Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0003873 (rheumatoid arthritis)
 53,068 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

IL-17 is a newly discovered T cell-derived cytokine whose role in osteoclast development has not been fully elucidated. Treatment of cocultures of mouse hemopoietic cells and primary osteoblasts with recombinant human IL-17 induced the formation of multinucleated cells, which satisfied major criteria of osteoclasts, including tartrate-resistant acid phosphatase activity, calcitonin receptors, and pit formation on dentine slices. Direct interaction between osteoclast progenitors and osteoblasts was required for IL-17-induced osteoclastogenesis, which was completely inhibited by adding indomethacin or NS398, a selective inhibitor of cyclooxgenase-2 (COX-2). Adding IL-17 increased prostaglandin E2 (PGE2) synthesis in cocultures of bone marrow cells and osteoblasts and in single cultures of osteoblasts, but not in single cultures of bone marrow cells. In addition, IL-17 dose-dependently induced expression of osteoclast differentiation factor (ODF) mRNA in osteoblasts. ODF is a membrane-associated protein that transduces an essential signal(s) to osteoclast progenitors for differentiation into osteoclasts. Osteoclastogenesis inhibitory factor (OCIF), a decoy receptor of ODF, completely inhibited IL-17-induced osteoclast differentiation in the cocultures. Levels of IL-17 in synovial fluids were significantly higher in rheumatoid arthritis (RA) patients than osteoarthritis (OA) patients. Anti-IL-17 antibody significantly inhibited osteoclast formation induced by culture media of RA synovial tissues. These findings suggest that IL-17 first acts on osteoblasts, which stimulates both COX-2-dependent PGE2 synthesis and ODF gene expression, which in turn induce differentiation of osteoclast progenitors into mature osteoclasts, and that IL-17 is a crucial cytokine for osteoclastic bone resorption in RA patients.
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PMID:IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis. 1022 78

In spite of their adverse side effects, natural and synthetic glucocorticoids (GCs) occupy a unique role in several fields of medicine. They are potent regulators of bone cell growth and differentiation and the actions on the skeleton and related tissues depend on several factors including the dose, duration of the exposure, the steroid type and the species. In humans some of the effects are indirect, such as the regulation of intestinal calcium absorption and PTH secretion. Other effects are due to the cellular response that occurs within the bone microenvironment. It has been well established in in vitro studies that GCs can promote osteoblast differentiation from mesenchymal osteoprogenitors both in rat calvarial culture and in adherent marrow stromal cells. Moreover, GCs are able to enhance expression of the mature osteoblast phenotype, increasing mineralized nodules, osteocalcin secretion, and the bone morphogenetic protein-6 message level. However, the mechanisms by which GCs affect bone metabolism are still unclear. Recent studies with GCs on bone cells suggested that the production of cytokines and growth factors and the expression of their receptors may also be influenced by GCs. In fact, GCs are able to inhibit the synthesis of cytokines, such as interleukin-1 which stimulates bone remodeling by monocytes and macrophages. Moreover, osteoprotegerin, a recently cloned member of the tumor necrosis factor receptor family, is down-regulated by GCs, offering a possible interpretation for the induction of bone resorption by GCs. GC-induced inhibition of bone resorbing cytokines may contribute to explain the therapeutic actions of GCs in several diseases such as rheumatoid arthritis and myeloma. Furthermore, GCs modulate osteoclast recruitment, even if there is no clear explanation for a direct effect of GCs on osteoclastic precursors. Sustained stimulation of matrix degradation by isolated avian osteoclasts incubated with GCs has been reported, as well as cytotoxic effects on osteoclastic cells from neonatal rat long bones.
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PMID:Corticosteroid-induced osteoporosis: pathogenesis and prevention. 1094 68

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 inflammatory 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-CSF-dependent and is modulated by corticosteroids. Cellular (T and B cells, dendritic cells) and humoral factors in RA synovium and bone may influence osteoclast formation and bone resorption by controlling OPGL/OPG production.
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PMID:Rheumatoid arthritis synovial macrophage-osteoclast differentiation is osteoprotegerin ligand-dependent. 1095 6

Osteoclast activation is a critical cellular process for pathological bone resorption, such as erosions in rheumatoid arthritis (RA) or generalized bone loss. Among many factors triggering excessive osteoclast activity, cytokines such as IL-1 or tumour necrosis factor (TNF)-alpha play a central role. New members of the TNF receptor ligand family (namely receptor activator of nuclear factor-kappa B [RANK] and RANK ligand [RANKL]) have been discovered whose cross-interaction is mandatory for the differentiation of osteoclasts from hemopoietic precursors, in both physiological and pathological situations. Osteoprotegerin, a decoy receptor which blocks this interaction, decreases osteoclast activity and could have a fascinating therapeutic potential in conditions associated with upregulated bone resorption.
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PMID:Bone loss. Factors that regulate osteoclast differentiation: an update. 1109 58

