Decreased angiogenesis and arthritic disease in rabbits treated with an αvβ3 antagonist

Storgard, Chris; Stupack, Dwayne G.; Jonczyk, Alfred; S, Goodman; Fox, Robert I.; Cheresh, David A.

doi:10.1172/jci3756

Cited by 294 publications

(209 citation statements)

References 31 publications

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“…In fact, apoptosis does occur under these circumstances. 15,[58][59][60] Cell surface expression of integrins in the antagonized 60 or unligated state 58 can promote apoptosis among otherwise attached and 'spread' cells.…”

Section: Antagonized Integrins Promote Apoptosis Of Adherent Cellsmentioning

confidence: 99%

Integrins as a distinct subtype of dependence receptors

Stupack

2005

Cell Death Differ

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In the absence of their cognate ligand, dependence receptors trigger programmed cell death. This function is the defining feature of dependence receptors, which include members of several different protein families. The integrins are a family of heterodimeric receptors for extracellular matrix (ECM) proteins, mediating cell anchorage and migration. Integrins share characteristics with dependence receptors, and integrin binding to substrate ECM ligands is essential for cell survival. Although integrins do not conform in all characteristics to the established definitions of dependence receptors, alterations in the expression of integrins and their ligands during physiological and pathological events, such as wound healing, angiogenesis and tumorigenesis, do regulate cell fate in a ligand-dependent manner. This biosensory function of integrins fits well with our current concept of dependence receptor action, and thus integrins may rightly be considered to comprise a distinct subclass of dependence receptor.

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Section: Antagonized Integrins Promote Apoptosis Of Adherent Cellsmentioning

confidence: 99%

Integrins as a distinct subtype of dependence receptors

Stupack

2005

Cell Death Differ

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“…Many other chronic inflammatory diseases (e.g., psoriasis and inflammatory bowel disease) display little evidence of autoimmunity. Angiogenesis inhibition may reduce arthritis severity in animal models of autoimmunity (21,23,25,27,28,37,38). Our data indicate that angiogenesis inhibition may prevent the progression from acute to chronic inflammation in situations where new blood vessel growth is the key switch to persistence.…”

Section: Discussionmentioning

confidence: 65%

“…FGF-2 is up-regulated at the cartilage-pannus interface in RA (40), and increased synovial fluid levels of FGF-2 are associated with greater disease severity (41,42). FGF-2 was also shown to augment antigen-induced arthritis in rabbits (27), and FGF-2 overexpression worsened inflammation and joint damage in adjuvant-induced arthritis in rats (43).…”

Section: Discussionmentioning

confidence: 99%

“…Sustained inhibition of angiogenesis that is begun during the induction, or at the onset, of synovitis can reduce inflammation and joint damage (21,23,27,37,38). However, adverse effects of long-term angiogenesis inhibition on physiologic blood vessel growth may outweigh the therapeutic benefit in chronic inflammatory diseases.…”

Section: Discussionmentioning

confidence: 99%

“…Those studies and studies of other antiangiogenic strategies (20,(26)(27)(28)(29) indicate that angiogenesis inhibition may have therapeutic potential in RA in humans. However, treatment of chronic inflammatory diseases with sustained inhibition of angiogenesis may lead to adverse events due to the blockade of physiologic blood vessel growth.…”

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confidence: 99%

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Angiogenesis and the persistence of inflammation in a rat model of proliferative synovitis

