Afsie Sabokbar | University of Oxford (original) (raw)
Papers by Afsie Sabokbar
Clinical Reviews in Allergy & Immunology, 2015
Osteoclasts are multinucleated cells derived from mononuclear phagocyte precursors (monocytes, ma... more Osteoclasts are multinucleated cells derived from mononuclear phagocyte precursors (monocytes, macrophages); in the canonical pathway of osteoclastogenesis, these cells fuse and differentiate to form specialised bone-resorbing osteoclasts in the presence of receptor activator for nuclear factor kappa B ligand (RANKL). Non-canonical pathways of osteoclastogenesis have been described in which several cytokines and growth factors are able to substitute for RANKL. These humoral factors can generally be divided into those which, like RANKL, are tumour necrosis family (TNF) superfamily members and those which are not; the former include TNFα lymphotoxin exhibiting inducible expression and competing with herpes simplex virus glycoprotein D for herpesvirus entry mediator, a receptor expressed by T lymphocytes (LIGHT), a proliferation inducing ligand (APRIL) and B cell activating factor (BAFF); the latter include transforming growth factor beta (TGF-β), interleukin-6 (IL-6), IL-8, IL-11, nerve growth factor (NGF), insulin-like growth factor-I (IGF-I) and IGF-II. This review summarises the evidence for these RANKL substitutes in inducing osteoclast differentiation from tissue-derived and circulating mononuclear phagocytes. It also assesses the role these factors are likely to play in promoting the pathological bone resorption seen in many inflammatory and neoplastic lesions of bone and joint including rheumatoid arthritis, aseptic implant loosening and primary and secondary tumours of bone.
Bone Cements and Cementing Technique, 2001
In the fibrous membrane surrounding an aseptically loose cemented implant, a heavy infiltrate of ... more In the fibrous membrane surrounding an aseptically loose cemented implant, a heavy infiltrate of foreign body macrophages is commonly seen in response to particles of polymethylmethacrylate (PMMA) bone cement and other biomaterials. We have previously shown that monocytes and macrophages responding to bone cement particles are capable of differentiating into osteoclastic cells that resorb bone. To determine whether radio-opaque additives [barium sulphate (BaSO4) and zirconium dioxide (ZrO2)] influence this process, particles of PMMA, with or without these radio-opaque agents, were added to mouse monocytes and co-cultured with osteoblast-like cells on bone slices. Osteoclast differentiation was assessed by determining the expression of the osteoclast-associated enzyme tartrate-resistant acid phosphatase (TRAP) and lacunar bone resorption. The addition of PMMA alone to these co-cultures caused no increase in TRAP expression or bone resorption relative to control co-cultures (i.e. no added particles). However, adding PMMA particles containing BaSO4 or ZrO2 caused an increase in TRAP expression and a highly significant increase in bone resorption. Particles containing BaSO4 were associated with 50% more bone resorption than particles containing ZrO2. These results suggest that radio-opaque agents in bone cement may contribute to the pathological bone resorption of aseptic loosening by enhancing macrophage-osteoclast differentiation, and that PMMA containing BaSO4 is likely to be associated with more osteolysis than PMMA containing ZrO2.
Journal of Tissue Engineering and Regenerative Medicine, 2013
In order to examine the differentiation potential of the tenocytes expanded in our defined cultur... more In order to examine the differentiation potential of the tenocytes expanded in our defined culture medium (reported previously) and the effect of sequential combination of the two culture conditions on human tenocytes, a two-dimensional and three-dimensional experimental approach was used. Human tenocytes were sequentially exposed to 1% fetal bovine serum (FBS) + 50 ng/ml plateletderived growth factor-BB (PDGF BB) + 50 ng/ml basic fibroblast growth factor (bFGF) for the first 14 days (expansion phase) followed by a further 14-day culture in the presence of 10 ng/ml transforming growth factor β-3 plus 50 ng/ml insulin-like growth factor 1, but in the absence of serum (differentiation phase). The results showed that by sequential treatment of human tenocytes maintaining a long-term two-dimensional tenocyte culture in vitro for up to 28 days was possible. These findings were further verified using a three-dimensional scaffold (Bombyx silk) whereby the tendon-like constructs formed resembled macroscopically and microscopically the constructs formed in 10% FBS supplemented culture media and the human hamstring tendon. These findings were further substantiated using haematoxylin and eosin staining, scanning electron microscopy and by immunohistochemical detection of type I collagen. In addition, the mechanical properties of the three-dimensional constructs were determined to be significantly superior to that of the natural human hamstring tendon. This is the first report to demonstrate a possible approach in expanding and differentiating human tenocytes for tendon tissue engineering.
