Suppression of arthritic bone destruction by adenovirus‐mediated dominant‐negative Ras gene transfer to synoviocytes and osteoclasts

Yamamoto, Aiichiro; Fukuda, Akira; Seto, Hiroaki; Miyazaki, Tsuyoshi; Kadono, Yuho; Sawada, Yasuhiro; Nakamura, Ichiro; Katagiri, Hideki; Asano, Tomohiko; Tanaka, Yoshiya; Oda, Hiromi; Nakamura, Kozo; Tanaka, Sakae

doi:10.1002/art.11214

Cited by 54 publications

(50 citation statements)

References 58 publications

(64 reference statements)

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“…This suggests that SD-282 healed bones in the late stage of CIA disease by reducing bone resorption and by forming new bone. We hy- pothesize that the effect of SD-282 on bone may be due to inhibition of osteoclast differentiation in the absence of IL-6 (Li et al, 2002(Li et al, , 2003Yamamoto et al, 2003) and/or osteoblastogenesis. We are in the process of testing the latter hypothesis.…”

Section: P38␣ Mapk Inhibitor Reverses Cartilage and Bone Destruction 139mentioning

confidence: 92%

A Selective p38α Mitogen-Activated Protein Kinase Inhibitor Reverses Cartilage and Bone Destruction in Mice with Collagen-Induced Arthritis

Medicherla¹,

Jing²,

Mangadu³

et al. 2006

J Pharmacol Exp Ther

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Section: P38␣ Mapk Inhibitor Reverses Cartilage and Bone Destruction 139mentioning

confidence: 92%

A Selective p38α Mitogen-Activated Protein Kinase Inhibitor Reverses Cartilage and Bone Destruction in Mice with Collagen-Induced Arthritis

Medicherla¹,

Jing²,

Mangadu³

et al. 2006

J Pharmacol Exp Ther

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“…Synovial cells were obtained as previously described (13,23,24). In brief, with enzymatic digestion, human synovial cells were isolated from synovial tissues of the knee joints of ten rheumatoid arthritis patients (37-75 years of age; mean, 60.3 years of age) at the time of total knee arthroplasty operations.…”

Section: Chemicals and Antibodiesmentioning

confidence: 99%

Distinct roles of Smad pathways and p38 pathways in cartilage-specific gene expression in synovial fibroblasts

Seto¹,

Kamekura²,

Miura³

et al. 2004

J. Clin. Invest.

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Nonstandard abbreviations used: anterior cruciate ligament (ACL); bone morphogenetic protein (BMP); constitutively active activin receptor-like kinase 3 (ALK3 CA ); constitutively active MKK6 (MKK6 CA ); hemagglutinin (HA); matrix metalloproteinase (MMP); medial meniscus (MM); osteoarthritis (OA); receptorregulated Smad (R-Smad); synovial fibroblast (SF); TGF-β-activating kinase 1 (TAK1). Conflict of interest:The authors have declared that no conflict of interest exists. IntroductionInjury to the articular cartilage occurs under various pathological conditions such as trauma, inflammation, and aging (1), and cartilage injury is followed by osteoarthritic changes of the affected joints. Osteoarthritis is the most common degenerative joint disorder, affecting nearly half of the elderly population. Osteoarthritis is characterized by degradation of articular cartilage and overgrowth of cartilage and bone, known as osteophytes, at the periphery of the articular surface, which results in pain and loss of joint function (1, 2). Microscopically, loss of proteoglycan and fibrillation of the articular surface are observed at the early stage of arthritis. At later stages, clefts are formed, and at the end stage, erosive changes in the articular cartilage appear. The high prevalence of this disease results in high costs for treating patients, and therefore the development of good therapeutics for osteoarthritis is a matter of great urgency. Because of the limited capacity of spontaneous healing, the regeneration of intact articular cartilage is one of the most challenging issues in the orthopedic field (3, 4). Transplantation of autologous chondrocytes or mesenchymal progenitor cells and autogenous osteochondral transplantation (mosaicplasty) have been successfully utilized for the repair of focal osteochondral defects (3, 5-11). However, the application of these technologies is limited to small defects due to the difficulty of obtaining a sufficient amount of cells or tissues. Synovium is a thin tissue lining the nonarticular surfaces of diarthrodial joints (12). Synovial tissues contain various types of cells, including type A cells, macrophage lineage cells, and type B cells, which are specialized synovial fibroblasts (SFs). It is now widely recognized that synovial tissues are involved primarily in the pathogenesis of arthritic joint disorders such as rheumatoid arthritis by producing the matrix-degenerating enzymes cystein proteases and matrix metalloproteinases (MMPs) and the proinflammatory cytokines interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-α) (12). We previously reported that SFs express a high level of receptor activator of NF-κB ligand, the osteoclast differentiation factor belonging to the TNF-α superfamily (13). In contrast to such catabolic actions, there is accumulating evidence that synovial cells have anabolic effects, leading to bone and cartilage production. Hunziker and Rosenburg reported that synovial cells can migrate into partial-thickness articular cartilage defects, where they prolifera...

