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Anwen Sian Williams - One of the best experts on this subject based on the ideXlab platform.
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ccl3 and mmp 9 are induced by tl1a during Death Receptor 3 tnfrsf25 dependent osteoclast function and systemic bone loss
Bone, 2017Co-Authors: Edward Chung Yern Wang, Fraser L Collins, Jessica O Williams, Anja Bloom, Michael D Stone, Ravinder K Singh, Lauren A Jordan, Laura R Mccabe, Anwen Sian WilliamsAbstract:Reduced bone density and secondary osteoporosis, resulting in increased risk of fracture, is a significant complicating factor in the inflammatory arthritides. While the exact etiology of systemic bone loss is not fully elucidated, recent insights into the tumor necrosis factor super family (TNFSF) revealed a potential role for Death Receptor 3 (DR3/TNFRSF25) and one of its ligands, TNF-like protein 1A (TL1A/TNFSF15). The mechanisms by which DR3/TL1A signalling modulates bone loss are unclear. We investigated the effect of DR3/TL1A signalling upon osteoclast-dependent chemokine and MMP production to unravel novel mechanisms whereby this pathway regulates OC formation and OC-dependent bone resorption. Collagen induced arthritis (CIA) was established in DR3wt and DR3ko mice, joints were sectioned and analysed histologically for bone damage while systemic trabecular bone loss distal to the affected joints was compared by micro-CT. Ablation of DR3 protected DBA/1 mice against the development and progression of CIA. In DR3ko, joints of the ankle and mid-foot were almost free of bone erosions and long bones of mice with CIA were protected against systemic trabecular bone loss. In vitro, expression of DR3 was confirmed on primary human CD14+ osteoclast precursors by flow cytometry. These cells were treated with TL1A in osteoclast differentiation medium and TRAP+ osteoclasts, bone resorption, levels of osteoclast-associated chemokines (CCL3, CCL2 and CXCL8) and MMP-9 measured. TL1A intensified human osteoclast differentiation and bone resorption and increased osteoclast-associated production of CCL3 and MMP-9. Our data reveals the DR3 pathway as an attractive therapeutic target to combat adverse bone pathology associated with inflammatory arthritis. We demonstrate that DR3 is critical in the pathogenesis of murine CIA and associated secondary osteoporosis. Furthermore, we identify a novel mechanism by which the DR3/TL1A pathway directly enhances human OC formation and resorptive activity, controlling expression and activation of CCL3 and MMP-9.
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review novel insights into tumor necrosis factor Receptor Death Receptor 3 and progranulin pathways in arthritis and bone remodeling
Arthritis & Rheumatism, 2016Co-Authors: Anwen Sian Williams, Edward Chung Yern Wang, Lorenz Thurner, Chuanju LiuAbstract:Approximately 30 members of the tumor necrosis factor Receptor superfamily (TNFRSF) have been identified. They are transmembrane proteins with cysteine‐rich motifs in their extracellular domains that bind to their cognate ligands 1. They are categorized into 3 groups: Death domain–containing Receptors, decoy Receptors, and TNFR‐associated factor–binding Receptors. Only 8 TNFRSF members contain a Death domain (TNFR type I [TNFRI], Death Receptor 3 [DR‐3], DR‐4, DR‐5, DR‐6, Fas, nerve growth factor Receptor, and ectodysplasin A Receptor [EDAR]), of which TNFRI and DR‐3 constitute the principal focus of this article. Interactions between TNF superfamily (TNFSF) ligands and TNFRSF Receptors help maintain tissue homeostasis by controlling survival, proliferation, differentiation, and effector function of immune cells. We limit our review to recent advances and novel insights into the roles of TNFRI and DR‐3 in bone and joint biology. Bone cells (osteoblasts, osteoclasts, and osteocytes), fibroblast‐like synoviocytes, chondrocytes, and immune cells that infiltrate the arthritic joint will at different times express a wide range of TNFRSF members and TNFSF ligands. An overview of the current status of our knowledge in this regard is provided in Table 1. The impact of TNFRI activation on bone and inflammatory joint diseases has been researched in great depth 2, 3, but little or no data in the field have been reported on other more recently discovered TNFRSF members such as TROY (TNFRSF expressed on the mouse embryo; TNFRSF19), EDAR, and