Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0003864 (arthritis)
 69,039 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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) are associated with osteolysis. These lesions generally contain a chronic inflammatory infiltrate in which macrophages form a significant fraction. One cellular mechanism whereby pathological bone resorption may be effected is through generation of increased numbers of bone-resorbing osteoclasts from macrophages. Production of humoral factors which stimulate mononuclear phagocyte-osteoclast differentiation and osteoclast activity is also likely to influence the extent of pathological bone resorption.
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PMID:Human osteoclast ontogeny and pathological bone resorption. 1021 24

Bone remodelling and bone loss are controlled by a balance between the tumour necrosis factor family molecule osteoprotegerin ligand (OPGL) and its decoy receptor osteoprotegerin (OPG). In addition, OPGL regulates lymph node organogenesis, lymphocyte development and interactions between T cells and dendritic cells in the immune system. The OPGL receptor, RANK, is expressed on chondrocytes, osteoclast precursors and mature osteoclasts. OPGL expression in T cells is induced by antigen receptor engagement, which suggests that activated T cells may influence bone metabolism through OPGL and RANK. Here we report that activated T cells can directly trigger osteoclastogenesis through OPGL. Systemic activation of T cells in vivo leads to an OPGL-mediated increase in osteoclastogenesis and bone loss. In a T-cell-dependent model of rat adjuvant arthritis characterized by severe joint inflammation, bone and cartilage destruction and crippling, blocking of OPGL through osteoprotegerin treatment at the onset of disease prevents bone and cartilage destruction but not inflammation. These results show that both systemic and local T-cell activation can lead to OPGL production and subsequent bone loss, and they provide a novel paradigm for T cells as regulators of bone physiology.
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PMID:Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. 1058 May 3

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.
Arthritis Res 2000
PMID:Bone loss. Factors that regulate osteoclast differentiation: an update. 1109 58

Osteoprotegerin ligand (OPGL, TNFS11) and its receptor RANK (TNFRS11A) are essential for the development and activation of osteoclasts and critical regulators of physiological bone remodeling and osteoporosis. Production of OPGL by activated T cells can directly regulate osteoclastogenesis and bone remodeling. This may explain why autoimmune diseases, cancers, leukemias, asthma and chronic viral infections such as hepatitis and HIV result in systemic and local bone loss. OPGL is also the pathogenetic factor that causes bone and cartilage destruction and clinical crippling in arthritis. Inhibition of OPGL binding to RANK via the natural decoy receptor osteoprotegerin (OPG) prevents bone loss in postmenopausal osteoporosis and cancer metastases and completely blocks crippling in a rat model of arthritis. Moreover, OPG expression is induced by estrogen which provides a molecular explanation of postmenopausal osteoporosis in women.
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PMID:Molecular control of bone remodeling and osteoporosis. 1112 82

We studied the relationship between osteoprotegerin (OPG)/osteoclastogenesis inhibitory factor (OCIF) concentration in synovial fluid from individuals with osteoarthritis (OA) of the knee and the severity of this condition. The study population included 111 Japanese women with knee OA (153 knees) and 23 normal controls. Osteoarthritic changes were graded according to the system of Kellgren and Lawrence. The concentration of OPG/OCIF in synovial fluid increased with severity of knee OA and was significantly higher in individuals with OA of grade IV than in those with OA of grade 0 or grade 1. It has been shown in a previous study that administration of OPG/OCIF prevents cartilage destruction in adjuvant-induced arthritis in rats. The increase in the concentration OPG/OCIF in synovial fluid of individuals with knee OA might thus reflect a compensatory response to degeneration of articular cartilage and serve to protect cartilage rather than be a cause of OA.
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PMID:Relationship between osteoprotegerin/osteoclastogenesis inhibitory factor concentration in synovial fluid and disease severity in individuals with osteoarthritis of the knee. 1117 66

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

Bone loss represents a major unsolved problem in rheumatoid arthritis (RA). The skeletal complications of RA consist of focal bone erosions and periarticular osteoporosis at sites of active inflammation, and generalized bone loss with reduced bone mass. New evidence indicates that osteoclasts are key mediators of all forms of bone loss in RA. TNF-alpha is one of the most potent osteoclastogenic cytokines produced in inflammation and is pivotal in the pathogenesis of RA. Production of tumor necrosis factor-alpha (TNF-alpha) and other proinflammatory cytokines in RA is largely CD4(+) T-cell dependent and mostly a result of interferon-gamma (IFN-gamma) secretion. Synovial T cells contribute to synovitis by secreting IFN-gamma and interleukin (IL)-17 as well as directly interacting with macrophages and fibroblasts through cell-to-cell contact mechanisms. Activated synovial T cells express both membrane-bound and soluble forms of receptor activator of NF-kappaB ligand (RANKL). In rheumatoid synovium, fibroblasts also provide an abundant source of RANKL. Furthermore, TNF-alpha and IL-1 target stromal-osteoblastic cells to increase IL-6, IL-11, and parathyroid hormone-related protein (PTHrP) production as well as expression of RANKL. In the presence of permissive levels of RANKL, TNF-alpha acts directly to stimulate osteoclast differentiation of macrophages and myeloid progenitor cells. In addition, TNF-alpha induces IL-1 release by synovial fibroblasts and macrophages, and IL-1, together with RANKL, is a major survival and activation signal for nascent osteoclasts. Consequently, TNF-alpha and IL-1, acting in concert with RANKL, can powerfully promote osteoclast recruitment, activation, and osteolysis in RA. The most convincing support for this hypothesis has come from in vivo studies of animal models. Protection of bone in the presence of continued inflammation in arthritic rats treated with osteoprotegerin (OPG) supports the concept that osteoclasts mediate bone loss, providing further evidence that OPG protects bone integrity by downregulating osteoclastogenesis and promoting osteoclast apoptosis. Modulation of the RANKL/OPG equilibrium in arthritis may provide additional skeletal benefits, such as chondroprotection. The nexus between T-cell activation, TNF-alpha overproduction, and the RANKL/OPG/RANK ligand-receptor system points to a unifying paradigm for the entire spectrum of skeletal pathology in RA. Strategies that address osteoclastic bone resorption will represent an important new facet of therapy for RA.
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PMID:Involvement of receptor activator of NFkappaB ligand and tumor necrosis factor-alpha in bone destruction in rheumatoid arthritis. 1185 40