In experimental arthritis, blocking of the receptor activator of nuclear factor kappaB ligand (RANKL) by osteoprotegerin (OPG) treatment prevents bone loss but not inflammation, suggesting that there are inflammation-related factors that regulate RANKL and OPG. However, it is not known which factors regulate RANKL and OPG in human inflammation-induced bone loss. To clarify the inflammation-related factors that play a role in periarticular osteoporosis in patients with rheumatoid arthritis (RA), the synovial fluid and synovium of the knee joint, and the periarticular cancellous bone of the femoral condyle were collected at surgery from postmenopausal women with RA or osteoarthritis (OA). All patients with RA had radiologic bone loss on the femoral condyles, while such a loss was not observed in patients with OA. The present study examined: (i) tumor necrosis factor alpha (TNFalpha), interleukin (IL)-1beta and IL-6 levels in synovial fluid: (ii) TNFalpha, IL-1beta and IL-6 messenger RNA (mRNA) expression in the synovium and the cancellous bone that contained bone marrow; and (iii) IL-6 and prostaglandin E2 (PGE2) production in cultured osteoblast-lineage cells derived from collagenase-treated cancellous bone fragments. Inflammation of the knee joints in patients with RA was confirmed by significantly higher proinflammatory cytokine levels in the synovial fluid and the synovium than those seen in patients with OA. In patients with RA, mRNA expression of IL-6, but not TNFalpha and IL-1beta, in the cancellous bone and IL-6 and PGE2 production in the osteoblast-lineage cells were significantly higher than in patients with OA. These findings suggest, for the first time, that IL-6 is involved in periarticular osteoporosis in postmenopausal women with RA. IL-6 and PGE2 released from osteoblast-lineage cells could be, at least in part, responsible for human inflammation-induced bone loss.
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PMID:Involvement of interleukin-6 and prostaglandin E2 in periarticular osteoporosis of postmenopausal women with rheumatoid arthritis. 1128 Nov 65

Skeletal mass is maintained by a balance between cells which resorb bone (osteoclasts) and cells which form bone (osteoblasts). Bone development and growth is an on-going, life-long process. Bone is formed during embryonic life, grows rapidly through childhood, and peaks around 20 years of age (formation exceeds resorption). For humans the skeleton then enters a long period, approximately 40 years, when bone mass remains relatively stable. Skeletal turnover continues but the net effect of resorption and formation on bone mass is zero. For women this ends when they enter menopause and similar bone loss occurs for men, but later in life. These opposite functions are coupled, resorption precedes formation, and osteoblasts, or their precursors, stromal cells, regulate osteoclast formation and activity. Until recently, the molecular nature of this regulation, was poorly understood. However, recent observations have identified members of the TNF family of ligands and receptors as critical regulators of osteoclastogenesis. Osteoprotegerin (OPG) a decoy receptor was first identified. Its ligand, receptor activator of nuclear factor-kappaB ligand (RANKL), was quickly found, and shown to be expressed on stromal cells and osteoblasts. Its cognate receptor, RANK, was found to be expressed in high levels on osteoclast precursors. The interaction between RANKL and RANK was shown to be required for osteoclast formation. These observations have provided a molecular understanding of the coupling between osteoclastic bone resorption and osteoblastic bone formation. Moreover, they provide a framework on which to base a clear understanding of normal (e.g. postmenopausal osteoporosis and age associated bone loss) and pathologic skeletal changes (e.g. osteopetrosis, glucocorticoid-induced osteoporosis, periodontal disease, bone metastases, Paget's disease, hyperparathyroidism, and rheumatoid arthritis).
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PMID:Control of osteoclastogenesis and bone resorption by members of the TNF family of receptors and ligands. 1131 14

Bone disease in rheumatoid arthritis affects the peri-articular and axial skeleton and is a major cause of disability. Recent studies have shown that pro-inflammatory cytokines stimulate the expression of osteoprotegerin ligand, a transmembrane protein of the tumour necrosis factor ligand superfamily, on synoviocytes and activated T cells. Osteoprotegerin ligand stimulates osteoclast formation and activation, membrane-bound and soluble osteoprotegerin ligand leading to osteoporosis as well as erosions. Bone densitometry using dual energy X-ray absorptiometry is an objective and precise method for monitoring this bone disease. Bone loss is more rapid in patients with early rheumatoid arthritis and correlates well with measures of inflammation and function. Data are emerging that monitoring bone loss of the hands in early rheumatoid arthritis could be an outcome measure and a prognostic indicator of future functional disability. Suppressing inflammation effectively and the use of bone active agents can reduce the rate of loss. In animal models, osteoprotegerin-a decoy receptor of osteoprotegerin ligand-blocks osteoporosis and erosions without affecting inflammation. The use of new biological agents could in future effectively prevent and treat rheumatoid bone disease.
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PMID:Bone changes in early rheumatoid arthritis. 1135 18