The Journal of Pathology, 2000
Osteoprotegerin ligand (OPGL) is a newly discovered molecule which is essential for osteoclast di... more Osteoprotegerin ligand (OPGL) is a newly discovered molecule which is essential for osteoclast differentiation. Both OPGL and its soluble decoy receptor, osteoprotegerin (OPG), which inhibits osteoclast formation, are known to be produced by osteoblasts and in¯ammatory cells found in the rheumatoid arthritis (RA) synovium. In this study, RA synovial macrophages were incubated in the presence or absence of OPGL, macrophage-colony stimulating factor (M-CSF), and dexamethasone for various time points. The results indicated that osteoclast formation from RA synovial macrophages is OPGL-dependent and that OPGL and M-CSF are the only humoral factors required for RA synovial macrophage±osteoclast differentiation. OPG was found to inhibit osteoclast formation by RA synovial macrophages in a dose-dependent manner. This study has shown that macrophages isolated from the synovium of RA patients are capable of differentiating into osteoclastic bone-resorbing cells; this process is OPGL-and M-CSFdependent and is modulated by corticosteroids. Cellular (T and B cells, dendritic cells) and humoral factors in RA synovium and bone may in¯uence osteoclast formation and bone resorption by controlling OPGL/OPG production.
The Journal of Arthroplasty, 1995
Concentrations of prostaglandin E 2, interleukin-6, and interleukin-8 were determined in the hip ... more Concentrations of prostaglandin E 2, interleukin-6, and interleukin-8 were determined in the hip joint synovial fluid of 20 patients undergoing primary (n = 12) and revision (n = 8) total hip arthroplasties. Levels of soluble adhesion molecules were also investigated in these patients. There was a significant and marked increase in levels of prostaglandin E 2 (P < .001), interleukin-6 (P < .011), interleukin-8 (P < .0002), soluble intercellular adhesion molecule 1 (P < .07), soluble vascular adhesion molecule 1 (P < .0006), and soluble endothelial leukocyte adhesion molecule 1 (P < .0003) in joint fluid of patients undergoing revision. On the basis of these observations, it is suggested that synovial fluid and its inflammatory contents could play a significant role in the pathogenesis of aseptic loosening in total hip arthroplasties.
Cells Tissues Organs, 2012
We have established that human tenocytes can differentiate in the absence of exogenous fetal bovi... more We have established that human tenocytes can differentiate in the absence of exogenous fetal bovine serum (FBS) but in the presence of insulin-like growth factor-1 (IGF-1) and transforming growth factor-β3 (TGF-β3). The extent of tenocyte differentiation was assessed by examining cell survival, collagen synthesis, cell morphology and expression of tenocyte differentiation markers such as scleraxis (Scx), tenomodulin (Tnmd), collagen type I (Col-I) and decorin (Dcn). Our results indicate that 50 ng/ml IGF-1 and 10 ng/ml TGF-β3 (in the absence of FBS) were capable of maintaining in vitro human tenocyte survival in 14-day cultures. The extent of collagen synthesis and messenger ribonucleic acid expression of Scx, Tnmd, Col-I and Dcn were significantly upregulated in response to IGF-1 and TGF-β3. These findings have shown for the first time that human tenocytes can be maintained in long-term culture, in serum-free conditions, making this approach a suitable one for the purpose of tendon...
Monocytes and macrophages are capable of degrading both the mineral and organic components of bon... more Monocytes and macrophages are capable of degrading both the mineral and organic components of bone and are known to secrete local factors which stimulate host osteoclastic bone resorption. Recent studies have shown that monocytes and macrophages, including those isolated from neoplastic and inflammatory lesions, can also be induced to differentiate into cells that show all the cytochemical and functional characteristics of mature osteoclasts, including lacunar bone resorption. Monocyte/macrophage-osteoclast differentiation occurs in the presence of osteoblasts/bone stromal cells (which express osteoclast differentiation factor) and macrophage-colony stimulating factor and is inhibited by osteoprotegerin. Various systemic hormones and local factors (e.g. cytokines, growth factors, prostaglandins) modulate osteoclast formation by controlling these cellular and humoral elements. Various pathological lesions of bone and joint (e.g. carcinomatous metastases, arthritis, aseptic loosening)...
