantly greater expression of OGN and LGALS1 in interstitial stroma and theca interna versus tunica and greater expression of ACD in tunica compared to theca interna. PLN was significantly higher in interstitial stroma compared to tunica and theca. Ingenuity pathway, network and upstream regulator analyses were undertaken. Cell survival was also upregulated in theca interna. The tunica albuginea was associated with GPCR and cAMP signalling, suggesting tunica contractility. It was also associated with TGF-β signalling and increased fibrous matrix. Western immunoblotting was positive for OGN, LGALS1, ALDH1A1, ACD and PLN with PLN and OGN highly expressed in tunica and interstitial stroma (each n = 6), but not in theca interna from antral follicles (n = 24). Immunohistochemistry localised LGALS1 and POSTN to extracellular matrix and PLN to smooth muscle cells. These results have identified novel differences between the ovarian stromal compartments.
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Affiliation(s)
- Katja Hummitzsch
- Discipline of Obstetrics and Gynaecology, School of Medicine, Robinson Research Institute, The University of Adelaide, Adelaide, South Australia, Australia
| | - Nicholas Hatzirodos
- Discipline of Obstetrics and Gynaecology, School of Medicine, Robinson Research Institute, The University of Adelaide, Adelaide, South Australia, Australia
| | - Anne M Macpherson
- Discipline of Obstetrics and Gynaecology, School of Medicine, Robinson Research Institute, The University of Adelaide, Adelaide, South Australia, Australia
| | - Jeff Schwartz
- School of Medicine, Griffith University, Gold Coast, Queensland, Australia
| | - Raymond J Rodgers
- Discipline of Obstetrics and Gynaecology, School of Medicine, Robinson Research Institute, The University of Adelaide, Adelaide, South Australia, Australia
| | - Helen F Irving-Rodgers
- Discipline of Obstetrics and Gynaecology, School of Medicine, Robinson Research Institute, The University of Adelaide, Adelaide, South Australia, Australia.,School of Medical Science, Griffith University, Gold Coast, Queensland, Australia
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26
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Pang X, Dong N, Zheng Z. Small Leucine-Rich Proteoglycans in Skin Wound Healing. Front Pharmacol 2020; 10:1649. [PMID: 32063855 PMCID: PMC6997777 DOI: 10.3389/fphar.2019.01649] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Accepted: 12/16/2019] [Indexed: 12/11/2022] Open
Abstract
Healing of cutaneous wounds is a complex and well-coordinated process requiring cooperation among multiple cells from different lineages and delicately orchestrated signaling transduction of a diversity of growth factors, cytokines, and extracellular matrix (ECM) at the wound site. Most skin wound healing in adults is imperfect, characterized by scar formation which results in significant functional and psychological sequelae. Thus, the reconstruction of the damaged skin to its original state is of concern to doctors and scientists. Beyond the traditional treatments such as corticosteroid injection and radiation therapy, several growth factors or cytokines-based anti-scarring products are being or have been tested in clinical trials to optimize skin wound healing. Unfortunately, all have been unsatisfactory to date. Currently, accumulating evidence suggests that the ECM not only functions as the structural component of the tissue but also actively modulates signal transduction and regulates cellular behaviors, and thus, ECM should be considered as an alternative target for wound management pharmacotherapy. Of particular interest are small leucine-rich proteoglycans (SLRPs), a group of the ECM, which exist in a wide range of connecting tissues, including the skin. This manuscript summarizes the most current knowledge of SLRPs regarding their spatial-temporal expression in the skin, as well as lessons learned from the genetically modified animal models simulating human skin pathologies. In this review, particular focus is given on the diverse roles of SLRP in skin wound healing, such as anti-inflammation, pro-angiogenesis, pro-migration, pro-contraction, and orchestrate transforming growth factor (TGF)β signal transduction, since cumulative investigations have indicated their therapeutic potential on reducing scar formation in cutaneous wounds. By conducting this review, we intend to gain insight into the potential application of SLRPs in cutaneous wound healing management which may pave the way for the development of a new generation of pharmaceuticals to benefit the patients suffering from skin wounds and their sequelae.
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Affiliation(s)
- Xiaoxiao Pang
- Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Stomatological Hospital of Chongqing Medical University, Chongqing, China
- Division of Growth and Development, School of Dentistry, University of California, Los Angeles, Los Angeles, CA, United States
| | - Nuo Dong
- Division of Growth and Development, School of Dentistry, University of California, Los Angeles, Los Angeles, CA, United States
| | - Zhong Zheng
- Division of Growth and Development, School of Dentistry, University of California, Los Angeles, Los Angeles, CA, United States
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Abstract
Purpose: Biglycan is a proteoglycan of the small leucine-rich repeat family. It is present in all connective tissues and plays key structural and signaling roles. This review aimed to compile available evidence in the characteristics and distribution of biglycan and its glycosylated and non-glycosylated forms in connective tissues with a specific focus on the contribution to homeostasis of bone and changes of biglycan structure with aging.Methods: The Pubmed database was searched and included the terms "biglycan", "proteoglycans", "glycosaminoglycans", "bone", "osteoblast", "osteocyte", "osteoclast", "aging", "inflammation", "cartilage". Abstracts were appraised and a series of original articles and reviews studied to generate this narrative review.Results: Based on the search, biglycan significantly affects bone development and homeostasis and can be significantly changed by the aging process in several connective tissues, which in turn affects the behavior of tissue and cell responses in aged networks. Further, as the understanding of the various forms of biglycan in vivo is expanded and the function of its components in vitro is dissected, this proteoglycan can potentially serve as a therapeutic or biomarker molecule to detect tissue destruction.Conclusions: Biglycan is a key player in skeletal bone homeostasis, and overall, there is more evidence on the role of biglycan in development and less in the adult physiological or diseased young and aged systems. Further understanding of its conformation, degradation peptides and post-translational modifications will be required to understand the role of biglycan in bone maintenance and to support the development of treatments for age-related bone dysfunctions.
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Affiliation(s)
- Patricia A Miguez
- Adams School of Dentistry, Division of Comprehensive Oral Health, The University of North Carolina, Chapel Hill, NC, USA
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Machaliński B, Rogińska D, Szumilas K, Zawiślak A, Wilk A, Stecewicz I, Brodkiewicz A, Wiszniewska B. Transcriptome Profile of Human Fibroblasts in an Ex Vivo Culture. Int J Med Sci 2020; 17:125-136. [PMID: 31929746 PMCID: PMC6945561 DOI: 10.7150/ijms.35693] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Accepted: 08/18/2019] [Indexed: 11/05/2022] Open
Abstract
Implantation of autologous fibroblasts is a method used to correct age-related changes in facial skin. The aim of this study was to establish the optimal population of cultured human fibroblasts according to the organization of the extracellular matrix in the dermis. Transcriptome profile analysis of cells derived from three consecutive passages indicated that fibroblasts after the second passage were the population with the greatest number of upregulated genes encoding the critical biological processes responsible for skin regeneration, such as extracellular matrix organization, collagen fibril organization, and cell adhesion. Furthermore, genes encoding proteinases responsible for the degradation of dermal extracellular matrix proteins were noticeably downregulated at this stage of culture. Autologous fibroblasts seem to be an optimal and safe biological filler for the renewal of all skin structures.