XEDAR (X‐linked ectodysplasin Receptor; TNFRSF27). The unexpected interaction between progranulin (PGRN) and both TNFRI and TNFRII is particularly interesting in the context of arthritis‐associated bone pathology. PGRN levels are elevated in the synovial fluid of patients with rheumatoid arthritis (RA), osteoarthritis (OA), and other arthropathies 4, 5, 6, and PGRN has been shown to inhibit TNF‐induced osteoclastogenesis and promote osteoblast differentiation in mice 7. However, PGRN has a higher binding affinity for TNFRII (antiinflammatory with osteoprotective function) than for TNFRI (predominantly proinflammatory with degenerative function), which suggests conflicting actions. The potential overall impact of these divergent PGRN signaling pathways on the architecture of the arthritic joint has been evaluated 8. Table 1 Cellular expression of Death domain–containing TNFRSF members and their association with arthritis*
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Death Receptor 3 tnfrsf25 increases mineral apposition by osteoblasts and region specific new bone formation in the axial skeleton of male dba 1 mice
Clinical & Developmental Immunology, 2015Co-Authors: Fraser L Collins, Edward Chung Yern Wang, Jessica O Williams, Anja Bloom, Michael D Stone, Ernest Choy, Anwen Sian WilliamsAbstract:Objectives. Genome wide association studies identified TNFSF member TNF-like protein 1A (TL1A, TNFSF15) as a potential modulator of ankylosing spondylitis (AS). TL1A is the only confirmed TNFSF ligand of Death Receptor 3 (DR3, TNFRSF25); however, its role in disease pathology is not characterised. We evaluated DR3’s role in controlling osteoblast- (OB-) dependent bone formation in vitro and in vivo. Methods. Osteoprogenitor cells and OB were cultured from male DR3-deficient () and wild-type () DBA/1 mice. DR3 and RANKL expression were tested by flow cytometry. Alkaline phosphatase and mineralization were quantified. Osteopontin, osteoprotegerin, and pro MMP-9 were measured by ELISA. A fluorescent probe (BoneTag) was used to measure in vivo mineralization in 10-month-old mice. Results. DR3 was expressed on osteoprogenitors and OB from mice. Alkaline phosphatase, osteopontin, and mineral apposition were significantly elevated in cultures. Levels of RANKL were comparable whilst osteoprotegerin was significantly increased in cultures. In vivo incorporation of BoneTag was significantly lower in the thoracic vertebrae of 10-month-old mice. Conclusions. These data identify new roles for DR3 in regulating OB-dependent bone mineral apposition. They potentially begin to explain the atypical pattern of new bone formation observed in the axial skeleton of grouped, aging DBA/1 mice.
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the Death Receptor 3 tnf like protein 1a pathway drives adverse bone pathology in inflammatory arthritis
Journal of Experimental Medicine, 2008Co-Authors: Melanie Bull, Zarabeth Mecklenburgh, Claudia Jane Calder, Carole Elford, Bronwen Alice James Evans, Tania F Rowley, Tomasz Jerzy ślebioda, Jason Peter Twohig, Anwen Sian Williams, Vadim Y TarabanAbstract:Rheumatoid arthritis (RA) is a chronic inflammatory disease of synovial joints that is associated with cartilage and bone destruction. Death Receptor 3 (DR3), a tumor necrosis factor (TNF) Receptor superfamily member, has recently been associated with the pathogenesis of RA. We demonstrate that absence of DR3 confers resistance to the development of adverse bone pathology in experimental antigen-induced arthritis (AIA). DR3ko mice exhibited a reduction in all histopathological hallmarks of AIA but, in particular, failed to develop subchondral bone erosions and were completely protected from this characteristic of AIA. In contrast, TNF-like protein 1A (TL1A), the ligand for DR3, exacerbated disease in a dose- and DR3-dependent fashion. Analysis of osteoclast number within AIA joint revealed a reduction in areas susceptible to bone erosion in DR3ko mice, whereas in vitro osteoclastogenesis assays showed that TL1A could directly promote osteoclastogenesis in mouse and man. Treatment with antagonistic anti-TL1A mAb protected animals in a systemic model of RA disease collagen-induced arthritis. We therefore conclude that the DR3–TL1A pathway regulates joint destruction in two murine models of arthritis and represents a potential novel target for therapeutic intervention in inflammatory joint disease.