ABSTRACT Background: The Birmingham Vasculitis Activity Score is a clinical tool to quantify dise... more ABSTRACT Background: The Birmingham Vasculitis Activity Score is a clinical tool to quantify disease activity in systemic vasculitis. Following its extensive use, a previous version of BVAS has been revised to improve the face validity and the feasibility. Changes were made and approved by an expert committee. Objective: To validate the third version of the Birmingham Vasculitis Activity Score (BVAS version 3) Methods: In a series of prospective, multi-centre studies, different aspects of the BVAS (version 3) were validated in patients with systemic vasculitis. The data collection was done using standardized data entry forms. The studies were approved by local ethics committees. The recruitment of controls was approved by the local clinical audit and effectiveness department. Results: The convergent validity was established by correlating the BVAS (version 3) to the physician’s treatment decision (Spearman's ρ 0.66, 95% CI 0.59-0.72), BVAS1 of version 2 (ρ 0.94, 95% CI 0.92-0.96), BVAS2 of version 2 in patients with persistent disease (ρ 0.60, 95% CI 0.21-0.83), C-reactive protein levels (�� 0.43, 95% CI 0.31-0.54), physician's global assessment (ρ 0.91, 95% CI 0.89-0.93), and vasculitis activity index (ρ 0.88, 95%CI 0.86-0.91). The BVAS (version 3) was reproducible and repeatable (intra-class correlation coefficients were 0.96 (95%CI 0.95-0.97) and 0.96 (95%CI 0.92-0.97) respectively). The BVAS (version 3) was sensitive to changing disease status with a fall of 16.9 (95% CI 14.8-18.9) units (P<0.001, paired t test) after 3 months of treatment. The BVAS (version 3) demonstrated an ability to differentiate systemic vasculitis from some non-vasculitis conditions. Conclusion: BVAS (version 3) is validated for use in clinical trials of systemic vasculitis. It is repeatable, reproducible, sensitive to change and can differentiate between systemic vasculitis and some non-vasculitic rheumatological conditions.
Introduction: Osteoclast-like multinucleated giant cells (MNGCs) are found in a number of soft ti... more Introduction: Osteoclast-like multinucleated giant cells (MNGCs) are found in a number of soft tissue sarcomas including malignant fibrous histiocytoma and leiomyosarcoma. The nature of these MNGCs is poorly understood and the cellular mechanisms underlying their accumulation in sarcomas is not known. Methods: We analysed by immunohistochemistry the expression of osteoclast, macrophage and smooth muscle markers by mononuclear and multinucleated cells in two cases of giant cell-rich leiomyosarcoma. We also characterised the role of mononuclear stromal cells and tumour-associated macrophages in the formation of MNGCs by RT-PCR, cell culture studies and immunohistochemistry/histochemistry for macrophage, osteoclast and smooth muscle markers Results: MNCGs in giant cell-rich leiomyosarcoma expressed an osteoclast-like phenotype, being negative for smooth muscle actin and CD14 but positive for tartrate-resistant acid phophatase (TRAP), CD45, CD68 and vitronectin receptor (VNR). Scattered...
The Journal of Pathology, 2000
We investigate how the properties of dark energy affect the cosmological measurements of neutrino... more We investigate how the properties of dark energy affect the cosmological measurements of neutrino mass and extra relativistic degrees of freedom. We limit ourselves to the most basic extensions of Λ cold dark matter (CDM) model, i.e. the wCDM model with one additional parameter w, and the w 0 w a CDM model with two additional parameters, w 0 and w a. In the cosmological fits, we employ the 2015 cosmic microwave background temperature and polarization data from the Planck mission, in combination with low-redshift measurements such as the baryon acoustic oscillations, Type Ia supernovae and the Hubble constant (H 0). Given effects of massive neutrinos on large-scale structure, we further include weak lensing, redshift space distortion, Sunyaev-Zeldovich cluster counts and Planck lensing data. We show that, though the cosmological constant Λ is still consistent with the current data, a phantom dark energy (w < −1) or an early phantom dark energy (i.e. quintom evolving from w < −1 to w > −1) is slightly more favoured by current observations, which leads to the fact that in both wCDM and w 0 w a CDM models we obtain a larger upper limit of m ν. We also show that in the three dark energy models, the constraints on N eff are in good accordance with each other, all in favour of the standard value 3.046, which indicates that the dark energy parameters almost have no impact on constraining N eff. Therefore, we conclude that the dark energy parameters can exert a significant influence on the cosmological weighing of neutrinos, but almost cannot affect the constraint on dark radiation.
Journal of Bone and Mineral Research, 1995
Desde un enfoque decolonial, este artículo recupera el concepto de extractivismo, a través de una... more Desde un enfoque decolonial, este artículo recupera el concepto de extractivismo, a través de una revisión crítica de las prácticas del capitalismo y del colonialismo, ambas inherentes, originarias de una misma raíz: el pensamiento occidentalo-céntrico. Las mutaciones del extractivismo económico en su expansión planetaria resultan evidentes en este texto, en las formas que describe de pillaje cognitivo (epistémico) y de constricción de la existencia (ontológico), además del desastre medioambiental que han ido provocando la aceleración de captación de recursos y materias primas, así como las imposiciones cada vez más violentas, armadas y genocidas, de ese capitalismo colonial, especialmente en el continente americano. El artículo, desde la voz de las víctimas, ofrece paradigmas y alternativas partiendo de la crítica de esas prácticas epistemicidas y de las resistencias indígenas al no-ser.