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Affiliation(s)
- Bogusław Machaliński
- Department of General Pathology, Pomeranian Medical University, Powstańców Wlkp. 72, 70-111 Szczecin, Poland
| | - Dorota Rogińska
- Department of General Pathology, Pomeranian Medical University, Powstańców Wlkp. 72, 70-111 Szczecin, Poland
| | - Kamila Szumilas
- Department of General Pathology, Pomeranian Medical University, Powstańców Wlkp. 72, 70-111 Szczecin, Poland
| | - Alicja Zawiślak
- Department of General Pathology, Pomeranian Medical University, Powstańców Wlkp. 72, 70-111 Szczecin, Poland
| | - Aleksandra Wilk
- Department of Histology and Embryology, Pomeranian Medical University, Powstańców Wlkp. 72, 70-111 Szczecin, Poland
| | - Iwona Stecewicz
- Department of General Pathology, Pomeranian Medical University, Powstańców Wlkp. 72, 70-111 Szczecin, Poland
| | - Andrzej Brodkiewicz
- Department of General Pathology, Pomeranian Medical University, Powstańców Wlkp. 72, 70-111 Szczecin, Poland
| | - Barbara Wiszniewska
- Department of Histology and Embryology, Pomeranian Medical University, Powstańców Wlkp. 72, 70-111 Szczecin, Poland
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Zhan S, Li J, Ge W. Multifaceted Roles of Asporin in Cancer: Current Understanding. Front Oncol 2019; 9:948. [PMID: 31608236 PMCID: PMC6771297 DOI: 10.3389/fonc.2019.00948] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Accepted: 09/09/2019] [Indexed: 12/13/2022] Open
Abstract
The small leucine-rich proteoglycan (SLRP) family consists of 18 members categorized into five distinct classes, the traditional classes I–III, and the non-canonical classes IV–V. Unlike the other class I SLRPs (decorin and biglycan), asporin contains a unique and conserved stretch of aspartate (D) residues in its N terminus, and germline polymorphisms in the D-repeat-length are associated with osteoarthritis and prostate cancer progression. Since the first discovery of asporin in 2001, previous studies have focused mainly on its roles in bone and joint diseases, including osteoarthritis, intervertebral disc degeneration and periodontal ligament mineralization. Recently, asporin gene expression was also reported to be dysregulated in tumor tissues of different types of cancer, and to act as oncogene in pancreatic, colorectal, gastric, and prostate cancers, and some types of breast cancer, though it is also reported to function as a tumor suppressor gene in triple-negative breast cancer. Furthermore, asporin is also positively or negatively correlated with tumor proliferation, migration, invasion, and patient prognosis through its regulation of different signaling pathways, including the TGF-β, EGFR, and CD44 pathways. In this review, we seek to elucidate the signaling pathways and functions regulated by asporin in different types of cancer and to highlight some important issues that require investigation in future research.
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Affiliation(s)
- Shaohua Zhan
- National Key Laboratory of Medical Molecular Biology, Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing, China.,National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology, Beijing, China
| | - Jinming Li
- National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology, Beijing, China
| | - Wei Ge
- National Key Laboratory of Medical Molecular Biology, Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing, China.,Affiliated Hospital of Hebei University, Baoding, China
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30
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Kim IS, Song W, Arakawa H. The Role of Low-Level Sodium Fluoride in Periodontal Inflammation. J HARD TISSUE BIOL 2019. [DOI: 10.2485/jhtb.28.159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Affiliation(s)
- Il-Shin Kim
- Department of Dental Hygiene, Honam University
| | - Wenqun Song
- Department of Oral Science, Graduate School of Dentistry, Kanagawa Dental University
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Costa RA, Martins RST, Capilla E, Anjos L, Power DM. Vertebrate SLRP family evolution and the subfunctionalization of osteoglycin gene duplicates in teleost fish. BMC Evol Biol 2018; 18:191. [PMID: 30545285 PMCID: PMC6293640 DOI: 10.1186/s12862-018-1310-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Accepted: 11/27/2018] [Indexed: 02/07/2023] Open
Abstract
Background Osteoglycin (OGN, a.k.a. mimecan) belongs to cluster III of the small leucine-rich proteoglycans (SLRP) of the extracellular matrix (ECM). In vertebrates OGN is a characteristic ECM protein of bone. In the present study we explore the evolution of SLRP III and OGN in teleosts that have a skeleton adapted to an aquatic environment. Results The SLRP gene family has been conserved since the separation of chondrichthyes and osteichthyes. Few gene duplicates of the SLRP III family exist even in the teleosts that experienced a specific whole genome duplication. One exception is ogn for which duplicate copies were identified in fish genomes. The ogn promoter sequence and in vitro mesenchymal stem cell (MSC) cultures suggest the duplicate ogn genes acquired divergent functions. In gilthead sea bream (Sparus aurata) ogn1 was up-regulated during osteoblast and myocyte differentiation in vitro, while ogn2 was severely down-regulated during bone-derived MSCs differentiation into adipocytes in vitro. Conclusions Overall, the phylogenetic analysis indicates that the SLRP III family in vertebrates has been under conservative evolutionary pressure. The retention of the ogn gene duplicates in teleosts was linked with the acquisition of different functions. The acquisition by OGN of functions other than that of a bone ECM protein occurred early in the vertebrate lineage. Electronic supplementary material The online version of this article (10.1186/s12862-018-1310-2) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- R A Costa
- Comparative Endocrinology and Integrative Biology Group, Centre of Marine Sciences, University of Algarve, Campus of Gambelas, 8005-139, Faro, Portugal
| | - R S T Martins
- Comparative Endocrinology and Integrative Biology Group, Centre of Marine Sciences, University of Algarve, Campus of Gambelas, 8005-139, Faro, Portugal.
| | - E Capilla
- Department of Cell Biology, Physiology and Immunology, Faculty of Biology, University of Barcelona, 08028, Barcelona, Spain
| | - L Anjos
- Comparative Endocrinology and Integrative Biology Group, Centre of Marine Sciences, University of Algarve, Campus of Gambelas, 8005-139, Faro, Portugal
| | - D M Power
- Comparative Endocrinology and Integrative Biology Group, Centre of Marine Sciences, University of Algarve, Campus of Gambelas, 8005-139, Faro, Portugal.
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Wang H, Zhang X, Wu W, Zhang M, Sam NB, Niu L. Association between the aspartic acid D-repeat polymorphisms and osteoarthritis susceptibility: An updated systematic review and meta-analyses. Medicine (Baltimore) 2018; 97:e13163. [PMID: 30407347 PMCID: PMC6250497 DOI: 10.1097/md.0000000000013163] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVES Association between the D-repeat of asporin (ASPN) gene and osteoarthritis (OA) was still inconsistent. We performed this meta-analysis to systematically assess the D-repeat polymorphisms in OA susceptibility. METHODS Relevant studies were enrolled by searching databases. Odd ratios (ORs) with 95% confidence intervals (95% CIs) were used for evaluating the association between ASPN gene and OA. Heterogeneity was calculated using the Q statistic, and three different subgroup analyses were performed on ethnicity, gender, and OA positions respectively. False discovery rate (FDR) was applied to regulate the multiple comparisons. RESULTS Twelve qualified articles involving 5190 OA patients and 5167 healthy controls were included. With D13 polymorphism, Caucasian male patients have low OA susceptibility (P = .008, PFDR = .024, OR [95% CI] = 0.83 [0.73-0.95]). As to D14 polymorphism, all male patients (P = .0004, PFDR = .001, OR [95% CI] = 1.38 [1.15-1.64]), Asian male patients (P = .01, PFDR = .01, OR [95% CI] = 1.72 [1.11-2.66]), and Caucasian male patients (P = .005, PFDR = .001, OR [95% CI] = 1.32 [1.09-1.60]) have high OA susceptibility. In the pooled-population of KOA with D14 polymorphism, overall male patients (P = .03, PFDR = .045, OR [95% CI] = 1.35 [1.02-1.78]) and Asian male patients (P = .01, PFDR = .03, OR [95% CI] = 1.72 [1.11-2.66]) have high OA risk. With D16 polymorphism, Latin America patients may have high OA risk (P = .04, PFDR = .15, OR [95% CI] = 1.43 [1.02-2.01]). CONCLUSION Our results suggest that D-repeat of ASPN gene is mainly associated with male patients. The D13 polymorphism plays a protective role for OA in Caucasians male individuals while D14 plays a risk factor for KOA in male patients.