The earlier known TNF family cytokines have fairly wide physiological actions, mainly in inflammation and immune responses. It is now considered feasible to develop these large proteins themselves as therapeutic agents, but in addition, modular organisation of structures of biological proteins, and the identification of localised ligand-receptor interaction sites, allow rational design of smaller, preferably nonpeptide molecules which interfere with these protein:protein interactions. Neutralising anti-TNF antibodies and soluble TNF receptor preparations were shown to have striking anti-inflammatory activities in clinical studies, particularly in rheumatoid arthritis. As the TNF beta:TNFR1 co-crystal structure was the first in the family to be solved, rational drug design based on the ligand:receptor interaction sites is more advanced. Ligand mutations and a peptide sequence from TNF-alpha have given useful information regarding ligand-receptor interactions. Small peptide sequences from TNFR I which interact with the ligand have shown some activity in blocking the biological actions of TNF. The physiological activities of several recently-discovered ligands are more limited, giving possibilities for selective treatment of several diseases. For example, TRAIL can induce apoptosis in a wide range of tumour cells with little effects on normal tissues, both in vitro and in vivo. The co-crystal structure of TRAIL with one of its signalling receptors TRAILR 2 has been solved, opening the way to rational small molecule drug design. TRANCE (RANKligand) has modulatory effects on the dendritic cell:T cell interaction in immune responses. However, it plays a more major controlling role in the development of osteoclasts and their bone resorbing activity. In this way, it is a very interesting drug development target for the treatment of bone disorders such as osteoporosis. A recombinant secreted inhibitory receptor, osteoprotegerin (OPG), is in Phase 1 clinical trial for the treatment of hyper-resorptive bone diseases. However, OPG also blocks TRAIL and may not be sufficiently specific in long term therapy, but it is hoped that inhibitors of the interaction of TRANCE and its specific signalling receptor, RANK, can be rationally designed.
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PMID:The use of TNF family ligands and receptors and agents which modify their interaction as therapeutic agents. 1146 75

Receptor activator of nuclear factor (NF-kappaB) ligand (RANKL), its cellular receptor, receptor activator of NF-kappaB (RANK), and the decoy receptor osteoprotegerin (OPG) constitute a novel cytokine system. RANKL produced by osteoblastic lineage cells and activated T lymphocytes is the essential factor for osteoclast formation, fusion, activation, and survival, thus resulting in bone resorption and bone loss. RANKL activates its specific receptor, RANK located on osteoclasts and dendritic cells, and its signaling cascade involves stimulation of the c-jun, NF-kappaB, and serine/threonine kinase PKB/Akt pathways. The effects of RANKL are counteracted by OPG which acts as a soluble neutralizing receptor. RANKL and OPG are regulated by various hormones (glucocorticoids, vitamin D, estrogen), cytokines (tumor necrosis factor alpha, interleukins 1, 4, 6, 11, and 17), and various mesenchymal transcription factors (such as cbfa-1, peroxisome proliferator-activated receptor gamma, and Indian hedgehog). Transgenic and knock-out mice with excessive or defective production of RANKL, RANK, and OPG display the extremes of skeletal phenotypes, osteoporosis and osteopetrosis. Abnormalities of the RANKL/OPG system have been implicated in the pathogenesis of postmenopausal osteoporosis, rheumatoid arthritis, Paget's disease, periodontal disease, benign and malignant bone tumors, bone metastases, and hypercalcemia of malignancy, while administration of OPG has been demonstrated to prevent or mitigate these disorders in animal models. RANKL and OPG are also important regulators of vascular biology and calcification and of the development of a lactating mammary gland during pregnancy, indicating a crucial role for this system in extraskeletal calcium handling. The discovery and characterization of RANKL, RANK, and OPG and subsequent studies have changed the concepts of bone and calcium metabolism, have led to a detailed understanding of the pathogenesis of metabolic bone diseases, and may form the basis of innovative therapeutic strategies.
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PMID:Role of receptor activator of nuclear factor-kappaB ligand and osteoprotegerin in bone cell biology. 1148 16

Rheumatic diseases are often associated with changes in bone metabolism. Excessive production and release of cytokines and other growth factors due to inflammation, e.g. tumor necrosis factor-alpha (TNF-alpha), receptor activator of NF-kappaB ligand (RANKL), interleukins such as IL-1 and IL-6, may cause alterations in bone homeostasis leading to bone degradation. Other components such as osteoprotegerin (OPG) and possibly the ligand-receptor pair hepatocyte growth factor (HGF) and c-met may counteract this destruction, we have measured the levels of OPG, and HGF c-met, in serum, synovial fluid (SF), and cartilage from patients with rheumatoid arthritis (RA) and other arthritides. We found a) elevated levels of both OPG and HGF in SF from RA patients relative to arthritides of other causes, b) increased levels of both OPG and HGF in SF from seropositive RA patients (RA+) compared to seronegative RA patients (RA-), c) elevated levels or both OPG and HGF in serum from RA patients compared to healthy controls, d) no correlation between severity of inflammation and levels of OPG or HGF, and e) presence of HGF c-met in both cartilage and synovial tissue. The most significant elevations of OPG and HGF were found in patients with RA, the rheumatic disease most frequently associated with the development of secondary osteoporosis.
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PMID:Elevated levels of osteoprotegerin (OPG) and hepatocyte growth factor (HGF) in rheumatoid arthritis. 1157 19


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