Rheumatoid arthritis (RA) is a systemic disorder characterized by synovial inflammation and subsequent destruction and deformity of synovial joints. The articular lesions start with synovitis, focal erosion of unmineralized cartilage, and then culminate in the destruction of subarticular bone by pannus tissue. Periarticular osteopenia and systemic osteoporosis follow as late complications of RA. Osteoclasts, specialized cells that resorb bone, play a central role in developing these osteolytic lesions. To elucidate the mechanism of osteoclastogenesis and bone destruction in autoimmune arthritis, we investigated the expression of RANK ligand (RANKL), RANK, and osteoprotegerin (OPG) mRNA in a mouse type II collagen-induced arthritis (CIA) model by in situ hybridization. The results indicated that most of the TRAP-positive mono- and multinucleated cells in the inflamed and proliferating synovium and in the pannus were RANK-positive authentic osteoclasts and their precursors. In the inflamed synovium and pannus of the mouse CIA model, synovial fibroblastic cells around these RANK-positive cells were strongly positive for RANKL. Moreover, RANKL-positive osteoblasts on the endosteal bone surface, at a distance from the affected synovial joints, increased significantly in the mouse CIA model prior to periarticular osteopenia and systemic osteoporosis. These data indicated that the RANKL-RANK system plays an important role for osteoclastogenesis in both local and systemic osteolytic lesions in autoimmune arthritis, and can therefore be a good target for therapeutic intervention.
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PMID:RANK ligand, RANK, and OPG expression in type II collagen-induced arthritis mouse. 1191 26

Histopathologic characterization of bone erosions from patients with rheumatoid arthritis (RA) and studies performed in animal models of inflammatory arthritis provide strong evidence that osteoclasts play an important role in focal marginal and subchondral bone loss in inflammatory arthritis. Much has been learned concerning the factors responsible for the induction and activation of osteoclasts associated with the bone erosions in RA. Therapies that target these osteoclast-inducing factors or other aspects of osteoclast-mediated bone resorption represent potential targets for blocking or at least attenuating bone destruction in RA. The demonstration of the role of the newly described osteoclastogenic factor receptor activator of nuclear factor kappaB ligand in RA synovial tissues and the successful prevention of bone erosions in animal models of arthritis with its inhibitor osteoprotegerin provide hope that specific therapies can be developed for preventing bone and joint destruction in RA, particularly in situations in which disease-modifying agents are ineffective in controlling disease activity.
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PMID:Pathogenesis of bone lesions in rheumatoid arthritis. 1201 Jun 7

Rheumatoid arthritis is characterized by progressive synovial inflammation and joint destruction. While matrix metalloproteinases (MMPs) are implicated in the erosion of unmineralized cartilage, bone destruction involves osteoclasts, the specialized cells that resorb calcified bone matrix. RANK ligand (RANKL) expressed by stromal cells and T cells, and its cognate receptor, RANK, were identified as a critical ligand-receptor pair for osteoclast differentiation and survival. A decoy receptor for RANKL, osteoprotegerin, (OPG) impinges on this system and regulates osteoclast numbers and activity. RANKL is also expressed in collagen-induced arthritis (CIA) in which focal collections of osteoclasts are prominent at sites of bone destruction. To determine the role of RANK signaling events in the effector phase of CIA, we investigated effects of Fc-osteoprotegerin fusion protein (Fc-OPG) in CIA. After induction of CIA in Dark Agouti rats, test animals were treated with or without Fc-OPG (3 mg/kg/day) subcutaneously for 5 days, beginning at the onset of disease. Paraffin-embedded joints were then analyzed histologically and the adjacent bone assessed by histomorphometry. Osteoclasts were identified using TRAP staining and expression of the mRNA for OPG and RANKL was identified by in situ hybridization. The results indicated that short-term Fc-OPG effectively prevented joint destruction, even though it had no impact on the inflammatory aspects of CIA. In arthritic joints, Fc-OPG depleted osteoclast numbers by over 75% and diminished bone erosion scores by over 60%. Although cartilage loss was also reduced by Fc-OPG, the effects on cartilage were less striking than those on bone. In arthritic joints OPG mRNA was highly expressed and co-localized with RANK ligand, and treatment with Fc-OPG did not affect the expression of endogenous RANKL or OPG mRNA. These data demonstrate that short term Fc-OPG treatment has powerful anti-erosive effects, principally on bone, even though synovitis is not affected. These findings indicate the potential utility of disrupting RANK signaling to preserve skeletal integrity in inflammatory arthritis.
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PMID:Osteoprotegerin reduces osteoclast numbers and prevents bone erosion in collagen-induced arthritis. 1236 14


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