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Affiliation(s)
- Honglin Wang
- Department of Microscopic Orthopedic, the Hefei Second People's Hospital and Hefei Affiliated Hospital of Anhui Medical University
| | - Xu Zhang
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University
| | - Wentao Wu
- School of Clinical Medicine, Wannan Medical College
| | - Mingyue Zhang
- School of Public Health, Anhui Medical University, Hefei City, Anhui Province, China
| | - Napoleon Bellua Sam
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University
- University for Development Studies, Ghana Students Information Systems Unit, University of Ghana, Accra, Ghana
| | - Lei Niu
- Department of Microscopic Orthopedic, the Hefei Second People's Hospital and Hefei Affiliated Hospital of Anhui Medical University
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Yu X, Liu H, Liu S, Chen X, Zhao X, Du Y, Li S. Periodontal ligament-associated protein-1 gets involved in experimental periodontitis. J Periodontal Res 2018; 54:180-189. [PMID: 30298589 DOI: 10.1111/jre.12618] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2018] [Revised: 09/02/2018] [Accepted: 09/08/2018] [Indexed: 01/27/2023]
Abstract
BACKGROUND AND OBJECTIVE Periodontal ligament-associated protein-1 (PLAP-1) is an important regulator of osteogenic differentiation of periodontal ligament cells and plays important role in the homeostasis of periodontal tissues. But the role of PLAP-1 in periodontitis is poorly understood. Expressions of PLAP-1 in experimental periodontitis are observed to elucidate whether PLAP-1 gets involved in the pathogenesis of periodontitis. MATERIAL AND METHODS Wistar rats were randomly allocated to two groups (n = 6/group): Ligation group and Control group. PLAP-1 expression in experimental periodontitis was assessed by immunohistochemistry and collagen fibers in periodontal ligament were observed using picrosirius red staining. Expressions of PLAP-1 and CD68 in periodontitis were colocalized by double-labelled immunofluorescence. To further examine the relationship between PLAP-1 and osteoclastogenesis in experimental periodontitis, acute periodontal inflammatory infiltration and alveolar bone destruction were induced by administering ligated rats with 10 ng/mL tumor necrosis factor alpha (TNF-α; ligation + TNF-α group, n = 6). Alveolar bone loss was observed by micro-computed tomography (Micro-CT), and osteoclasts were identified by tartrate-resistant acid phosphatase staining (TRAP). Expressions of PLAP-1 in TNF-α stimulated human periodontal ligament cells were also detected at 24 and 48 hours by western blotting. RESULTS PLAP-1 expression levels in periodontal ligament cells and collagen fibers were lower in the ligation group,compared with the control group. Similarly, TNF-α decreased PLAP-1 expression in human periodontal ligament cells in vitro. Degradation or destruction of collagen fibers accompanied the reduced PLAP-1 expression in the periodontal ligament in the ligation group. Colocalization of PLAP-1 and CD68 revealed the positive relationship between PLAP-1 and CD68+ infiltrating cells in periodontitis. More PLAP-1-positive inflammatory cells were found in the ligation + TNF-α group, compared with the ligation + saline group. CONCLUSION PLAP-1-positive inflammatory cells are involved in the pathogenesis of periodontitis. An increase in PLAP-1-positive inflammatory cell number contributes periodontal inflammation and alveolar bone loss.
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Affiliation(s)
- Xijiao Yu
- Department of Endodontics, Jinan Stomatological Hospital, Jinan, China.,Shandong Provincial Key Laboratory of Oral Tissue Regeneration, School and Hospital of Stomatology, Shandong University, Jinan, China
| | - Hongmei Liu
- Department of Endodontics, Jinan Stomatological Hospital, Jinan, China
| | - Shuang Liu
- Shandong Provincial Key Laboratory of Oral Tissue Regeneration, School and Hospital of Stomatology, Shandong University, Jinan, China
| | - Xue Chen
- Shandong Provincial Key Laboratory of Oral Tissue Regeneration, School and Hospital of Stomatology, Shandong University, Jinan, China
| | - Xinyu Zhao
- Shandong Provincial Key Laboratory of Oral Tissue Regeneration, School and Hospital of Stomatology, Shandong University, Jinan, China
| | - Yi Du
- Department of Endodontics, Jinan Stomatological Hospital, Jinan, China
| | - Shu Li
- Shandong Provincial Key Laboratory of Oral Tissue Regeneration, School and Hospital of Stomatology, Shandong University, Jinan, China
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Zhu X, Jiang L, Lu Y, Wang C, Zhou S, Wang H, Tian T. Association of aspartic acid repeat polymorphism in the asporin gene with osteoarthritis of knee, hip, and hand: A PRISMA-compliant meta-analysis. Medicine (Baltimore) 2018; 97:e0200. [PMID: 29561445 PMCID: PMC5895348 DOI: 10.1097/md.0000000000010200] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
Abstract
OBJECTIVE Several human studies have been conducted to explore the association between aspirin (ASPN) D-repeat polymorphisms and OA susceptibility, but these provide inconsistent results. Our primary aim is to examine whether D-repeat polymorphisms are related to OA risk. METHODS We conducted a meta-analysis to investigate the association between ASPN D-repeat polymorphisms and OA. Electronic database was searched, including PubMed, Embase, CNKI, Ovid, and the reference lists of relevant articles published from the inception to January 24, 2018. The included studies were assessed in the following allele model: D14 allele versus others combined, D13 allele versus others combined, D15 allele versus others combined, and D14 allele versus D13 allele. Female population was also analyzed separately. RESULTS Eleven articles (12 comparisons) with 4975 patients of knee, hip, and/or hand OA and 3754 controls were considered in this meta-analysis. For the D13 allele, OR and 95% CI in combined population indicated an borderline association (odds ratio [OR] = 0.94, confidence interval [CI]: 0.89-0.99, P = .027). No significant association between OA and the D14 allele and D15 allele in all pooled studies were observed. CONCLUSION Our result based on previously published studies demonstrated that the ASPN D13 allele was a protective factor for OA of knee, hip, and hand. For D14 and D15 allele, our present meta-analysis did not demonstrate statistically significant association. Further studies with larger sample size would be required.
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Affiliation(s)
- Xiaoyue Zhu
- Department of Epidemiology, School of Public Health, Nantong University, Nantong, Jiangsu Province
| | - Liying Jiang
- Shanghai Key Laboratory for Molecular Imaging, Shanghai University of Medicine & Health Sciences, Shanghai
| | - Yihua Lu
- Department of Epidemiology, School of Public Health, Nantong University, Nantong, Jiangsu Province
| | - Chunli Wang
- College of Chemistry and Chemical Engineering, Nantong University, Nantong, Jiangsu Province, P.R. China
| | - Shuai Zhou
- Department of Epidemiology, School of Public Health, Nantong University, Nantong, Jiangsu Province
| | - He Wang
- Department of Epidemiology, School of Public Health, Nantong University, Nantong, Jiangsu Province
| | - Tian Tian
- Department of Epidemiology, School of Public Health, Nantong University, Nantong, Jiangsu Province
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Min S, Song EAC, Oyelakin A, Gluck C, Smalley K, Romano RA. Functional characterization and genomic studies of a novel murine submandibular gland epithelial cell line. PLoS One 2018; 13:e0192775. [PMID: 29462154 PMCID: PMC5819789 DOI: 10.1371/journal.pone.0192775] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2017] [Accepted: 01/30/2018] [Indexed: 01/10/2023] Open
Abstract
A better understanding of the normal and diseased biology of salivary glands (SG) has been hampered, in part, due to difficulties in cultivating and maintaining salivary epithelial cells. Towards this end, we have generated a mouse salivary gland epithelial cell (mSGc) culture system that is well-suited for the molecular characterization of SG cells and their differentiation program. We demonstrate that mSGc can be maintained for multiple passages without a loss of proliferation potential, readily form 3D-spheroids and importantly express a panel of well-established salivary gland epithelial cell markers. Moreover, mSGc 3D-spheroids also exhibit functional maturation as evident by robust agonist-induced intracellular calcium signaling. Finally, transcriptomic characterization of mSGc by RNA-seq and hierarchical clustering analysis with adult organ RNA-seq datasets reveal that mSGc retain most of the molecular attributes of adult mouse salivary gland. This well-characterized mouse salivary gland cell line will fill a critical void in the field by offering a valuable resource to examine various mechanistic aspects of mouse salivary gland biology.
