Novel gene therapy for rheumatoid arthritis by FADD gene transfer: induction of apoptosis of rheumatoid synoviocytes but not chondrocytes

Kobayashi, Tetsuya; Okamoto, Kazuyoshi; Kobata, Tetsuji; Hasunuma, Tomoko; Kato, Tomohiro; Hamada, Hirofumi; Nishioka, Kusuki

doi:10.1038/sj.gt.3301127

Cited by 55 publications

(19 citation statements)

References 30 publications

(37 reference statements)

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“…Thus, synovial hyperplasia caused by inhibition of apoptosis plays a role in arthritis [Urayama et al, 2001]. In this regard, local injection of FADD adenovirus induced apoptosis in vivo in proliferating human rheumatoid synovium engrafted into the severe combined immunodeficient mouse [Kobayashi et al, 2000]. In this study, chondrocytes were unaffected by the FADD adenovirus construct.…”

Section: Effect Of Hydrostatic Pressure On Chondrocyte Faddmentioning

confidence: 64%

Pathophysiological Mechanisms in Osteoarthritis Lead to Novel Therapeutic Strategies

Malemud¹,

Islam²,

Haqqi³

2003

Cells Tissues Organs

175

141

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Osteoarthritis (OA) is a debilitating, progressive disease of diarthrodial joints associated with aging. At the molecular level, OA is characterized by an imbalance between anabolic (i.e. extracellular matrix biosynthesis) and catabolic (i.e. extracellular matrix degradation) pathways in which articular cartilage is the principal site of tissue injury responses. The pathophysiology of OA also involves the synovium in that ‘nonclassical’ inflammatory synovial processes contribute to OA progression. Chondrocytes are critical to the OA process in that the progression of OA can be judged by the vitality of chondrocytes and their ability to resist apoptosis. Growth factors exemplified by insulin-like growth factor-1, its binding proteins and transforming growth factor-β contribute to anabolic pathways including compensatory biosynthesis of extracellular matrix proteins. Catabolic pathways are altered by cytokine genes such as interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-α) which are upregulated in OA. In addition, IL-1 and TNF-α downregulate extracellular matrix protein biosynthesis while concomitantly upregulating matrix metalloproteinase (MMP) gene expression. When MMPs are activated, cartilage extracellular matrix degradation ensues apparently because levels of endogenous cartilage MMP inhibitors cannot regulate MMP activity. Therapeutic strategies designed to modulate the imbalance between anabolic and catabolic pathways in OA may include neutralizing cytokine activity or MMP gene expression or inhibiting signaling pathways which result in apoptosis dependent on mature caspase activity or mitogen-activated protein kinase (MAPK) activity. MAPK activity appears critical for regulating chondrocyte and synoviocyte apoptosis and MMP genes.

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Section: Effect Of Hydrostatic Pressure On Chondrocyte Faddmentioning

confidence: 64%

Pathophysiological Mechanisms in Osteoarthritis Lead to Novel Therapeutic Strategies

Malemud¹,

Islam²,

Haqqi³

2003

Cells Tissues Organs

175

141

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“…Furthermore, Ad-FADD-induced apoptosis was limited to cells of the synovium tissue and did not affect chondrocytes. These results suggest that FADD gene transfer can induce apoptosis of RA synoviocytes both in vitro and in vivo, and consequently may be effective in the treatment of RA (110).…”

Section: Discussionmentioning

confidence: 94%

The natural history and prognosis of rheumatoid arthritis: association of radiographic outcome with process variables, joint motion and immune proteins

Graudal

2004

Scandinavian Journal of Rheumatology

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“…In severe combined immunodeficient (SCID) mice engrafted with human RA synovium, the local injection of a replication-defective adenovirus expressing FADD induces apoptosis in the synovium and suppresses synoviocyte proliferation 88 . In addition, FADD can sequester MyD88 (an adapter protein essential for most TLR signalling), thereby hindering the activation of the transcription factor NF-κB.…”

Section: Extrinsic Pathway Of Apoptosis In Ramentioning

confidence: 99%

The inflammatory role of phagocyte apoptotic pathways in rheumatic diseases

2016

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Rheumatoid arthritis affects nearly 1% of the world's population and is a debilitating autoimmune condition that can result in joint destruction. During the past decade, inflammatory functions have been described for signalling molecules classically involved in apoptotic and non-apoptotic death pathways, including but not limited to toll-like receptor signalling, inflammasome activation, cytokine production, macrophage polarization and antigen citrullination. In light of these remarkable advances in the understanding of inflammatory mechanisms of the death machinery, this review provides a snapshot of the available evidence implicating death pathways, especially within the phagocyte populations of the innate immune system, in the perpetuation of rheumatoid arthritis. Elevated levels of signalling mediators of both the extrinsic and intrinsic apoptotic as well as the autophagy death pathways are observed in the joints of patients with rheumatoid arthritis. Furthermore, in rheumatoid arthritis patients, risk polymorphisms are present in signalling molecules of the extrinsic apoptotic and autophagy death pathways. Although research into the mechanisms underlying these death pathways has made considerable progress, this review highlights areas where further investigation is particularly needed. This exploration is critical, as new discoveries in this field could lead to the development of novel therapeutic targets for rheumatoid arthritis and other rheumatic diseases.

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Novel gene therapy for rheumatoid arthritis by FADD gene transfer: induction of apoptosis of rheumatoid synoviocytes but not chondrocytes

Cited by 55 publications

References 30 publications

Pathophysiological Mechanisms in Osteoarthritis Lead to Novel Therapeutic Strategies

Pathophysiological Mechanisms in Osteoarthritis Lead to Novel Therapeutic Strategies

The natural history and prognosis of rheumatoid arthritis: association of radiographic outcome with process variables, joint motion and immune proteins

The inflammatory role of phagocyte apoptotic pathways in rheumatic diseases

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