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“…Such inhibitors also reduce severity of collagen-induced arthritis (an animal model of RA) by suppressing Ras and IKK-mediated activation of NF-B (53). Previously observed suppression of bone destruction by dominant negative Ras may be partly due to inhibition of proteases such as ADAMTS-4 and MMPs (54,55).…”

Section: Discussionmentioning

confidence: 91%

Adaptor Proteins and Ras Synergistically Regulate IL-1-Induced ADAMTS-4 Expression in Human Chondrocytes

Ahmad

Sylvester

Ahmad

et al. 2009

The Journal of Immunology

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Aggrecanases (a dystrophin and metalloproteinase with thrombospondin motif, ADAMTSs) are principal proteases involved in cartilage extracellular matrix aggrecan degradation. The role and relative contribution of MyD88, IRAK1, and TRAF6 adaptor proteins in IL-1β regulation of aggrecanase-1 (ADAMTS-4) is unknown. By small interfering RNAs-mediated knockdown, we show that IL-1β-induced up-regulation of ADAMTS-4 in chondrocytes requires MyD88, IRAK1, and TRAF6 adaptor proteins. However, partial inhibition of ADAMTS-4 induction by their knockdown suggested the involvement of additional signaling proteins. Because IL-1β is also known to induce reactive oxygen species (ROS) through Ras-mediated activation of NADPH oxidase, we investigated the implication of Ras in ADAMTS-4 regulation. Ras knockdown, or inhibition of ROS by antioxidants along with the ablation of MyD88, IRAK1, or TRAF6 more potently down-regulated IL-1β-induced ADAMTS-4. In addition, IL-1β-induced phosphorylation of downstream effectors, IκB kinase αβ, IκBα, and activation of transcription factor NF-κB was significantly reduced in the MyD88-, IRAK1-, TRAF6-, or Ras-deficient cells. The combined knockdown of Ras and individual adaptor proteins strongly blocked the activation of IKKαβ, IκBα, and NF-κB. These findings suggest that Ras, ROS along with MyD88, IRAK1, or TRAF6 synergistically mediate ADAMTS-4 regulation by IL1-β. Thus, complete ablation of ADAMTS-4 induction could be achieved by combined inhibition of Ras and individual adaptor proteins, which may be of therapeutic value in arthritis.

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Suppression of arthritic bone destruction by adenovirus‐mediated dominant‐negative Ras gene transfer to synoviocytes and osteoclasts

Cited by 54 publications

References 58 publications

A Selective p38α Mitogen-Activated Protein Kinase Inhibitor Reverses Cartilage and Bone Destruction in Mice with Collagen-Induced Arthritis

A Selective p38α Mitogen-Activated Protein Kinase Inhibitor Reverses Cartilage and Bone Destruction in Mice with Collagen-Induced Arthritis

Distinct roles of Smad pathways and p38 pathways in cartilage-specific gene expression in synovial fibroblasts

Adaptor Proteins and Ras Synergistically Regulate IL-1-Induced ADAMTS-4 Expression in Human Chondrocytes

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