Edward Chung Yern Wang - One of the best experts on this subject based on the ideXlab platform.
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ccl3 and mmp 9 are induced by tl1a during Death Receptor 3 tnfrsf25 dependent osteoclast function and systemic bone loss
Bone, 2017Co-Authors: Edward Chung Yern Wang, Fraser L Collins, Jessica O Williams, Anja Bloom, Michael D Stone, Ravinder K Singh, Lauren A Jordan, Laura R Mccabe, Anwen Sian WilliamsAbstract:Reduced bone density and secondary osteoporosis, resulting in increased risk of fracture, is a significant complicating factor in the inflammatory arthritides. While the exact etiology of systemic bone loss is not fully elucidated, recent insights into the tumor necrosis factor super family (TNFSF) revealed a potential role for Death Receptor 3 (DR3/TNFRSF25) and one of its ligands, TNF-like protein 1A (TL1A/TNFSF15). The mechanisms by which DR3/TL1A signalling modulates bone loss are unclear. We investigated the effect of DR3/TL1A signalling upon osteoclast-dependent chemokine and MMP production to unravel novel mechanisms whereby this pathway regulates OC formation and OC-dependent bone resorption. Collagen induced arthritis (CIA) was established in DR3wt and DR3ko mice, joints were sectioned and analysed histologically for bone damage while systemic trabecular bone loss distal to the affected joints was compared by micro-CT. Ablation of DR3 protected DBA/1 mice against the development and progression of CIA. In DR3ko, joints of the ankle and mid-foot were almost free of bone erosions and long bones of mice with CIA were protected against systemic trabecular bone loss. In vitro, expression of DR3 was confirmed on primary human CD14+ osteoclast precursors by flow cytometry. These cells were treated with TL1A in osteoclast differentiation medium and TRAP+ osteoclasts, bone resorption, levels of osteoclast-associated chemokines (CCL3, CCL2 and CXCL8) and MMP-9 measured. TL1A intensified human osteoclast differentiation and bone resorption and increased osteoclast-associated production of CCL3 and MMP-9. Our data reveals the DR3 pathway as an attractive therapeutic target to combat adverse bone pathology associated with inflammatory arthritis. We demonstrate that DR3 is critical in the pathogenesis of murine CIA and associated secondary osteoporosis. Furthermore, we identify a novel mechanism by which the DR3/TL1A pathway directly enhances human OC formation and resorptive activity, controlling expression and activation of CCL3 and MMP-9.
