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

Our objective was to clarify the heterogeneity in response to infliximab treatment in rheumatoid arthritis (RA); to this end, a bioassay was designed to explore the contribution of circulating tumour necrosis factor (TNF)-alpha bioactivity and its possible link to response. The bioassay is based on the induction of IL-6 and osteoprotegerin (OPG) production by synoviocytes in response to TNF-alpha. RA synoviocytes were cultured with TNF-alpha (5 ng/ml) and 42 RA plasma samples collected just before starting therapy. Levels of IL-6 and OPG were measured in supernatants. In 20 of the patients, plasma samples collected before and 4 hours after the first and the ninth infusions were tested in the same way. Plasma concentrations of TNF-alpha and p55 and p75 soluble receptors were measured using ELISA. TNF-alpha induced IL-6 and OPG production by synoviocytes, which was further increased with patient plasma dilutions and inhibited by infliximab. With plasma samples obtained before the first infusion, the IL-6-induced production was greater in patients with a good clinical response than in the poor responders (44.4 +/- 23.3 ng/ml versus 27.4 +/- 20.9 ng/ml; P = 0.05). This high circulating TNF-alpha bioactivity was strongly inhibited with the first infliximab infusion. The difference between IL-6 levels induced with plasma samples obtained before and 4 hours after the first infusion was greater in patients with a good clinical response (40.0 +/- 23.7 ng/ml versus 3.4 +/- 10.0 ng/ml; P = 0.001). Similar findings were obtained for OPG production (7.0 +/- 6.2 ng/ml versus 0.0 +/- 3.0 ng/ml; P < 0.05). Levels of circulating TNF-alpha bioactivity were predictive of clinical response to TNF-alpha inhibition, confirming a key role for TNF-alpha in these RA patients.
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PMID:Circulating tumour necrosis factor-alpha bioactivity in rheumatoid arthritis patients treated with infliximab: link to clinical response. 1564 35

Over the past decade there have been major advances in our understanding of the factors that regulate osteoclast formation and activity. It is now apparent that receptor activator NFkappaB (RANK), its ligand, RANKL (also known as TRANCE, osteoclast differentiation factor and osteoprotegerin (OPG) ligand) and the natural RANKL inhibitor, OPG, are the key factors regulating osteoclast formation in normal bone physiology. The molecular interactions of these molecules regulate osteoclast formation and subsequent bone loss in disease and there is now strong evidence that the bone loss associated with inflammatory diseases, such as rheumatoid arthritis, periodontal disease and peri-implant loosening, is regulated by the action of RANK, RANKL, and OPG. These molecules are targets for the pharmacological regulation of severe bone loss in several common inflammatory diseases.
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PMID:Bone lysis and inflammation. 1569 7

Osteoprotegerin (OPG) is an osteoclastogenesis inhibitory factor that we have cloned, and is a decoy receptor that inhibits the binding of an osteoclast differentiation factor, RANKL and its receptor RANK. Pharmacological and developmental approaches have demonstrated that OPG inhibits osteoclastogenesis and bone resorption in vivo. OPG may be useful for and applicable to the treatment of bone destruction in rheumatoid arthritis.
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PMID:[OPG, a possible candidate for the treatment of rheumatoid arthritis]. 1577 48

Recent discovery of factors involved in bone destruction in Rheumatoid Arthritis (RA) identified its molecular mechanism. Osteoclast differentiation factor (ODF, also called receptor activator of NF-kappaB ligand (RANKL) ) that controls osteoclast differentiation and function has a major role in the bone destruction among them. Osteoclastogenesis inhibitory factor (OCIF, also called osteoprotegerin (OPG) ) that is a decoy receptor for ODF/RANKL is a specific inhibitor of bone destruction. OPG/OCIF may be useful for and applicable to the treatment of bone destruction in RA.
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PMID:[Osteoprotegerin (OPG/OCIF) inhibits bone destruction in rheumatoid arthritis models]. 1577 61

Rheumatoid arthritis is characterized by the presence of inflammatory synovitis and destruction of joint cartilage and bone. Tissue proteinases released by synovia, chondrocytes and pannus can cause cartilage destruction and cytokine-activated osteoclasts have been implicated in bone erosions. Rheumatoid arthritis synovial tissues produce a variety of cytokines and growth factors that induce monocyte differentiation to osteoclasts and their proliferation, activation and longer survival in tissues. More recently, a major role in bone erosion has been attributed to the receptor activator of nuclear factor kappa B ligand (RANKL) released by activated lymphocytes and osteoblasts. In fact, osteoclasts are markedly activated after RANKL binding to the cognate RANK expressed on the surface of these cells. RANKL expression can be upregulated by bone-resorbing factors such as glucocorticoids, vitamin D3, interleukin 1 (IL-1), IL-6, IL-11, IL-17, tumor necrosis factor-alpha, prostaglandin E2, or parathyroid hormone-related peptide. Supporting this idea, inhibition of RANKL by osteoprotegerin, a natural soluble RANKL receptor, prevents bone loss in experimental models. Tumor growth factor-beta released from bone during active bone resorption has been suggested as one feedback mechanism for upregulating osteoprotegerin and estrogen can increase its production on osteoblasts. Modulation of these systems provides the opportunity to inhibit bone loss and deformity in chronic arthritis.
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PMID:RANK, RANKL and osteoprotegerin in arthritic bone loss. 1578 27