Rheumatology, Apr 1, 2018
Background: Inflammation, local joint destruction and systemic bone loss are common complications... more Background: Inflammation, local joint destruction and systemic bone loss are common complications in patients with rheumatoid arthritis (RA). We have identified that localised pre-receptor activation of glucocorticoids (GC) by the enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11b-HSD1) is increased within sites of inflammation and surrounding tissues, such as synovium and bone. Whilst this greatly increases local bioavailability of cortisol, which supports resolution of inflammation, in chronic disease, GCs drive may drive catabolic pathways that contribute to joint destruction and systemic bone loss. Methods: To determine the contribution of 11b-HSD1 activated glucocorticoids to joint destruction and inflammatory bone loss, we crossed an 11b-HSD1 null mouse onto a transgenic murine model of chronic polyarthritis (TNF-Tg) to generate TNF-tg 11bKO mice. Clinical measures of joint inflammation, mobility and behaviour were collected between four and nine weeks of age. Paw swelling was determined using calliper measurements. Histology was assessed in formalin fixed sections following staining with haematoxylin and eosin, safranin O or TRAP staining. Juxta articular and systemic bone losses were measured by micro-Ct. synovitis was determined by Image J analysis of histology sections. Results: 11b-HSD1 was completely knocked out within sites of inflammation in the TNF-tg 11bKO mouse. At nine weeks, both clinical and inflammation scores were markedly exacerbated in TNF-tg 11bKO animals relative to TNF-tg counterparts (inflammation score; TNF-tg, 4.3 AE 2.26 versus TNF-tg 11bKO , 11.08 AE 0.86; p < 0.001). This was supported by marked increases in joint swelling and juxta articular bone loss from these animals (erosion scores, TNFtg, 5.2 AE 0.61 versus TNF-tg 11bKO , 9.0 AE 0.66; p < 0.005). Closer examination of joint destruction revealed that the pannus was larger and more extensive within subchondral bone, whilst evidence of cartilage degradation was significantly worse in the TNF-tg 11bKO mouse (synovitis size, TNFtg, 26763 (AU) AE 3200 versus TNF-tg 11bKO , 530276 AE 3225; p < 0.005). Systemic bone loss determined by bone volume to tissue volume (BV/ TV), trabecular thickness (TT) and trabecular number (TN) was also greatly exacerbated within the TNF-tg 11bKO mouse (TNF-tg, BV/TV 5.7 AE 0.75, TT 73.5 AE 6.4, TN 0.00077 AE 0.00004 versus TNF-tg 11bKO BV/ TV 1.8 AE 0.36, TT 7359.77 AE 3.7, TN 0.0003 AE 0.00005; P < 0.001, P < 0.005, P < 0.001 respectively). Conclusion: This study demonstrates that rather than contributing to catabolic pathways of tissue destruction, local GC activation by 11b-HSD1 is critical in mediating the suppression inflammation, joint destruction, synovitis and inflammatory bone loss in this murine model of chronic polyarthritis. Disclosures: The authors have declared no conflicts of interest.
THURSDAY, 14 JUNE 2018, 2018
Background: IL-17RD is a member of the IL-17 receptor family. In contrast to the other IL-17 rece... more Background: IL-17RD is a member of the IL-17 receptor family. In contrast to the other IL-17 receptors, IL-17RA,-RB,-RC and-RE, little is known about the ligand and function of IL-17RD. Recently, IL-17RD has been described to negatively regulate a selection of IL-17A responsive genes. IL-17RD is therefore proposed to limit IL-17A signalling. Objectives: In this study we examined IL-17RD expression in multiple cells types and its role in the development of collagen induced arthritis. Methods: Human synovial fibroblasts from Rheumatoid Arthritis (RA) patients were stimulated with tumour necrosis factor a (TNFa), interleukin 1 b (IL-1b) or IL-17A for multiple time points. IL-17RD expression levels were measured via qPCR. Collagen induced arthritis (CIA) was induced in IL-17RD knockout mice and wildtype littermates. At days 1 and 21, mice were immunised intradermally with chicken collagen type II in complete Freund's adjuvant (CFA). Mice were scored 3 times a week for clinical disease defined as swollen joints with a maximum score of 8. Due to ethical reasons, mice were removed from the experiments when they reached a score of 6. CD4 + memory T cells, CD8 + memory T cells, CD19 + B cells and monocytes were isolated from WT spleens and analysed for IL-17RD expression. Blood neutrophil migration assays were performed in vitro using WT and IL-17RD deficient (IL-17RD KO) mouse synovial fibroblasts. Results: Human synovial fibroblasts from RA patients have baseline expression of IL-17RD. Upon stimulation with TNFa a significant downregulation of IL-17RD expression was measured from 24 hours onwards. IL1b stimulation had a similar effect as TNFa on IL-17RD expression. Lack of IL-17RD did not result in differences in CIA severity, but the incidence of CIA was reduced. IL-17RD is mainly expressed in synovial fibroblasts. IL-17RD KO synovial fibroblasts attract less neutrophils likely by lower production of neutrophil attractants. Conclusions: An inflammatory environment causes synovial fibroblasts to downregulate IL-17RD expression. Lack of IL-17RD reduces the incidence CIA, which is an IL-17-driven model. The decrease in CIA incidence is likely explained via the reduced attraction of neutrophils to the site of inflammation.