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review novel insights into tumor necrosis factor Receptor Death Receptor 3 and progranulin pathways in arthritis and bone remodeling
Arthritis & Rheumatism, 2016Co-Authors: Anwen Sian Williams, Edward Chung Yern Wang, Lorenz Thurner, Chuanju LiuAbstract:Approximately 30 members of the tumor necrosis factor Receptor superfamily (TNFRSF) have been identified. They are transmembrane proteins with cysteine‐rich motifs in their extracellular domains that bind to their cognate ligands 1. They are categorized into 3 groups: Death domain–containing Receptors, decoy Receptors, and TNFR‐associated factor–binding Receptors. Only 8 TNFRSF members contain a Death domain (TNFR type I [TNFRI], Death Receptor 3 [DR‐3], DR‐4, DR‐5, DR‐6, Fas, nerve growth factor Receptor, and ectodysplasin A Receptor [EDAR]), of which TNFRI and DR‐3 constitute the principal focus of this article. Interactions between TNF superfamily (TNFSF) ligands and TNFRSF Receptors help maintain tissue homeostasis by controlling survival, proliferation, differentiation, and effector function of immune cells. We limit our review to recent advances and novel insights into the roles of TNFRI and DR‐3 in bone and joint biology. Bone cells (osteoblasts, osteoclasts, and osteocytes), fibroblast‐like synoviocytes, chondrocytes, and immune cells that infiltrate the arthritic joint will at different times express a wide range of TNFRSF members and TNFSF ligands. An overview of the current status of our knowledge in this regard is provided in Table 1. The impact of TNFRI activation on bone and inflammatory joint diseases has been researched in great depth 2, 3, but little or no data in the field have been reported on other more recently discovered TNFRSF members such as TROY (TNFRSF expressed on the mouse embryo; TNFRSF19), EDAR, and XEDAR (X‐linked ectodysplasin Receptor; TNFRSF27). The unexpected interaction between progranulin (PGRN) and both TNFRI and TNFRII is particularly interesting in the context of arthritis‐associated bone pathology. PGRN levels are elevated in the synovial fluid of patients with rheumatoid arthritis (RA), osteoarthritis (OA), and other arthropathies 4, 5, 6, and PGRN has been shown to inhibit TNF‐induced osteoclastogenesis and promote osteoblast differentiation in mice 7. However, PGRN has a higher binding affinity for TNFRII (antiinflammatory with osteoprotective function) than for TNFRI (predominantly proinflammatory with degenerative function), which suggests conflicting actions. The potential overall impact of these divergent PGRN signaling pathways on the architecture of the arthritic joint has been evaluated 8. Table 1 Cellular expression of Death domain–containing TNFRSF members and their association with arthritis*
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Death Receptor 3 tnfrsf25 increases mineral apposition by osteoblasts and region specific new bone formation in the axial skeleton of male dba 1 mice
Clinical & Developmental Immunology, 2015Co-Authors: Fraser L Collins, Edward Chung Yern Wang, Jessica O Williams, Anja Bloom, Michael D Stone, Ernest Choy, Anwen Sian WilliamsAbstract:Objectives. Genome wide association studies identified TNFSF member TNF-like protein 1A (TL1A, TNFSF15) as a potential modulator of ankylosing spondylitis (AS). TL1A is the only confirmed TNFSF ligand of Death Receptor 3 (DR3, TNFRSF25); however, its role in disease pathology is not characterised. We evaluated DR3’s role in controlling osteoblast- (OB-) dependent bone formation in vitro and in vivo. Methods. Osteoprogenitor cells and OB were cultured from male DR3-deficient () and wild-type () DBA/1 mice. DR3 and RANKL expression were tested by flow cytometry. Alkaline phosphatase and mineralization were quantified. Osteopontin, osteoprotegerin, and pro MMP-9 were measured by ELISA. A fluorescent probe (BoneTag) was used to measure in vivo mineralization in 10-month-old mice. Results. DR3 was expressed on osteoprogenitors and OB from mice. Alkaline phosphatase, osteopontin, and mineral apposition were significantly elevated in cultures. Levels of RANKL were comparable whilst osteoprotegerin was significantly increased in cultures. In vivo incorporation of BoneTag was significantly lower in the thoracic vertebrae of 10-month-old mice. Conclusions. These data identify new roles for DR3 in regulating OB-dependent bone mineral apposition. They potentially begin to explain the atypical pattern of new bone formation observed in the axial skeleton of grouped, aging DBA/1 mice.
Fraser L Collins - One of the best experts on this subject based on the ideXlab platform.