We studied the effects of estrogen on human fibroblast-like synovial cells in rheumatoid arthritis (RA-FLS) focusing on receptor activator of NF-kappaB ligand (RANKL) and its decoy receptor osteoprotegerin (OPG), the osteoclast formation and function regulators that have a substantial role in bone erosion of RA. Estrogen influences osteoporosis and the onset of RA clinically. The cellular responses of RA-FLS to estrogen are initiated via two high-affinity estrogen receptors (ERs). Culture of RA-FLS in the presence of 10(-6) M 17beta-estradiol (E2) increased expression of estrogen receptor (ER)-alpha, but not ER-beta. OPG mRNA expression was significantly increased, whereas RANKL mRNA was unaffected. E2 treatment also significantly increased the amount of OPG released in the culture supernatant. The increase of OPG and ER-alpha was specifically antagonized by the pure estrogen antagonist ICI 182780. Tamoxifen, a selective ER moderator, did not increase OPG. The results indicate that estrogen stimulates secretion of OPG from RA-FLS by acting on ER-alpha, which likely prevents bone erosion in RA.
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PMID:Estrogen specifically stimulates expression and production of osteoprotegerin from rheumatoid synovial fibroblasts. 1580 5

The OPG/RANKL/RANK system plays an important role in osteoclastogenesis and represents a great progress in bone biology. RANKL, which expresses on the surface of osteoblast/stromal cells and activated T cells, binds to RANK on the osteoclastic precursors or mature osteoclasts, and promotes osteoclastogenesis and bone resorption. While osteoprotegerin (OPG), which is expressed by osteoblasts/stromal cells, strongly inhibits bone resorption by binding to its ligand RANKL and thereby blocks the interaction between BANKL and RANK. A number of cytokines and hormones exert their effects on bone metabolism by regulating the OPG/RANKL ratio in the bone marrow microenvironment. RANK is also expressed on mammary epithelial cells and RANKL expression in these cells is induced by pregnancy hormones, RANKL and RANK are essential for the formation of the lactating mammary gland and the transmission of maternal calcium to neonates in mammalian species. Modulation of these systems provides a unique opportunity to develop novel therapeutics to inhibit bone loss in osteoporosis, rheumatoid arthritis, and bone metastasis of cancer. Further research should be focused on the cooperation of OPG/RANKL/RANK system with other signal pathways and the interactions among bone remodeling, immune system and endocrinology system. Currently, the development of OPG analogues or compounds which may stimulate OPG expression is becoming an attractive industry which may be profitable to both patients and manufacturers.
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PMID:[The OPG/RANKL/RANK system and bone resorptive disease]. 1597 75

It has recently been discovered that the receptor activator of nuclear kappaB-ligand (RANKL) plays a key role in the activation, differentiation and proliferation ofosteoblasts. The effects of RANKL are counteracted by the decoy receptor osteoprotegerin (OPG), which protects against bone resorption by preventing RANKL from coupling to its receptor RANK. An increase in the balance between RANKL and OPG leads to increased bone resorption (both locally and generalised), e.g. in patients with postmenopausal osteoporosis, glucocorticoid-induced osteoporosis, multiple myeloma, other malignancies with skeletal metastases, or rheumatoid arthritis. The development of new anti-osteoporotic drugs, based on the restoration of the imbalance between RANKL and OPG, may be a breakthrough in optimising the treatment of patients with bone diseases. However, the results of studies on fracture reduction, the safety profile, the costs of the new drugs and their comparison with bisphosphonates, currently the gold standard in osteoporosis treatment, must be awaited.
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PMID:[Clinical implications of new insights into the regulation of bone resorption]. 1610 10

Inflammatory diseases lead to systemic osteoporosis. Causal factors include increased circulating concentrations of inflammatory cytokines such as interleukin 6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha), glucocorticoid medication, and reduced physical activity. In addition, disturbances of vitamin D metabolism play an important role for the development of inflammation induced osteoporosis. Therefore, D-hormone analogs offer an important treatment option. 1,25-dihydroxyvitamin D (D-hormone) prevented bone loss in the rat model of inflammation mediated osteopenia and in an arthritis model. One explanation is that animals and humans with inflammatory diseases exhibit markedly reduced circulating concentrations of D-hormone, partly the result of inhibition of renal 1-alpha-hydroxylase by TNF-alpha. In addition, the number of vitamin D receptors is reduced by glucocorticoids. Moreover, D-hormone has pleiotropic effects not only on calcium homoeostasis but also on muscle (improving power), the nervous system, and the immune system. D-hormone inhibits the release of cytokines (IL-1, IL-6, TNF-alpha) from macrophages and stimulates osteoprotegerin secretion in vitro and improves arthritis in animal models. This article reviews the interaction between inflammatory disease and vitamin D metabolism, summarizes the rationale for the therapeutic use of alfacalcidol, and provides recent data from controlled clinical trials comparing the effect of alfacalcidol versus plain vitamin D in secondary osteoporosis. Alfacalcidol, but not plain vitamin D, has pleiotropic effects improving bone and muscle metabolism and clinical symptoms in patients with rheumatoid arthritis.
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PMID:Alfacalcidol versus plain vitamin D in inflammation induced bone loss. 1614 48

Identification of RANKL/ODF (receptor activator of NF-kappaB ligand/osteoclast differentiation factor), RANK(receptor activator of NF-kappaB) and OPG/OCIF(osteoprotegerin/ osteoclastogenesis inhibitory factor) revealed the mechanisms regulating osteoclast differentiation and function. RANKL-RANK signaling is essential for the physiological osteoclast development and plays a major role in the pathological bone destruction. OPG and anti-RANKL antibody act as a specific inhibitor of RANKL and are useful and applicable to osteoporosis and rheumatoid arthritis.
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PMID:[OPG, anti-rANKL antibody]. 1616 25


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