Ashraf

Mapp

Walsh

2010

Arthritis & Rheumatism

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Objective. To determine whether blood vessel growth at the onset of resolving synovitis leads to its subsequent persistence and whether inhibiting this angiogenesis at the onset of persistent inflammation leads to its subsequent resolution.Methods. Inflammation and angiogenesis were induced by injection of 0.03% carrageenan and/or 6 pmoles of fibroblast growth factor 2 (FGF-2) into rat knees. A brief treatment with the angiogenesis inhibitor PPI-2458 (5 mg/kg orally on alternate days) was administered 1 day before and up to 3 days after synovitis induction. Controls comprised naive and vehicle-treated rats. Synovial angiogenesis was measured using the endothelial cell proliferation index, and inflammation was determined by measuring joint swelling and macrophage percentage area. Data are presented as the geometric mean (95% confidence interval).Results. Intraarticular injection of 0.03% carrageenan into rat knees produced acute synovitis, which was not associated with synovial angiogenesis and which resolved within 29 days. Injection of FGF-2 (6 pmoles) induced synovial angiogenesis without significant synovitis. Stimulation of angiogenesis with FGF-2 at the time of carrageenan injection was followed by synovitis that persisted for 29 days. Persistence of carrageenan/FGF-2-induced synovitis was prevented by systemic administration of 3 doses of the angiogenesis inhibitor PPI-2458 during the acute phase.Conclusion. Our findings indicate that conversion of acute inflammation to chronic inflammation may be due to the stimulation of angiogenesis, and brief antiangiogenic treatment during the acute phase of synovitis may prevent its subsequent progression. Clinical studies will be needed to determine whether brief antiangiogenic treatment may reduce the burden of inflammatory joint diseases such as rheumatoid arthritis by facilitating the resolution of early synovitis.

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A 55-Year-Old Woman With Rheumatoid Arthritis

Goldring

2000

JAMA

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DR PARKER: Mrs J is a 55-year-old woman with moderately severe rheumatoid arthritis (RA) that was diagnosed in 1985 after several years of intermittently swollen and painful joints. Due to her illness, she retired from her profession as a restaurateur. She still experiences daily pain in her joints and is facing surgery on her feet. She is married, lives in the Boston suburbs, and has managed care insurance.Mrs J first noted pain and swelling in her wrists and knees. Later, she experienced morning stiffness, pain, and disfigurement of her hands and feet. After years of symptoms, she was referred to a rheumatologist who made the diagnosis of RA. She did not have adequate clinical responses to oral or intramuscular gold, methotrexate, penicillamine, hydroxychloroquine sulfate, or cyclosporine, mostly because of adverse effects. She took minocycline for 3 months, allowing her to taper her prednisone dosage, but developed yeast infections. Mrs J's arthritis responds "magically" to prednisone, but she dislikes the adverse effects, including cushingoid appearance, weight gain, and diabetes. She describes feeling "run-down" when she tries to taper the prednisone regimen.Mrs J reports significant progress with her joint symptoms with exercise, especially in the water. She also uses mechanical tools to help with daily tasks such as opening jars. Despite her illness, she has remained very active with her family and in the local community. She finds chiropractic treatments quite useful.Her medical history is notable for insulin-dependent diabetes mellitus, Sjö gren syndrome, and gastritis. Her sister and mother have arthritis. She has 2 sons in good health.Her current medications include leflunomide (Arava; Hoechst Marion Roussel, Kansas City, Mo), 20 mg/d; prednisone, 10 mg in the morning and 5 mg at night; vitamin D, 50 000 U twice weekly; trazodone, 50 mg at bedtime; calcium, 1000 mg/d; folic acid, 1 mg/d; troglitazone (Rezulin; Parke-Davis, Morris Plains, NJ), 400 mg/d; and insulin.Abnormal findings on physical examination included her slightly cushingoid appearance with synovitis with warmth and soft tissue swelling in her wrists and metacarpophalangeal joints. She has ulnar deviation and swan neck deformities in her hands, a left knee effusion, and soft tissue swelling in both ankles. Her most recent laboratory test results include an erythrocyte sedimentation rate of 40 mm/h and rheumatoid factor of 183 IU/mL. MRS J: HER UNDERSTANDING AND PERCEPTIONS

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Decreased angiogenesis and arthritic disease in rabbits treated with an αvβ3 antagonist

Cited by 294 publications

References 31 publications

Integrins as a distinct subtype of dependence receptors

Integrins as a distinct subtype of dependence receptors

Angiogenesis and the persistence of inflammation in a rat model of proliferative synovitis

A 55-Year-Old Woman With Rheumatoid Arthritis

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