Clinical Reviews in Allergy & Immunology, 2015
Osteoclasts are multinucleated cells derived from mononuclear phagocyte precursors (monocytes, ma... more Osteoclasts are multinucleated cells derived from mononuclear phagocyte precursors (monocytes, macrophages); in the canonical pathway of osteoclastogenesis, these cells fuse and differentiate to form specialised bone-resorbing osteoclasts in the presence of receptor activator for nuclear factor kappa B ligand (RANKL). Non-canonical pathways of osteoclastogenesis have been described in which several cytokines and growth factors are able to substitute for RANKL. These humoral factors can generally be divided into those which, like RANKL, are tumour necrosis family (TNF) superfamily members and those which are not; the former include TNFα lymphotoxin exhibiting inducible expression and competing with herpes simplex virus glycoprotein D for herpesvirus entry mediator, a receptor expressed by T lymphocytes (LIGHT), a proliferation inducing ligand (APRIL) and B cell activating factor (BAFF); the latter include transforming growth factor beta (TGF-β), interleukin-6 (IL-6), IL-8, IL-11, nerve growth factor (NGF), insulin-like growth factor-I (IGF-I) and IGF-II. This review summarises the evidence for these RANKL substitutes in inducing osteoclast differentiation from tissue-derived and circulating mononuclear phagocytes. It also assesses the role these factors are likely to play in promoting the pathological bone resorption seen in many inflammatory and neoplastic lesions of bone and joint including rheumatoid arthritis, aseptic implant loosening and primary and secondary tumours of bone.
Bone Cements and Cementing Technique, 2001
In the fibrous membrane surrounding an aseptically loose cemented implant, a heavy infiltrate of ... more In the fibrous membrane surrounding an aseptically loose cemented implant, a heavy infiltrate of foreign body macrophages is commonly seen in response to particles of polymethylmethacrylate (PMMA) bone cement and other biomaterials. We have previously shown that monocytes and macrophages responding to bone cement particles are capable of differentiating into osteoclastic cells that resorb bone. To determine whether radio-opaque additives [barium sulphate (BaSO4) and zirconium dioxide (ZrO2)] influence this process, particles of PMMA, with or without these radio-opaque agents, were added to mouse monocytes and co-cultured with osteoblast-like cells on bone slices. Osteoclast differentiation was assessed by determining the expression of the osteoclast-associated enzyme tartrate-resistant acid phosphatase (TRAP) and lacunar bone resorption. The addition of PMMA alone to these co-cultures caused no increase in TRAP expression or bone resorption relative to control co-cultures (i.e. no added particles). However, adding PMMA particles containing BaSO4 or ZrO2 caused an increase in TRAP expression and a highly significant increase in bone resorption. Particles containing BaSO4 were associated with 50% more bone resorption than particles containing ZrO2. These results suggest that radio-opaque agents in bone cement may contribute to the pathological bone resorption of aseptic loosening by enhancing macrophage-osteoclast differentiation, and that PMMA containing BaSO4 is likely to be associated with more osteolysis than PMMA containing ZrO2.
Journal of Tissue Engineering and Regenerative Medicine, 2013
In order to examine the differentiation potential of the tenocytes expanded in our defined cultur... more In order to examine the differentiation potential of the tenocytes expanded in our defined culture medium (reported previously) and the effect of sequential combination of the two culture conditions on human tenocytes, a two-dimensional and three-dimensional experimental approach was used. Human tenocytes were sequentially exposed to 1% fetal bovine serum (FBS) + 50 ng/ml plateletderived growth factor-BB (PDGF BB) + 50 ng/ml basic fibroblast growth factor (bFGF) for the first 14 days (expansion phase) followed by a further 14-day culture in the presence of 10 ng/ml transforming growth factor β-3 plus 50 ng/ml insulin-like growth factor 1, but in the absence of serum (differentiation phase). The results showed that by sequential treatment of human tenocytes maintaining a long-term two-dimensional tenocyte culture in vitro for up to 28 days was possible. These findings were further verified using a three-dimensional scaffold (Bombyx silk) whereby the tendon-like constructs formed resembled macroscopically and microscopically the constructs formed in 10% FBS supplemented culture media and the human hamstring tendon. These findings were further substantiated using haematoxylin and eosin staining, scanning electron microscopy and by immunohistochemical detection of type I collagen. In addition, the mechanical properties of the three-dimensional constructs were determined to be significantly superior to that of the natural human hamstring tendon. This is the first report to demonstrate a possible approach in expanding and differentiating human tenocytes for tendon tissue engineering.