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Affiliation(s)
- Sangwon Min
- Department of Oral Biology, School of Dental Medicine, State University of New York at Buffalo, Buffalo, New York, United States of America
| | - Eun-Ah Christine Song
- Department of Oral Biology, School of Dental Medicine, State University of New York at Buffalo, Buffalo, New York, United States of America
| | - Akinsola Oyelakin
- Department of Oral Biology, School of Dental Medicine, State University of New York at Buffalo, Buffalo, New York, United States of America
| | - Christian Gluck
- Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York, United States of America
| | - Kirsten Smalley
- Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York, United States of America
| | - Rose-Anne Romano
- Department of Oral Biology, School of Dental Medicine, State University of New York at Buffalo, Buffalo, New York, United States of America
- Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York, United States of America
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Simkova D, Kharaishvili G, Korinkova G, Ozdian T, Suchánková-Kleplová T, Soukup T, Krupka M, Galandakova A, Dzubak P, Janikova M, Navratil J, Kahounova Z, Soucek K, Bouchal J. The dual role of asporin in breast cancer progression. Oncotarget 2018; 7:52045-52060. [PMID: 27409832 PMCID: PMC5239534 DOI: 10.18632/oncotarget.10471] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2015] [Accepted: 06/29/2016] [Indexed: 12/18/2022] Open
Abstract
Asporin has been reported as a tumor suppressor in breast cancer, while asporin-activated invasion has been described in gastric cancer. According to our in silico search, high asporin expresion associates with significantly better relapse free survival (RFS) in patients with low-grade tumors but RFS is significantly worse in patients with grade 3 tumors. In line with other studies, we have confirmed asporin expression by RNA scope in situ hybridization in cancer associated fibroblasts. We have also found asporin expression in the Hs578T breast cancer cell line which we confirmed by quantitative RT-PCR and western blotting. From multiple testing, we found that asporin can be downregulated by bone morphogenetic protein 4 while upregulation may be facilited by serum-free cultivation or by three dimensional growth in stiff Alvetex scaffold. Downregulation by shRNA inhibited invasion of Hs578T as well as of CAFs and T47D cells. Invasion of asporin-negative MDA-MB-231 and BT549 breast cancer cells through collagen type I was enhanced by recombinant asporin. Besides other investigations, large scale analysis of aspartic acid repeat polymorphism will be needed for clarification of the asporin dual role in progression of breast cancer.
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Affiliation(s)
- Dana Simkova
- Department of Clinical and Molecular Pathology, Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic
| | - Gvantsa Kharaishvili
- Department of Clinical and Molecular Pathology, Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic
| | - Gabriela Korinkova
- Department of Clinical and Molecular Pathology, Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic
| | - Tomas Ozdian
- Laboratory of Experimental Medicine, Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic
| | - Tereza Suchánková-Kleplová
- Department of Histology and Embryology, Faculty of Medicine in Hradec Kralove, Charles University, Hradec Kralove, Czech Republic
| | - Tomas Soukup
- Department of Histology and Embryology, Faculty of Medicine in Hradec Kralove, Charles University, Hradec Kralove, Czech Republic
| | - Michal Krupka
- Department of Immunology, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic
| | - Adela Galandakova
- Department of Medical Chemistry and Biochemistry, Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic
| | - Petr Dzubak
- Laboratory of Experimental Medicine, Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic
| | - Maria Janikova
- Department of Clinical and Molecular Pathology, Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic
| | - Jiri Navratil
- Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Institute, Brno, Czech Republic
| | - Zuzana Kahounova
- Department of Cytokinetics, Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Brno, Czech Republic.,Center of Biomolecular and Cellular Engineering, International Clinical Research Center, St. Anne's University Hospital Brno, Brno, Czech Republic
| | - Karel Soucek
- Department of Cytokinetics, Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Brno, Czech Republic.,Center of Biomolecular and Cellular Engineering, International Clinical Research Center, St. Anne's University Hospital Brno, Brno, Czech Republic.,Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic
| | - Jan Bouchal
- Department of Clinical and Molecular Pathology, Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic
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Taipale M, Solovieva S, Leino-Arjas P, Männikkö M. Functional polymorphisms in asporin and CILP together with joint loading predispose to hand osteoarthritis. BMC Genet 2017; 18:108. [PMID: 29233086 PMCID: PMC5727665 DOI: 10.1186/s12863-017-0585-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2017] [Accepted: 12/07/2017] [Indexed: 01/07/2023] Open
Abstract
Background Osteoarthritis (OA) is the most common degenerative joint disease afflicting people in the Western world and has a strong genetic influence. The aim of this study was to examine the association of two known functional polymorphisms in the TGF-β inhibiting genes, asporin (ASPN) and cartilage intermediate layer protein (CILP), with hand OA and potential gene-occupational hand loading interaction. Results Statistically significant interaction of the CILP rs2073711 T and ASPN D15 alleles with hand OA was observed (OR = 2.48, 95% CI 1.27–4.85, p = 0.008) in a Finnish hand OA cohort of 543 women (aged 45–63). When stratified by variation in working tasks, low variation of working tasks increased the risk further (OR = 3.00, 95% CI 1.35–6.66, p = 0.007). Based on the analysis of ASPN and CILP protein-coding regions, functional studies were performed with one observed variant, rs41278695 in the ASPN gene. Analyses showed that bone morphogenetic protein 2 (BMP2) mediated expression of aggrecan (Agc1) and type II collagen (Col2a1) was significantly suppressed (p = 0.011 and p = 0.023, respectively) in a murine chondrocytic cell line (ATDC5) with cells stably expressing ASPN rs41278695. Conclusions The carriage of either ASPN D15 or CILP rs2073711 TT is associated with increased risk of symmetrical hand OA, particularly in individuals with low variation in work tasks. ASPN rs41278695 SNP had an effect on Agc1 and Col2a1 gene expression when induced with BMP-2 suggesting an effect on the cartilage extracellular matrix composition.
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Affiliation(s)
- Mari Taipale
- Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Aapistie 5, 90220, Oulu, Finland.,Biocenter Oulu and Faculty of Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland
| | - Svetlana Solovieva
- Department of Epidemiology and Biostatistics, Centre of Expertise for Health and Work Ability, Finnish Institute of Occupational Health, Helsinki, Finland
| | - Päivi Leino-Arjas
- Department of Epidemiology and Biostatistics, Centre of Expertise for Health and Work Ability, Finnish Institute of Occupational Health, Helsinki, Finland
| | - Minna Männikkö
- Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Aapistie 5, 90220, Oulu, Finland. .,Biocenter Oulu and Faculty of Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland.