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ccl3 and mmp 9 are induced by tl1a during Death Receptor 3 tnfrsf25 dependent osteoclast function and systemic bone loss
Bone, 2017Co-Authors: Edward Chung Yern Wang, Fraser L Collins, Jessica O Williams, Anja Bloom, Michael D Stone, Ravinder K Singh, Lauren A Jordan, Laura R Mccabe, Anwen Sian WilliamsAbstract:Reduced bone density and secondary osteoporosis, resulting in increased risk of fracture, is a significant complicating factor in the inflammatory arthritides. While the exact etiology of systemic bone loss is not fully elucidated, recent insights into the tumor necrosis factor super family (TNFSF) revealed a potential role for Death Receptor 3 (DR3/TNFRSF25) and one of its ligands, TNF-like protein 1A (TL1A/TNFSF15). The mechanisms by which DR3/TL1A signalling modulates bone loss are unclear. We investigated the effect of DR3/TL1A signalling upon osteoclast-dependent chemokine and MMP production to unravel novel mechanisms whereby this pathway regulates OC formation and OC-dependent bone resorption. Collagen induced arthritis (CIA) was established in DR3wt and DR3ko mice, joints were sectioned and analysed histologically for bone damage while systemic trabecular bone loss distal to the affected joints was compared by micro-CT. Ablation of DR3 protected DBA/1 mice against the development and progression of CIA. In DR3ko, joints of the ankle and mid-foot were almost free of bone erosions and long bones of mice with CIA were protected against systemic trabecular bone loss. In vitro, expression of DR3 was confirmed on primary human CD14+ osteoclast precursors by flow cytometry. These cells were treated with TL1A in osteoclast differentiation medium and TRAP+ osteoclasts, bone resorption, levels of osteoclast-associated chemokines (CCL3, CCL2 and CXCL8) and MMP-9 measured. TL1A intensified human osteoclast differentiation and bone resorption and increased osteoclast-associated production of CCL3 and MMP-9. Our data reveals the DR3 pathway as an attractive therapeutic target to combat adverse bone pathology associated with inflammatory arthritis. We demonstrate that DR3 is critical in the pathogenesis of murine CIA and associated secondary osteoporosis. Furthermore, we identify a novel mechanism by which the DR3/TL1A pathway directly enhances human OC formation and resorptive activity, controlling expression and activation of CCL3 and MMP-9.
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Death Receptor 3 tnfrsf25 increases mineral apposition by osteoblasts and region specific new bone formation in the axial skeleton of male dba 1 mice
Clinical & Developmental Immunology, 2015Co-Authors: Fraser L Collins, Edward Chung Yern Wang, Jessica O Williams, Anja Bloom, Michael D Stone, Ernest Choy, Anwen Sian WilliamsAbstract:Objectives. Genome wide association studies identified TNFSF member TNF-like protein 1A (TL1A, TNFSF15) as a potential modulator of ankylosing spondylitis (AS). TL1A is the only confirmed TNFSF ligand of Death Receptor 3 (DR3, TNFRSF25); however, its role in disease pathology is not characterised. We evaluated DR3’s role in controlling osteoblast- (OB-) dependent bone formation in vitro and in vivo. Methods. Osteoprogenitor cells and OB were cultured from male DR3-deficient () and wild-type () DBA/1 mice. DR3 and RANKL expression were tested by flow cytometry. Alkaline phosphatase and mineralization were quantified. Osteopontin, osteoprotegerin, and pro MMP-9 were measured by ELISA. A fluorescent probe (BoneTag) was used to measure in vivo mineralization in 10-month-old mice. Results. DR3 was expressed on osteoprogenitors and OB from mice. Alkaline phosphatase, osteopontin, and mineral apposition were significantly elevated in cultures. Levels of RANKL were comparable whilst osteoprotegerin was significantly increased in cultures. In vivo incorporation of BoneTag was significantly lower in the thoracic vertebrae of 10-month-old mice. Conclusions. These data identify new roles for DR3 in regulating OB-dependent bone mineral apposition. They potentially begin to explain the atypical pattern of new bone formation observed in the axial skeleton of grouped, aging DBA/1 mice.
Chuanju Liu - One of the best experts on this subject based on the ideXlab platform.