The Journal of Pathology, 2000
Osteoprotegerin ligand (OPGL) is a newly discovered molecule which is essential for osteoclast di... more Osteoprotegerin ligand (OPGL) is a newly discovered molecule which is essential for osteoclast differentiation. Both OPGL and its soluble decoy receptor, osteoprotegerin (OPG), which inhibits osteoclast formation, are known to be produced by osteoblasts and in¯ammatory cells found in the rheumatoid arthritis (RA) synovium. In this study, RA synovial macrophages were incubated in the presence or absence of OPGL, macrophage-colony stimulating factor (M-CSF), and dexamethasone for various time points. The results indicated that osteoclast formation from RA synovial macrophages is OPGL-dependent and that OPGL and M-CSF are the only humoral factors required for RA synovial macrophage±osteoclast differentiation. OPG was found to inhibit osteoclast formation by RA synovial macrophages in a dose-dependent manner. This study has shown that macrophages isolated from the synovium of RA patients are capable of differentiating into osteoclastic bone-resorbing cells; this process is OPGL-and M-CSFdependent and is modulated by corticosteroids. Cellular (T and B cells, dendritic cells) and humoral factors in RA synovium and bone may in¯uence osteoclast formation and bone resorption by controlling OPGL/OPG production.
The Journal of Arthroplasty, 1995
Concentrations of prostaglandin E 2, interleukin-6, and interleukin-8 were determined in the hip ... more Concentrations of prostaglandin E 2, interleukin-6, and interleukin-8 were determined in the hip joint synovial fluid of 20 patients undergoing primary (n = 12) and revision (n = 8) total hip arthroplasties. Levels of soluble adhesion molecules were also investigated in these patients. There was a significant and marked increase in levels of prostaglandin E 2 (P < .001), interleukin-6 (P < .011), interleukin-8 (P < .0002), soluble intercellular adhesion molecule 1 (P < .07), soluble vascular adhesion molecule 1 (P < .0006), and soluble endothelial leukocyte adhesion molecule 1 (P < .0003) in joint fluid of patients undergoing revision. On the basis of these observations, it is suggested that synovial fluid and its inflammatory contents could play a significant role in the pathogenesis of aseptic loosening in total hip arthroplasties.
Cells Tissues Organs, 2012
We have established that human tenocytes can differentiate in the absence of exogenous fetal bovi... more We have established that human tenocytes can differentiate in the absence of exogenous fetal bovine serum (FBS) but in the presence of insulin-like growth factor-1 (IGF-1) and transforming growth factor-β3 (TGF-β3). The extent of tenocyte differentiation was assessed by examining cell survival, collagen synthesis, cell morphology and expression of tenocyte differentiation markers such as scleraxis (Scx), tenomodulin (Tnmd), collagen type I (Col-I) and decorin (Dcn). Our results indicate that 50 ng/ml IGF-1 and 10 ng/ml TGF-β3 (in the absence of FBS) were capable of maintaining in vitro human tenocyte survival in 14-day cultures. The extent of collagen synthesis and messenger ribonucleic acid expression of Scx, Tnmd, Col-I and Dcn were significantly upregulated in response to IGF-1 and TGF-β3. These findings have shown for the first time that human tenocytes can be maintained in long-term culture, in serum-free conditions, making this approach a suitable one for the purpose of tendon...
Monocytes and macrophages are capable of degrading both the mineral and organic components of bon... more Monocytes and macrophages are capable of degrading both the mineral and organic components of bone and are known to secrete local factors which stimulate host osteoclastic bone resorption. Recent studies have shown that monocytes and macrophages, including those isolated from neoplastic and inflammatory lesions, can also be induced to differentiate into cells that show all the cytochemical and functional characteristics of mature osteoclasts, including lacunar bone resorption. Monocyte/macrophage-osteoclast differentiation occurs in the presence of osteoblasts/bone stromal cells (which express osteoclast differentiation factor) and macrophage-colony stimulating factor and is inhibited by osteoprotegerin. Various systemic hormones and local factors (e.g. cytokines, growth factors, prostaglandins) modulate osteoclast formation by controlling these cellular and humoral elements. Various pathological lesions of bone and joint (e.g. carcinomatous metastases, arthritis, aseptic loosening)...
ABSTRACT Background: The Birmingham Vasculitis Activity Score is a clinical tool to quantify dise... more ABSTRACT Background: The Birmingham Vasculitis Activity Score is a clinical tool to quantify disease activity in systemic vasculitis. Following its extensive use, a previous version of BVAS has been revised to improve the face validity and the feasibility. Changes were made and approved by an expert committee. Objective: To validate the third version of the Birmingham Vasculitis Activity Score (BVAS version 3) Methods: In a series of prospective, multi-centre studies, different aspects of the BVAS (version 3) were validated in patients with systemic vasculitis. The data collection was done using standardized data entry forms. The studies were approved by local ethics committees. The recruitment of controls was approved by the local clinical audit and effectiveness department. Results: The convergent validity was established by correlating the BVAS (version 3) to the physician’s treatment decision (Spearman's ρ 0.66, 95% CI 0.59-0.72), BVAS1 of version 2 (ρ 0.94, 95% CI 0.92-0.96), BVAS2 of version 2 in patients with persistent disease (ρ 0.60, 95% CI 0.21-0.83), C-reactive protein levels (�� 0.43, 95% CI 0.31-0.54), physician's global assessment (ρ 0.91, 95% CI 0.89-0.93), and vasculitis activity index (ρ 0.88, 95%CI 0.86-0.91). The BVAS (version 3) was reproducible and repeatable (intra-class correlation coefficients were 0.96 (95%CI 0.95-0.97) and 0.96 (95%CI 0.92-0.97) respectively). The BVAS (version 3) was sensitive to changing disease status with a fall of 16.9 (95% CI 14.8-18.9) units (P<0.001, paired t test) after 3 months of treatment. The BVAS (version 3) demonstrated an ability to differentiate systemic vasculitis from some non-vasculitis conditions. Conclusion: BVAS (version 3) is validated for use in clinical trials of systemic vasculitis. It is repeatable, reproducible, sensitive to change and can differentiate between systemic vasculitis and some non-vasculitic rheumatological conditions.
