TGF‐α and ErbB2 production in synovial joint tissue: increased expression in arthritic joints

Hallbeck, Anna-Lotta; Walz, Thomas; Briheim, Kristina; Wasteson, Åke

doi:10.1080/03009740510017715

Cited by 41 publications

(37 citation statements)

References 12 publications

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“…Many of the group I RTKs, such as EGFR (HER-1 or ErbB-1), HER-2 (ErbB-2), HER-3 (ErbB-3), and HER-4 (ErbB-4), are widely expressed on several types of epithelial and mesenchymal cells (12), and expression of both transforming growth factor ␣ and ErbB-2 is increased in synovial tissue from arthritic joints (30). High levels of EGF have been observed in synovial fluid samples from RA patients, and data also suggested that mitotic signals from EGF could be transmitted by interaction with ErbB-2 receptor on synovial cells (31).…”

Section: Discussionmentioning

confidence: 99%

Antagonism of the human epidermal growth factor receptor family controls disease severity in murine collagen‐induced arthritis

Sumariwalla¹,

Pei²,

Zhang³

et al. 2008

Arthritis & Rheumatism

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Objective. To evaluate the therapeutic potential of the human epidermal growth factor receptor (HER) family inhibitor, herstatin, in an animal model of arthritis.Methods. Constructs of herstatin and modified tissue plasminogen activator (tPA)-herstatin were expressed in HEK 293T cells, and secreted protein was analyzed by Western blotting. Tissue PA-herstatin adenovirus (Ad-tPA-Her) was prepared, and titers established. Gene expression of Ad-tPA-Her was determined by polymerase chain reaction using HeLa cells. Pharmacokinetics of gene and protein expression in vivo in liver tissue and serum samples were confirmed via intravenous administration of Ad-tPA-Her. Clinical signs of disease were monitored in arthritic DBA/1 mice after therapeutic administration of Ad-tPA-Her, and histologic analysis of hind foot specimens was performed.Results. Native herstatin was not secreted in supernatants, while modified tPA-herstatin was detected in abundance. HeLa cells stably expressed the tPA-herstatin gene when infected with virus. Additionally, tPA-herstatin gene and protein expression was observed over time in mice treated with virus. Importantly, Ad-tPA-Her, when administered therapeutically to arthritic mice, controlled clinical and histologic signs of disease and reduced the number of joints with severe damage.Conclusion. Our results support the notion that the human epidermal growth factor receptor family has a role in the progression of collagen-induced arthritis. The novel tPA-herstatin fusion protein could be used as an effective therapeutic tool for control of inflammatory disorders involving an angiogenic component.

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Section: Discussionmentioning

confidence: 99%

Antagonism of the human epidermal growth factor receptor family controls disease severity in murine collagen‐induced arthritis

Sumariwalla¹,

Pei²,

Zhang³

et al. 2008

Arthritis & Rheumatism

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“…The most well-established role for Mig-6 in cancer cells is as a negative feedback regulator of EGFR (3)(4)(5)(6), and EGFR signaling is known to play an important role in bone development (28)(29)(30)(31). TGF-α, one of the ligands for EGFR, has been reported to be increased in human osteoarthritic joints (32), and it can induce articular cartilage degradation in animal models (33,34). EGFR signaling appears to be activated in the chondrocytes of the articular cartilage and in the osteophyte of the Mig-6 flox/flox ;Col2a1 Cre knee joints (Fig.…”

Section: Discussionmentioning

confidence: 99%

Cartilage-specific deletion of Mig-6 results in osteoarthritis-like disorder with excessive articular chondrocyte proliferation

Staal

Williams

Beier

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Significance Mitogen-inducible gene 6 (Mig-6) was found to be an important factor in maintaining joint homeostasis, and its loss in mice results in the development of an osteoarthritis (OA)-like disorder in multiple synovial joints. However, it was unclear in what cells Mig-6 was expressed and what cells were causal for developing the OA-like phenotype. Here we report that Mig-6 is uniquely expressed in the cells surrounding entire surface of the synovial joint, including chondrocytes in the superficial zone of the articular cartilage and in the meniscus, and synovial lining cells. We found that although chondrocytes play a critical role in developing the OA-like disorder in the knees, other cell types are likely required for full development of the Mig-6–deficient joint phenotype.