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review novel insights into tumor necrosis factor Receptor Death Receptor 3 and progranulin pathways in arthritis and bone remodeling
Arthritis & Rheumatism, 2016Co-Authors: Anwen Sian Williams, Edward Chung Yern Wang, Lorenz Thurner, Chuanju LiuAbstract:Approximately 30 members of the tumor necrosis factor Receptor superfamily (TNFRSF) have been identified. They are transmembrane proteins with cysteine‐rich motifs in their extracellular domains that bind to their cognate ligands 1. They are categorized into 3 groups: Death domain–containing Receptors, decoy Receptors, and TNFR‐associated factor–binding Receptors. Only 8 TNFRSF members contain a Death domain (TNFR type I [TNFRI], Death Receptor 3 [DR‐3], DR‐4, DR‐5, DR‐6, Fas, nerve growth factor Receptor, and ectodysplasin A Receptor [EDAR]), of which TNFRI and DR‐3 constitute the principal focus of this article. Interactions between TNF superfamily (TNFSF) ligands and TNFRSF Receptors help maintain tissue homeostasis by controlling survival, proliferation, differentiation, and effector function of immune cells. We limit our review to recent advances and novel insights into the roles of TNFRI and DR‐3 in bone and joint biology. Bone cells (osteoblasts, osteoclasts, and osteocytes), fibroblast‐like synoviocytes, chondrocytes, and immune cells that infiltrate the arthritic joint will at different times express a wide range of TNFRSF members and TNFSF ligands. An overview of the current status of our knowledge in this regard is provided in Table 1. The impact of TNFRI activation on bone and inflammatory joint diseases has been researched in great depth 2, 3, but little or no data in the field have been reported on other more recently discovered TNFRSF members such as TROY (TNFRSF expressed on the mouse embryo; TNFRSF19), EDAR, and XEDAR (X‐linked ectodysplasin Receptor; TNFRSF27). The unexpected interaction between progranulin (PGRN) and both TNFRI and TNFRII is particularly interesting in the context of arthritis‐associated bone pathology. PGRN levels are elevated in the synovial fluid of patients with rheumatoid arthritis (RA), osteoarthritis (OA), and other arthropathies 4, 5, 6, and PGRN has been shown to inhibit TNF‐induced osteoclastogenesis and promote osteoblast differentiation in mice 7. However, PGRN has a higher binding affinity for TNFRII (antiinflammatory with osteoprotective function) than for TNFRI (predominantly proinflammatory with degenerative function), which suggests conflicting actions. The potential overall impact of these divergent PGRN signaling pathways on the architecture of the arthritic joint has been evaluated 8. Table 1 Cellular expression of Death domain–containing TNFRSF members and their association with arthritis*
Vadim Y Taraban - One of the best experts on this subject based on the ideXlab platform.
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the Death Receptor 3 tnf like protein 1a pathway drives adverse bone pathology in inflammatory arthritis
Journal of Experimental Medicine, 2008Co-Authors: Melanie Bull, Zarabeth Mecklenburgh, Claudia Jane Calder, Carole Elford, Bronwen Alice James Evans, Tania F Rowley, Tomasz Jerzy ślebioda, Jason Peter Twohig, Anwen Sian Williams, Vadim Y TarabanAbstract:Rheumatoid arthritis (RA) is a chronic inflammatory disease of synovial joints that is associated with cartilage and bone destruction. Death Receptor 3 (DR3), a tumor necrosis factor (TNF) Receptor superfamily member, has recently been associated with the pathogenesis of RA. We demonstrate that absence of DR3 confers resistance to the development of adverse bone pathology in experimental antigen-induced arthritis (AIA). DR3ko mice exhibited a reduction in all histopathological hallmarks of AIA but, in particular, failed to develop subchondral bone erosions and were completely protected from this characteristic of AIA. In contrast, TNF-like protein 1A (TL1A), the ligand for DR3, exacerbated disease in a dose- and DR3-dependent fashion. Analysis of osteoclast number within AIA joint revealed a reduction in areas susceptible to bone erosion in DR3ko mice, whereas in vitro osteoclastogenesis assays showed that TL1A could directly promote osteoclastogenesis in mouse and man. Treatment with antagonistic anti-TL1A mAb protected animals in a systemic model of RA disease collagen-induced arthritis. We therefore conclude that the DR3–TL1A pathway regulates joint destruction in two murine models of arthritis and represents a potential novel target for therapeutic intervention in inflammatory joint disease.