Introduction: Osteoclast-like multinucleated giant cells (MNGCs) are found in a number of soft ti... more Introduction: Osteoclast-like multinucleated giant cells (MNGCs) are found in a number of soft tissue sarcomas including malignant fibrous histiocytoma and leiomyosarcoma. The nature of these MNGCs is poorly understood and the cellular mechanisms underlying their accumulation in sarcomas is not known. Methods: We analysed by immunohistochemistry the expression of osteoclast, macrophage and smooth muscle markers by mononuclear and multinucleated cells in two cases of giant cell-rich leiomyosarcoma. We also characterised the role of mononuclear stromal cells and tumour-associated macrophages in the formation of MNGCs by RT-PCR, cell culture studies and immunohistochemistry/histochemistry for macrophage, osteoclast and smooth muscle markers Results: MNCGs in giant cell-rich leiomyosarcoma expressed an osteoclast-like phenotype, being negative for smooth muscle actin and CD14 but positive for tartrate-resistant acid phophatase (TRAP), CD45, CD68 and vitronectin receptor (VNR). Scattered...
The Journal of Pathology, 2000
We investigate how the properties of dark energy affect the cosmological measurements of neutrino... more We investigate how the properties of dark energy affect the cosmological measurements of neutrino mass and extra relativistic degrees of freedom. We limit ourselves to the most basic extensions of Λ cold dark matter (CDM) model, i.e. the wCDM model with one additional parameter w, and the w 0 w a CDM model with two additional parameters, w 0 and w a. In the cosmological fits, we employ the 2015 cosmic microwave background temperature and polarization data from the Planck mission, in combination with low-redshift measurements such as the baryon acoustic oscillations, Type Ia supernovae and the Hubble constant (H 0). Given effects of massive neutrinos on large-scale structure, we further include weak lensing, redshift space distortion, Sunyaev-Zeldovich cluster counts and Planck lensing data. We show that, though the cosmological constant Λ is still consistent with the current data, a phantom dark energy (w < −1) or an early phantom dark energy (i.e. quintom evolving from w < −1 to w > −1) is slightly more favoured by current observations, which leads to the fact that in both wCDM and w 0 w a CDM models we obtain a larger upper limit of m ν. We also show that in the three dark energy models, the constraints on N eff are in good accordance with each other, all in favour of the standard value 3.046, which indicates that the dark energy parameters almost have no impact on constraining N eff. Therefore, we conclude that the dark energy parameters can exert a significant influence on the cosmological weighing of neutrinos, but almost cannot affect the constraint on dark radiation.
Journal of Bone and Mineral Research, 1995
Desde un enfoque decolonial, este artículo recupera el concepto de extractivismo, a través de una... more Desde un enfoque decolonial, este artículo recupera el concepto de extractivismo, a través de una revisión crítica de las prácticas del capitalismo y del colonialismo, ambas inherentes, originarias de una misma raíz: el pensamiento occidentalo-céntrico. Las mutaciones del extractivismo económico en su expansión planetaria resultan evidentes en este texto, en las formas que describe de pillaje cognitivo (epistémico) y de constricción de la existencia (ontológico), además del desastre medioambiental que han ido provocando la aceleración de captación de recursos y materias primas, así como las imposiciones cada vez más violentas, armadas y genocidas, de ese capitalismo colonial, especialmente en el continente americano. El artículo, desde la voz de las víctimas, ofrece paradigmas y alternativas partiendo de la crítica de esas prácticas epistemicidas y de las resistencias indígenas al no-ser.