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Candidate gene investigation of spinal degenerative osteoarthritis in Greek population. Spine J 2017; 17:1881-1888. [PMID: 28662992 DOI: 10.1016/j.spinee.2017.06.025] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2016] [Revised: 06/01/2017] [Accepted: 06/21/2017] [Indexed: 02/03/2023]
Abstract
BACKGROUND CONTEXT Few data exist concerning the natural history of degenerative osteoarthritis (OA) of the spine and its associated gene investigation. Degenerative spinal OA demonstrates an international prevalence of 15% in the general population. PURPOSE The aim of this Greek case-control study is to examine gene polymorphisms that have been previously shown or hypothesized to be correlated to degenerative OA. Gene polymorphisms, especially for OA, have never been previously studied in the Greek population. STUDY DESIGN/SETTING The study was conducted from May 2009 to December 2012. Eligible subjects who agreed to take part in the study were Greek adults from all of Greece, referred for consultation to the Palliative Care and Pain Relief Unit of Aretaieion University Hospital, in Athens, Greece. PATIENT SAMPLE A total of 601 matched pairs (cases and controls) participated in the study, 258 patients (188 women and 70 men) with clinically and radiologically confirmed degenerative OA and 243 control subjects (138 women and 105 men). OUTCOME MEASURES All patients presented with chronic pain at the spine (cervical, thoracic or lumbar) caused by sympomatic osteophytes or disc narrowing, whereas clinical diagnosis of OA was based on the presence of both joint symptoms and evidence of structural changes seen on plain conventional X-rays. METHODS We investigated genetic variation across candidate OA gene GDF5, CDMP1, CDMP2, Asporin, SMAD3, and chromosomal region 7q22, in a sample of 258 patients with clinically and radiologically confirmed degenerative OA, and 243 control subjects from the Greek population. All subjects (patients and controls) were subsequently matched for the epidemiologic, demographic, and clinical risk factors, to prevent selection biases. A tagging single nucleotide polymorphism (SNP) approach was pursued to cover variation across all targeted loci. Single marker tests as well as haplotypic tests of association were performed. There is no conflict of interest, and also, there are no study funding sources. RESULTS We found significant association of spine OA with SNPs and haplotypes along the 7q22 chromosomal region and the SMAD3 gene. At 7q22, single marker association tests showed SNPs rs3801954 and rs2023685 to be associated with the disorder (p-value .0312 and .0041, respectively), but only SNP rs2023685 retained a significant p-value (.046) after performing 1,000 permutation tests. At the SMAD3 gene, SNP rs422342 was also found to be statistically associated (p-value .0282) to intervertebral disc degeneration (permutation p-value .042). CONCLUSIONS This is the first study to investigate genetic variation in relation to spine OA in the Greek population. Our results indicate that the genetic basis of the disease may differ in the Greek population in relation to populations of Asian origin, although larger sample sizes are required to underpin the full extent of the involvement of analyzed loci.
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Liu R, Yuan X, Yu J, Quan Q, Meng H, Wang C, Wang A, Guo Q, Peng J, Lu S. An updated meta-analysis of the asporin gene D-repeat in knee osteoarthritis: effects of gender and ethnicity. J Orthop Surg Res 2017; 12:148. [PMID: 29020967 PMCID: PMC5637337 DOI: 10.1186/s13018-017-0647-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2017] [Accepted: 09/23/2017] [Indexed: 02/06/2023] Open
Abstract
Background Knee osteoarthritis (KOA) is the most prevalent form of knee joint disease and characterized by the progressive degeneration of articular cartilage. Although pathology of KOA remains unknown, genetic factors are considered to be the major cause. Asporin is a group of biologically active components of extracellular matrix (ECM) in articular cartilage, and asporin gene (ASPN) D-repeat polymorphism was reported to be associated with KOA. Thus, our meta-analysis is aimed at investigation of the association between asporin D-repeat polymorphism and susceptibility of KOA. Methods We gathered data from MEDLINE, Embase, OVID, and ScienceDirect to search relevant published epidemiological studies through April 2017. Compared with previous studies, our meta-analysis is the first study to investigate the association of ASPN D15, D16, and D17 alleles and KOA susceptibility by ethnic- and sex-stratified subgroup analysis. Results We found no significant association between D15 allele and susceptibility to KOA (OR = 1.05, 95% CI 0.95–1.17) in overall population. The same results were observed in the analysis of D16 (OR = 1.01, 95% CI 0.80–1.28) and D17 alleles (OR = 1.28, 95% CI 0.91–1.80). The ethnic- and sex-subgroup analyses did not alter the ORs. However, significant association was detected in the sensitivity analysis of D17 in overall population (OR = 1.05, 95% CI 0.95–1.17) and Asian population (OR = 1.78, 95% CI 1.02–3.11, P < 0.05). Conclusion Our results indicated that D-repeat polymorphism of ASPN may not play a major role in susceptibility of KOA in ethnic- and sex-specific analysis. Because of the limitations of the present meta-analysis, firm conclusions could not be drawn based on the current evidence, and further studies are required to detect genuine role of ASPN.
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Affiliation(s)
- Ruoxi Liu
- Institute of Orthopedics, Beijing Key Laboratory of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, Chinese PLA General Hospital, FuXing Road 28th, Beijing, 100853, China
| | - Xueling Yuan
- Institute of Orthopedics, Beijing Key Laboratory of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, Chinese PLA General Hospital, FuXing Road 28th, Beijing, 100853, China
| | - Jing Yu
- Department of Kampo Medicine, Yokohama University of Pharmacy, 601 Matano-cho, Totsuka-ku, Yokohama-shi, Kanagawa-ken, 245-0066, Japan
| | - Qi Quan
- Institute of Orthopedics, Beijing Key Laboratory of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, Chinese PLA General Hospital, FuXing Road 28th, Beijing, 100853, China
| | - Haoye Meng
- Institute of Orthopedics, Beijing Key Laboratory of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, Chinese PLA General Hospital, FuXing Road 28th, Beijing, 100853, China
| | - Cheng Wang
- Institute of Orthopedics, Beijing Key Laboratory of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, Chinese PLA General Hospital, FuXing Road 28th, Beijing, 100853, China
| | - Aiyuan Wang
- Institute of Orthopedics, Beijing Key Laboratory of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, Chinese PLA General Hospital, FuXing Road 28th, Beijing, 100853, China
| | - Quanyi Guo
- Institute of Orthopedics, Beijing Key Laboratory of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, Chinese PLA General Hospital, FuXing Road 28th, Beijing, 100853, China
| | - Jiang Peng
- Institute of Orthopedics, Beijing Key Laboratory of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, Chinese PLA General Hospital, FuXing Road 28th, Beijing, 100853, China.
| | - Shibi Lu
- Institute of Orthopedics, Beijing Key Laboratory of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, Chinese PLA General Hospital, FuXing Road 28th, Beijing, 100853, China.
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Maccarana M, Svensson RB, Knutsson A, Giannopoulos A, Pelkonen M, Weis M, Eyre D, Warman M, Kalamajski S. Asporin-deficient mice have tougher skin and altered skin glycosaminoglycan content and structure. PLoS One 2017; 12:e0184028. [PMID: 28859141 PMCID: PMC5578652 DOI: 10.1371/journal.pone.0184028] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2017] [Accepted: 08/16/2017] [Indexed: 11/24/2022] Open
Abstract
The main structural component of connective tissues is fibrillar, cross-linked collagen whose fibrillogenesis can be modulated by Small Leucine-Rich Proteins/Proteoglycans (SLRPs). Not all SLRPs’ effects on collagen and extracellular matrix in vivo have been elucidated; one of the less investigated SLRPs is asporin. Here we describe the successful generation of an Aspn-/- mouse model and the investigation of the Aspn-/- skin phenotype. Functionally, Aspn-/- mice had an increased skin mechanical toughness, although there were no structural changes present on histology or immunohistochemistry. Electron microscopy analyses showed 7% thinner collagen fibrils in Aspn-/- mice (not statistically significant). Several matrix genes were upregulated, including collagens (Col1a1, Col1a2, Col3a1), matrix metalloproteinases (Mmp2, Mmp3) and lysyl oxidases (Lox, Loxl2), while lysyl hydroxylase (Plod2) was downregulated. Intriguingly no differences were observed in collagen protein content or in collagen cross-linking-related lysine oxidation or hydroxylation. The glycosaminoglycan content and structure in Aspn-/- skin was profoundly altered: chondroitin/dermatan sulfate was more than doubled and had an altered composition, while heparan sulfate was halved and had a decreased sulfation. Also, decorin and biglycan were doubled in Aspn-/- skin. Overall, asporin deficiency changes skin glycosaminoglycan composition, and decorin and biglycan content, which may explain the changes in skin mechanical properties.
