C-H Chou1, D E Attarian2, H-G Wisniewski3, P A Band4, V B Kraus5. 1. Department of Pathology, Duke University, School of Medicine, Durham, NC 27710, USA; Duke Molecular Physiology Institute and Division of Rheumatology, Department of Medicine, Duke University School of Medicine, Durham, NC 27701, USA. 2. Department of Orthopaedic Surgery, Duke University School of Medicine, Durham, NC 27710, USA. 3. Matrix Biology Institute, Fort Lee, NJ 07024, USA. 4. Department of Orthopedic Surgery, Biochemistry & Molecular Pharmacology, New York University, School of Medicine, and NYU Hospital for Joint Diseases, New York, NY 10003, USA. 5. Duke Molecular Physiology Institute and Division of Rheumatology, Department of Medicine, Duke University School of Medicine, Durham, NC 27701, USA. Electronic address: vbk@duke.edu.
Abstract
PURPOSE: To explore mechanisms underlying the association of TSG-6 with osteoarthritis (OA) progression. METHODS: TSG-6-mediated heavy chain (HC) transfer (TSG-6 activity) and its association with inflammatory mediators were quantified in knee OA (n=25) synovial fluids (SFs). Paired intact and damaged cartilages from the same individuals (20 tibial and 12 meniscal) were analyzed by qRT-PCR and immunohistochemistry (IHC) for gene and protein expression of TSG-6 and components of Inter-alpha-Inhibitor (IαI) and TSG-6 activity ± spiked in IαI. Primary chondrocyte cultures (n=5) ± IL1β or TNFα were evaluated for gene expression. The effects of TSG-6 activity on cartilage extracellular matrix (ECM) assembly were explored using quantitative hyaluronan (HA)-aggrecan binding assays. RESULTS: TSG-6 activity was significantly associated (R > 0.683, P < 0.0002) with inflammatory mediators including TIMP-1, A2M, MMP3, VEGF, VCAM-1, ICAM-1 and IL-6. Although TSG-6 protein and mRNA were highly expressed in damaged articular and meniscal cartilage and cytokine-treated chondrocytes, there was little or no cartilage expression of components of the IαI complex (containing HC1). By IHC, TSG-6 was present throughout lesioned cartilage but HC1 only at lesioned surfaces. TSG-6 impaired HA-aggrecan assembly, but TSG-6 mediated HA-HC formation reduced this negative effect. CONCLUSIONS: TSG-6 activity is a global inflammatory biomarker in knee OA SF. IαI, supplied from outside cartilage, only penetrates the cartilage surface, restricting TSG-6 activity (HC transfer) to this region. Therefore, unopposed TSG-6 in intermediate and deep regions of OA cartilage could possibly block matrix assembly, leading to futile synthesis and account for increased risk of OA progression.
PURPOSE: To explore mechanisms underlying the association of TSG-6 with osteoarthritis (OA) progression. METHODS:TSG-6-mediated heavy chain (HC) transfer (TSG-6 activity) and its association with inflammatory mediators were quantified in knee OA (n=25) synovial fluids (SFs). Paired intact and damaged cartilages from the same individuals (20 tibial and 12 meniscal) were analyzed by qRT-PCR and immunohistochemistry (IHC) for gene and protein expression of TSG-6 and components of Inter-alpha-Inhibitor (IαI) and TSG-6 activity ± spiked in IαI. Primary chondrocyte cultures (n=5) ± IL1β or TNFα were evaluated for gene expression. The effects of TSG-6 activity on cartilage extracellular matrix (ECM) assembly were explored using quantitative hyaluronan (HA)-aggrecan binding assays. RESULTS:TSG-6 activity was significantly associated (R > 0.683, P < 0.0002) with inflammatory mediators including TIMP-1, A2M, MMP3, VEGF, VCAM-1, ICAM-1 and IL-6. Although TSG-6 protein and mRNA were highly expressed in damaged articular and meniscal cartilage and cytokine-treated chondrocytes, there was little or no cartilage expression of components of the IαI complex (containing HC1). By IHC, TSG-6 was present throughout lesioned cartilage but HC1 only at lesioned surfaces. TSG-6 impaired HA-aggrecan assembly, but TSG-6 mediated HA-HC formation reduced this negative effect. CONCLUSIONS:TSG-6 activity is a global inflammatory biomarker in knee OA SF. IαI, supplied from outside cartilage, only penetrates the cartilage surface, restricting TSG-6 activity (HC transfer) to this region. Therefore, unopposed TSG-6 in intermediate and deep regions of OA cartilage could possibly block matrix assembly, leading to futile synthesis and account for increased risk of OA progression.
Authors: V B Kraus; G McDaniel; J L Huebner; T V Stabler; C F Pieper; S W Shipes; N A Petry; P S Low; J Shen; T A McNearney; P Mitchell Journal: Osteoarthritis Cartilage Date: 2016-04-12 Impact factor: 6.576
Authors: H-G Wisniewski; E Colón; V Liublinska; R J Karia; T V Stabler; M Attur; S B Abramson; P A Band; V B Kraus Journal: Osteoarthritis Cartilage Date: 2013-12-12 Impact factor: 6.576
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Authors: A E Bello; W E Garrett; H Wang; J Lohnes; E DeLong; B Caterson; V B Kraus Journal: Osteoarthritis Cartilage Date: 1997-11 Impact factor: 6.576
Authors: Alia Mallah; Mahmoud Amr; Haneen Abusharkh; Bernard Van Wie; Arda Gozen; Juana Mendenhall; Edwin Tingstad; Vincent Idone; Nehal I Abu-Lail Journal: J Immunol Regen Med Date: 2021-10-08
Authors: Ching-Heng Chou; Vaibhav Jain; Jason Gibson; David E Attarian; Collin A Haraden; Christopher B Yohn; Remi-Martin Laberge; Simon Gregory; Virginia B Kraus Journal: Sci Rep Date: 2020-07-02 Impact factor: 4.379
Authors: Christian Lattermann; Caitlin E-W Conley; Darren L Johnson; Emily K Reinke; Laura J Huston; Janet L Huebner; Ching-Heng Chou; Virginia B Kraus; Kurt P Spindler; Cale A Jacobs Journal: Biomed Res Int Date: 2018-07-19 Impact factor: 3.411