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“…9 It has been known for several years that TGFa levels are increased in the synovium and synovial fluid of patients with OA or rheumatoid arthritis (RA). 12,13 Therefore, our discovery that TGFa is produced by articular chondrocytes represents an additional source of TGFa production in OA. Furthermore, recent evidence in mice has shown that a constitutive activation of EGFR signaling leads to OA pathogenesis.…”

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confidence: 99%

Rho/ROCK and MEK/ERK activation by transforming growth factor-α induces articular cartilage degradation

Appleton

Usmani

Mort

et al. 2010

Laboratory Investigation

106

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Identification and characterization of therapeutic targets for joint conditions, such as osteoarthritis (OA), is exceedingly important for addressing the increasing burden of disease. Transforming growth factor-a (TGFa) is upregulated by articular chondrocytes in experimentally induced and human OA. To test the potential involvement of TGFa, which is an activator of epidermal growth factor receptor (EGFR) signaling, in joint degeneration and to identify signaling mechanisms mediating articular chondrocyte responses to TGFa, rat chondrocytes and osteochondral explants were treated with TGFa and various inhibitors of intracellular signaling pathways. Stimulation of EGFR signaling in articular chondrocytes by TGFa resulted in the activation of RhoA/ROCK (Rho kinase), MEK (MAPK/ERK kinase)/ERK (extracellularsignal-regulated kinase), PI3K (phosphoinositide 3-kinase) and p38 MAPK (mitogen-activated protein kinase) pathways. Modification of the chondrocyte actin cytoskeleton was stimulated by TGFa, but inhibition of only Rho or ROCK activation prevented morphological changes. TGFa suppressed expression of anabolic genes including Sox9, type II collagen and aggrecan, which were rescued only by inhibiting MEK/ERK activation. Furthermore, catabolic factor upregulation by TGFa was prevented by ROCK and p38 MAPK inhibition, including matrix metalloproteinase-13 and tumor necrosis factor-a, which are well known to contribute to cartilage digestion in OA. To assess the ability of TGFa to stimulate degradation of mature articular cartilage, type II collagen and aggrecan cleavage fragments were analyzed in rat osteochondral explants exposed to exogenous TGFa. Normal articular cartilage contained low levels of both cleavage fragments, but high levels were observed in the cartilage treated with TGFa. Selective inhibition of MEK/ERK and Rho/ROCK activation greatly reduced or completely prevented excess type II collagen and aggrecan degradation in response to TGFa. These data suggest that TGFa is a strong stimulator of cartilage degradation and that Rho/ROCK and MEK/ERK signaling have critical roles in mediating these effects. KEYWORDS: articular cartilage; chondrocyte; epidermal growth factor receptor; osteoarthritis; transforming growth factor alpha Osteoarthritis (OA) is a chronic, degenerative, synovial joint condition, which affects the knees, hips and other smaller joints of B10% of the North American population. The societal burden of OA is increasing and OA already accounts for 25% of visits to primary care physicians and for 50% of nonsteroidal anti-inflammatory drug prescriptions.1,2 Approximately 80% of individuals have radiographic evidence of OA by age 65 years, of which 60% are symptomatic.1 Furthermore, progressive joint degeneration combined with an inherently low capacity for articular cartilage regeneration makes treatment very difficult. As current therapies are strictly palliative, identification and characterization of therapeutic targets is exceedingly important to meet the increasing burden of disease. Althou...

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TGF‐α and ErbB2 production in synovial joint tissue: increased expression in arthritic joints

Abstract: The presence of TGF-alpha in normal SF and SM may indicate a physiological maintenance function. The increased expression of TGF-alpha and ErbB2 in RA SF and SM may give rise to an abnormal growth pattern, contributing to inflammatory synovial hyperplasia.

Cited by 41 publications

References 12 publications

Antagonism of the human epidermal growth factor receptor family controls disease severity in murine collagen‐induced arthritis

Antagonism of the human epidermal growth factor receptor family controls disease severity in murine collagen‐induced arthritis

Cartilage-specific deletion of Mig-6 results in osteoarthritis-like disorder with excessive articular chondrocyte proliferation

Rho/ROCK and MEK/ERK activation by transforming growth factor-α induces articular cartilage degradation

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