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Affiliation(s)
- Marco Maccarana
- Department of Experimental Medical Sciences, Lund University, Lund, Sweden
| | - René B. Svensson
- Institute of Sports Medicine, Bispebjerg Hospital, and Center for Healthy Aging, University of Copenhagen, Copenhagen, Denmark
| | - Anki Knutsson
- Department of Experimental Medical Sciences, Lund University, Lund, Sweden
| | - Antonis Giannopoulos
- Institute of Sports Medicine, Bispebjerg Hospital, and Center for Healthy Aging, University of Copenhagen, Copenhagen, Denmark
| | - Mea Pelkonen
- Department of Experimental Medical Sciences, Lund University, Lund, Sweden
| | - MaryAnn Weis
- Department of Orthopaedics and Sports Medicine, University of Washington, Seattle, Washington, United States of America
| | - David Eyre
- Department of Orthopaedics and Sports Medicine, University of Washington, Seattle, Washington, United States of America
| | - Matthew Warman
- Children’s Hospital Boston, Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Sebastian Kalamajski
- Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden
- * E-mail:
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Miyamoto Y, Kanzaki H, Wada S, Tsuruoka S, Itohiya K, Kumagai K, Hamada Y, Nakamura Y. Asporin stably expressed in the surface layer of mandibular condylar cartilage and augmented in the deeper layer with age. Bone Rep 2017; 7:41-50. [PMID: 28875156 PMCID: PMC5574816 DOI: 10.1016/j.bonr.2017.07.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2017] [Revised: 06/30/2017] [Accepted: 07/20/2017] [Indexed: 12/29/2022] Open
Abstract
Mandibular condylar cartilage (MCC) exhibits dual roles both articular cartilage and growth center. Of many growth factors, TGF-β has been implicated in the growth of articular cartilage including MCC. Recently, Asporin, decoy to TGF-β, was discovered and it blocks TGF-β signaling. Asporin is expressed in a variety of tissues including osteoarthritic articular cartilage, though there was no report of Asporin expression in MCC. In the present study, we investigated the temporal and spatial expression of Asporin in MCC. Gene expression profile of MCC and epiphyseal cartilage in tibia of 5 weeks old ICR mice were firstly compared with microarray analysis using the laser capture microdissected samples. Variance of gene expression was further confirmed by real-time RT-PCR and immunohistochemical staining at 1,3,10, and 20 weeks old. TGF-β and its signaling molecule, phosphorylated Smad-2/3 (p-Smad2/3), were also examined by immunohistochemical staining. Microarray analysis revealed that Asporin was highly expressed in MCC. Real-time RT-PCR analysis confirmed that the fibrous layer of MCC exhibited stable higher Asporin expression at any time points as compared to epiphyseal cartilage. This was also observed in immunohistochemical staining. Deeper layer in MCC augmented Asporin expression with age. Whereas, TGF-β was stably highly observed in the layer. The fibrous layer of MCC exhibited weak staining of p-Smad2/3, though the proliferating layer of MCC was strongly stained as compared to epiphyseal cartilage of tibia at early time point. Consistent with the increase of Asporin expression in the deeper layer of MCC, the intensity of p-Smad-2/3 staining was decreased with age. In conclusion, we discovered that Asporin was stably expressed at the fibrous layer of MCC, which makes it possible to manage both articular cartilage and growth center at the same time.
Asporin gene and protein were highly expressed in mandibular condylar cartilage as compared to tibial epiphyseal cartilage. Asporin in mandibular condylar cartilage was augmented with age. TGF-β signaling is suppressed by augmented Asporin and decreased TGF-β production in mandibular condylar cartilage.
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Affiliation(s)
- Yutaka Miyamoto
- Department of orthodontics, School of Dental Medicine, Tsurumi University, 2-1-3 Tsurumi, Tsurumi-ku, Yokohama 230-8501, Kanagawa Pref., Japan
| | - Hiroyuki Kanzaki
- Department of orthodontics, School of Dental Medicine, Tsurumi University, 2-1-3 Tsurumi, Tsurumi-ku, Yokohama 230-8501, Kanagawa Pref., Japan
| | - Satoshi Wada
- Department of orthodontics, School of Dental Medicine, Tsurumi University, 2-1-3 Tsurumi, Tsurumi-ku, Yokohama 230-8501, Kanagawa Pref., Japan
| | - Sari Tsuruoka
- Department of orthodontics, School of Dental Medicine, Tsurumi University, 2-1-3 Tsurumi, Tsurumi-ku, Yokohama 230-8501, Kanagawa Pref., Japan
| | - Kanako Itohiya
- Department of orthodontics, School of Dental Medicine, Tsurumi University, 2-1-3 Tsurumi, Tsurumi-ku, Yokohama 230-8501, Kanagawa Pref., Japan
| | - Kenichi Kumagai
- Department of Oral and Maxillofacial Surgery, School of Dental Medicine, Tsurumi University, 2-1-3 Tsurumi, Tsurumi-ku, Yokohama 230-8501, Kanagawa Pref., Japan
| | - Yoshiki Hamada
- Department of Oral and Maxillofacial Surgery, School of Dental Medicine, Tsurumi University, 2-1-3 Tsurumi, Tsurumi-ku, Yokohama 230-8501, Kanagawa Pref., Japan
| | - Yoshiki Nakamura
- Department of orthodontics, School of Dental Medicine, Tsurumi University, 2-1-3 Tsurumi, Tsurumi-ku, Yokohama 230-8501, Kanagawa Pref., Japan
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Sekimoto T, Ishii M, Emi M, Kurogi S, Funamoto T, Yonezawa Y, Tajima T, Sakamoto T, Hamada H, Chosa E. Copy number loss in the region of the ASPN gene in patients with acetabular dysplasia: ASPN CNV in acetabular dysplasia. Bone Joint Res 2017; 6:439-445. [PMID: 28747338 PMCID: PMC5539304 DOI: 10.1302/2046-3758.67.bjr-2016-0094.r1] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2016] [Accepted: 05/15/2017] [Indexed: 11/25/2022] Open
Abstract
Objectives We have previously investigated an association between the genome copy number variation (CNV) and acetabular dysplasia (AD). Hip osteoarthritis is associated with a genetic polymorphism in the aspartic acid repeat in the N-terminal region of the asporin (ASPN) gene; therefore, the present study aimed to investigate whether the CNV of ASPN is involved in the pathogenesis of AD. Methods Acetabular coverage of all subjects was evaluated using radiological findings (Sharp angle, centre-edge (CE) angle, acetabular roof obliquity (ARO) angle, and minimum joint space width). Genomic DNA was extracted from peripheral blood leukocytes. Agilent’s region-targeted high-density oligonucleotide tiling microarray was used to analyse 64 female AD patients and 32 female control subjects. All statistical analyses were performed using EZR software (Fisher’s exact probability test, Pearson’s correlation test, and Student’s t-test). Results CNV analysis of the ASPN gene revealed a copy number loss in significantly more AD patients (9/64) than control subjects (0/32; p = 0.0212). This loss occurred within a 60 kb region on 9q22.31, which harbours the gene for ASPN. The mean radiological parameters of these AD patients were significantly worse than those of the other subjects (Sharp angle, p = 0.0056; CE angle, p = 0.0076; ARO angle, p = 0.0065), and all nine patients required operative therapy such as total hip arthroplasty or pelvic osteotomy. Moreover, six of these nine patients had a history of operative or conservative therapy for developmental dysplasia of the hip. Conclusions Copy number loss within the region harbouring the ASPN gene on 9q22.31 is associated with severe AD. A copy number loss in the ASPN gene region may play a role in the aetiology of severe AD. Cite this article: T. Sekimoto, M. Ishii, M. Emi, S. Kurogi, T. Funamoto, Y. Yonezawa, T. Tajima, T. Sakamoto, H. Hamada, E. Chosa. Copy number loss in the region of the ASPN gene in patients with acetabular dysplasia: ASPN CNV in acetabular dysplasia. Bone Joint Res 2017;6:439–445. DOI: 10.1302/2046-3758.67.BJR-2016-0094.R1.