Rheumatology, Apr 1, 2018
Background: Inflammation, local joint destruction and systemic bone loss are common complications... more Background: Inflammation, local joint destruction and systemic bone loss are common complications in patients with rheumatoid arthritis (RA). We have identified that localised pre-receptor activation of glucocorticoids (GC) by the enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11b-HSD1) is increased within sites of inflammation and surrounding tissues, such as synovium and bone. Whilst this greatly increases local bioavailability of cortisol, which supports resolution of inflammation, in chronic disease, GCs drive may drive catabolic pathways that contribute to joint destruction and systemic bone loss. Methods: To determine the contribution of 11b-HSD1 activated glucocorticoids to joint destruction and inflammatory bone loss, we crossed an 11b-HSD1 null mouse onto a transgenic murine model of chronic polyarthritis (TNF-Tg) to generate TNF-tg 11bKO mice. Clinical measures of joint inflammation, mobility and behaviour were collected between four and nine weeks of age. Paw swelling was determined using calliper measurements. Histology was assessed in formalin fixed sections following staining with haematoxylin and eosin, safranin O or TRAP staining. Juxta articular and systemic bone losses were measured by micro-Ct. synovitis was determined by Image J analysis of histology sections. Results: 11b-HSD1 was completely knocked out within sites of inflammation in the TNF-tg 11bKO mouse. At nine weeks, both clinical and inflammation scores were markedly exacerbated in TNF-tg 11bKO animals relative to TNF-tg counterparts (inflammation score; TNF-tg, 4.3 AE 2.26 versus TNF-tg 11bKO , 11.08 AE 0.86; p < 0.001). This was supported by marked increases in joint swelling and juxta articular bone loss from these animals (erosion scores, TNFtg, 5.2 AE 0.61 versus TNF-tg 11bKO , 9.0 AE 0.66; p < 0.005). Closer examination of joint destruction revealed that the pannus was larger and more extensive within subchondral bone, whilst evidence of cartilage degradation was significantly worse in the TNF-tg 11bKO mouse (synovitis size, TNFtg, 26763 (AU) AE 3200 versus TNF-tg 11bKO , 530276 AE 3225; p < 0.005). Systemic bone loss determined by bone volume to tissue volume (BV/ TV), trabecular thickness (TT) and trabecular number (TN) was also greatly exacerbated within the TNF-tg 11bKO mouse (TNF-tg, BV/TV 5.7 AE 0.75, TT 73.5 AE 6.4, TN 0.00077 AE 0.00004 versus TNF-tg 11bKO BV/ TV 1.8 AE 0.36, TT 7359.77 AE 3.7, TN 0.0003 AE 0.00005; P < 0.001, P < 0.005, P < 0.001 respectively). Conclusion: This study demonstrates that rather than contributing to catabolic pathways of tissue destruction, local GC activation by 11b-HSD1 is critical in mediating the suppression inflammation, joint destruction, synovitis and inflammatory bone loss in this murine model of chronic polyarthritis. Disclosures: The authors have declared no conflicts of interest.
THURSDAY, 14 JUNE 2018, 2018
Background: IL-17RD is a member of the IL-17 receptor family. In contrast to the other IL-17 rece... more Background: IL-17RD is a member of the IL-17 receptor family. In contrast to the other IL-17 receptors, IL-17RA,-RB,-RC and-RE, little is known about the ligand and function of IL-17RD. Recently, IL-17RD has been described to negatively regulate a selection of IL-17A responsive genes. IL-17RD is therefore proposed to limit IL-17A signalling. Objectives: In this study we examined IL-17RD expression in multiple cells types and its role in the development of collagen induced arthritis. Methods: Human synovial fibroblasts from Rheumatoid Arthritis (RA) patients were stimulated with tumour necrosis factor a (TNFa), interleukin 1 b (IL-1b) or IL-17A for multiple time points. IL-17RD expression levels were measured via qPCR. Collagen induced arthritis (CIA) was induced in IL-17RD knockout mice and wildtype littermates. At days 1 and 21, mice were immunised intradermally with chicken collagen type II in complete Freund's adjuvant (CFA). Mice were scored 3 times a week for clinical disease defined as swollen joints with a maximum score of 8. Due to ethical reasons, mice were removed from the experiments when they reached a score of 6. CD4 + memory T cells, CD8 + memory T cells, CD19 + B cells and monocytes were isolated from WT spleens and analysed for IL-17RD expression. Blood neutrophil migration assays were performed in vitro using WT and IL-17RD deficient (IL-17RD KO) mouse synovial fibroblasts. Results: Human synovial fibroblasts from RA patients have baseline expression of IL-17RD. Upon stimulation with TNFa a significant downregulation of IL-17RD expression was measured from 24 hours onwards. IL1b stimulation had a similar effect as TNFa on IL-17RD expression. Lack of IL-17RD did not result in differences in CIA severity, but the incidence of CIA was reduced. IL-17RD is mainly expressed in synovial fibroblasts. IL-17RD KO synovial fibroblasts attract less neutrophils likely by lower production of neutrophil attractants. Conclusions: An inflammatory environment causes synovial fibroblasts to downregulate IL-17RD expression. Lack of IL-17RD reduces the incidence CIA, which is an IL-17-driven model. The decrease in CIA incidence is likely explained via the reduced attraction of neutrophils to the site of inflammation.