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Affiliation(s)
- T Sekimoto
- Department of Medicine of Sensory and Motor Organs, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan
| | - M Ishii
- CNV Laboratory, DNA Chip Research Institute, 1-15-1 Kaigan, Minatoku, Tokyo 105-0022, Japan
| | - M Emi
- Thoracic Oncology and Cancer Biology, University of Hawaii Cancer Center, 651 Ilalo Street, BSB231, Honolulu, HI 96813, USA
| | - S Kurogi
- Department of Medicine of Sensory and Motor Organs, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan
| | - T Funamoto
- Department of Medicine of Sensory and Motor Organs, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan
| | - Y Yonezawa
- Division of Data Management, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan
| | - T Tajima
- Department of Medicine of Sensory and Motor Organs, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan
| | - T Sakamoto
- Department of Medicine of Sensory and Motor Organs, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan
| | - H Hamada
- Department of Medicine of Sensory and Motor Organs, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan
| | - E Chosa
- Department of Medicine of Sensory and Motor Organs, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan
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Wang S, Liu C, Sun Z, Yan P, Liang H, Huang K, Li C, Tian J. IL-1β increases asporin expression via the NF-κB p65 pathway in nucleus pulposus cells during intervertebral disc degeneration. Sci Rep 2017. [PMID: 28646230 PMCID: PMC5482889 DOI: 10.1038/s41598-017-04384-3] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
Disc degeneration (DD) is a multifaceted chronic process that alters the structure and function of intervertebral discs. The pathophysiology of degeneration is not completely understood, but the consensus is that changes in genes encoding extracellular matrix (ECM) proteins in the disc are the leading factors contributing to DD. Asporin is an ECM protein that has been shown to be increased in degenerated intervertebral discs, but little is known about how asporin is regulated during DD. In exploring the intricate mechanism, we confirmed that asporin was abundantly increased in patients’ degenerated nucleus pulposus. Consistently, the increased asporin expression with degeneration was also proved by rabbit intervertebral disc degeneration (IDD) model. Mechanistically, IL-1β upregulated asporin expression by activating the p65 pathway in human nucleus pulposus cells. Furthermore, p65 mediated asporin expression by binding to −41/−31 bp on asporin promoter. Functionally, asporin was the intermediator of IL-1β-inhibited aggrecan and collagen Π expression and played a negative role in TGF-β-induced aggrecan and collagen Π formation in human nucleus pulposus cells. Therefore, identifying asporin as a negative regulator of aggrecan and collagen Π and elucidating its induction mechanisms in human nucleus pulposus cells provides new insight for asporin induction during IDD.
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Affiliation(s)
- Shengjie Wang
- Department of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 100, Haining Road, Shanghai, 200080, People's Republic of China
| | - Chao Liu
- Department of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 100, Haining Road, Shanghai, 200080, People's Republic of China
| | - Zhongyi Sun
- Department of Orthopedics, Songjiang District Central Hospital of Shanghai, 746, middle-Zhongshan Road, Shanghai, 201600, People's Republic of China
| | - Peng Yan
- Department of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 100, Haining Road, Shanghai, 200080, People's Republic of China
| | - He Liang
- Department of Orthopedics, Songjiang District Central Hospital of Shanghai, 746, middle-Zhongshan Road, Shanghai, 201600, People's Republic of China
| | - Kai Huang
- Department of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 100, Haining Road, Shanghai, 200080, People's Republic of China
| | - Changwei Li
- Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases with Integrated Chinese-Western Medicine, Shanghai Institute of Traumatology and Orthopedics, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, People's Republic of China.
| | - Jiwei Tian
- Department of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 100, Haining Road, Shanghai, 200080, People's Republic of China.
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Olivares AM, Jelcick AS, Reinecke J, Leehy B, Haider A, Morrison MA, Cheng L, Chen DF, DeAngelis MM, Haider NB. Multimodal Regulation Orchestrates Normal and Complex Disease States in the Retina. Sci Rep 2017; 7:690. [PMID: 28386079 PMCID: PMC5429617 DOI: 10.1038/s41598-017-00788-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2016] [Accepted: 03/13/2017] [Indexed: 12/20/2022] Open
Abstract
Regulation of biological processes occurs through complex, synergistic mechanisms. In this study, we discovered the synergistic orchestration of multiple mechanisms regulating the normal and diseased state (age related macular degeneration, AMD) in the retina. We uncovered gene networks with overlapping feedback loops that are modulated by nuclear hormone receptors (NHR), miRNAs, and epigenetic factors. We utilized a comprehensive filtering and pathway analysis strategy comparing miRNA and microarray data between three mouse models and human donor eyes (normal and AMD). The mouse models lack key NHRS (Nr2e3, RORA) or epigenetic (Ezh2) factors. Fifty-four total miRNAs were differentially expressed, potentially targeting over 150 genes in 18 major representative networks including angiogenesis, metabolism, and immunity. We identified sixty-eight genes and 5 miRNAS directly regulated by NR2E3 and/or RORA. After a comprehensive analysis, we discovered multimodal regulation by miRNA, NHRs, and epigenetic factors of three miRNAs (miR-466, miR1187, and miR-710) and two genes (Ell2 and Entpd1) that are also associated with AMD. These studies provide insight into the complex, dynamic modulation of gene networks as well as their impact on human disease, and provide novel data for the development of innovative and more effective therapeutics.
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Affiliation(s)
- A M Olivares
- Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA, United States of America
| | - A S Jelcick
- Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
| | - J Reinecke
- Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
| | - B Leehy
- Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
| | - A Haider
- Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA, United States of America
| | - M A Morrison
- Ophthalmology and Visual Sciences, John A. Moran Eye Center, University of Utah School of Medicine, Salt Lake City, Utah, United States of America
| | - L Cheng
- Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA, United States of America
| | - D F Chen
- Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA, United States of America
| | - M M DeAngelis
- Ophthalmology and Visual Sciences, John A. Moran Eye Center, University of Utah School of Medicine, Salt Lake City, Utah, United States of America
| | - N B Haider
- Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA, United States of America.
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Yamada S, Ozawa Y, Tomoeda M, Matoba R, Matsubara K, Murakami S. Regulation of PLAP-1 Expression in Periodontal Ligament Cells. J Dent Res 2016; 85:447-51. [PMID: 16632759 DOI: 10.1177/154405910608500510] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Periodontal-ligament-associated protein-1 ( PLAP-1) is preferentially expressed in the periodontal ligament (PDL) and encodes a novel small leucine-rich repeat proteoglycan protein. PLAP-1 expression was induced during the course of cytodifferentiation of PDL cells into mineralized-tissue-forming cells in vitro, suggesting the possible involvement of PLAP-1 in the mineralization process of PDL cells. In this study, we hypothesized that PLAP-1 expression is regulated by mineralization-related cytokines in PDL cells. PLAP-1 expression was clearly down-regulated when the cytodifferentiation of PDL cells was reversibly inhibited by fibroblast growth factor-2 (FGF-2). In contrast, bone morphogenetic protein-2 (BMP-2) enhanced PLAP-1 expression. Up-regulation of PLAP-1 expression by BMP-2 was confirmed at the protein level when PDL cells were immunostained with anti-PLAP-1 polyclonal antibody. These results revealed the cytokine-mediated regulatory mechanisms of PLAP-1 expression and suggested that PLAP-1 expression may be associated with the process of cytodifferentiation of PDL cells.
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Affiliation(s)
- S Yamada
- Department of Periodontology, Osaka University Graduate School of Dentistry, Suita, Japan
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Simkova D, Kharaishvili G, Slabakova E, Murray PG, Bouchal J. Glycoprotein asporin as a novel player in tumour microenvironment and cancer progression. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2016; 160:467-473. [PMID: 27605398 DOI: 10.5507/bp.2016.037] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2016] [Accepted: 07/08/2016] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Small leucine rich proteoglycans (SLRPs), major non-collagen components of the extracellular matrix (ECM), have multiple biological roles with diverse effects. Asporin, a member of the SLRPs class I, competes with other molecules in binding to collagen and affects its mineralization. Its role in cancer is only now being elucidated. METHODS The PubMed online database was used to search relevant reviews and original articles. Furthermore, altered asporin expression was analysed in publicly available genome-wide expression data at the Gene Expression Omnibus database. RESULTS Polymorphisms in the N-terminal polyaspartate domain, which binds calcium, are associated with osteoarthritis and prostate cancer. Asporin also promotes the progression of scirrhous gastric cancer where it is required for coordinated invasion by cancer associated fibroblasts and cancer cells. Besides the enhanced expression of asporin observed in multiple cancer types, such as breast, prostate, gastric, pancreas and colon cancer, tumour suppressive effects of asporin were described in triple-negative breast cancer. We also discuss a number of factors modulating asporin expression in different cell types relevant for alterations toing the tumour microenvironment. CONCLUSION The apparent contradicting tumour promoting and suppressive effects of asporin require further investigation. Deciphering the role of asporin and other SLRPs in tumour-stroma interactions is needed for a better understanding of cancer progression and potentially also for novel tumour microenvironment based therapies.
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Affiliation(s)
- Dana Simkova
- Department of Clinical and Molecular Pathology and Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic
| | - Gvantsa Kharaishvili
- Department of Clinical and Molecular Pathology and Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic
| | - Eva Slabakova
- Department of Cytokinetics, Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Brno, Czech Republic
| | - Paul G Murray
- Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
| | - Jan Bouchal
- Department of Clinical and Molecular Pathology and Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic
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Jiang X, Wu CA, Wang Y, Shi KJ, Jiang XZ, Zheng S, Tian W. Knockdown of asporin affects transforming growth factor-β1-induced matrix synthesis in human intervertebral annulus cells. J Orthop Translat 2016; 7:1-6. [PMID: 30035083 PMCID: PMC5987567 DOI: 10.1016/j.jot.2016.05.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2016] [Revised: 04/18/2016] [Accepted: 05/16/2016] [Indexed: 11/24/2022] Open
Abstract
Background/Objective Asporin is associated with osteoarthritis and lumbar disk degeneration. Previous studies in chondrocytes showed that asporin can bind to transforming growth factor-β1 (TGF-β1) and downregulate matrix biosynthesis. However, this has not been studied in intervertebral disk (IVD) cells. This study aimed to inspect the expression of asporin under TGF-β1 stimulation and its effect on TGF-β1-induced matrix biosynthesis in human intervertebral annulus cells. Methods Human intervertebral annulus cells were obtained from the pathological region of IVD in eight patients. After primary culture and redifferentiation in alginate beads, cells were reseeded and treated with different concentrations (5 ng/mL, 10 ng/mL, and 15 ng/mL) of TGF-β1 for up to 24 hours. Total RNA extracted from the cells and those with asporin knockdown were subjected to real-time polymerase chain reaction analysis to examine the expression of asporin and extracellular matrix genes. Results TGF-β1 stimulation induces asporin transcription significantly in a dose- and time-dependent manner. Knockdown of endogenous asporin leads to the upregulated expression of collagen II alpha 1 and aggrecan. Conclusion Our results have verified a functional feedback loop between TGF-β1 and asporin in human intervertebral annulus cells indicating that TGF-β1-induced annulus matrix biosynthesis can be significantly upregulated by knockdown of asporin. Therefore, asporin could be a potential new therapeutic target and inhibition of asporin could be adopted to enhance the anabolic effect of TGF-β1 in human intervertebral annulus cells in degenerative IVD diseases.
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Affiliation(s)
- Xu Jiang
- Department of Orthopaedics, Beijing Jishuitan Hospital, 4 Clinical Medical College of Peking University, Beijing, China
| | - Cheng Ai Wu
- Department of Molecular Orthopaedics, Beijing Institute of Traumatology and Orthopaedics, Beijing, China
| | - Ying Wang
- Department of Molecular Orthopaedics, Beijing Institute of Traumatology and Orthopaedics, Beijing, China
| | - Ke-Jian Shi
- Department of Molecular Orthopaedics, Beijing Institute of Traumatology and Orthopaedics, Beijing, China
| | - Xiao-Zhou Jiang
- Department of Orthopaedics, Beijing Jishuitan Hospital, 4 Clinical Medical College of Peking University, Beijing, China
| | - Shan Zheng
- Department of Orthopaedics, Beijing Jishuitan Hospital, 4 Clinical Medical College of Peking University, Beijing, China
| | - Wei Tian
- Department of Orthopaedics, Beijing Jishuitan Hospital, 4 Clinical Medical College of Peking University, Beijing, China
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Luehders K, Sasai N, Davaapil H, Kurosawa-Yoshida M, Hiura H, Brah T, Ohnuma SI. The small leucine-rich repeat secreted protein Asporin induces eyes in Xenopus embryos through the IGF signalling pathway. Development 2016; 142:3351-61. [PMID: 26443635 DOI: 10.1242/dev.124438] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Small leucine-rich repeat proteoglycan (SLRP) family proteins play important roles in a number of biological events. Here, we demonstrate that the SLRP family member Asporin (ASPN) plays a crucial role in the early stages of eye development in Xenopus embryos. During embryogenesis, ASPN is broadly expressed in the neuroectoderm of the embryo. Overexpression of ASPN causes the induction of ectopic eyes. By contrast, blocking ASPN function with a morpholino oligonucleotide (ASPN-MO) inhibits eye formation, indicating that ASPN is an essential factor for eye development. Detailed molecular analyses revealed that ASPN interacts with insulin growth factor receptor (IGFR) and is essential for activating the IGF receptor-mediated intracellular signalling pathway. Moreover, ASPN perturbed the Wnt, BMP and Activin signalling pathways, suggesting that ASPN thereby creates a favourable environment in which the IGF signal can dominate. ASPN is thus a novel secreted molecule essential for eye induction through the coordination of multiple signalling pathways.
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Affiliation(s)
- Kristin Luehders
- Ocular Biology and Therapeutic unit (ORBIT), Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, UK
| | - Noriaki Sasai
- Ocular Biology and Therapeutic unit (ORBIT), Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, UK Developmental Biomedical Science, Graduate School of Biological Sciences, Nara Institute of Science and Technology (NAIST), 8916-5, Takayama-cho, Ikoma 630-0192, Japan
| | - Hongorzul Davaapil
- Ocular Biology and Therapeutic unit (ORBIT), Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, UK
| | - Maiko Kurosawa-Yoshida
- Department of Oncology, The Hutchison/MRC Research Centre, University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK
| | - Hitoshi Hiura
- Ocular Biology and Therapeutic unit (ORBIT), Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, UK
| | - Tara Brah
- Ocular Biology and Therapeutic unit (ORBIT), Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, UK
| | - Shin-ichi Ohnuma
- Ocular Biology and Therapeutic unit (ORBIT), Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, UK Department of Oncology, The Hutchison/MRC Research Centre, University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK
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Ueda M, Goto T, Kuroishi KN, Gunjigake KK, Ikeda E, Kataoka S, Nakatomi M, Toyono T, Seta Y, Kawamoto T. Asporin in compressed periodontal ligament cells inhibits bone formation. Arch Oral Biol 2016; 62:86-92. [DOI: 10.1016/j.archoralbio.2015.11.010] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2015] [Revised: 10/07/2015] [Accepted: 11/17/2015] [Indexed: 01/15/2023]
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