Cyclosporin A Induces Proliferation in Human Gingival Fibroblasts via Induction of Transforming Growth Factor‐β1

Cotrim, P.; Martelli‐Júnior, Hercílio; Graner, Edgard; Sauk, John J.; Coletta, Ricardo D.

doi:10.1902/jop.2003.74.11.1625

Cited by 73 publications

(84 citation statements)

References 46 publications

(45 reference statements)

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“…Similar gene induction for TGF␤ and TIMP-1 in CSA-treated fibroblasts has been reported (30,31). The precise molecular mechanism of TGF␤ induction in chondrocytes is unclear.…”

Section: Discussionsupporting

confidence: 51%

Calcineurin modulates the catabolic and anabolic activity of chondrocytes and participates in the progression of experimental osteoarthritis

Yoo

Park

Yoon

et al. 2007

Arthritis & Rheumatism

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Objective. To determine whether intracellular calcineurin (Cn), a calcium-activated phosphatase, regulates the anabolic and catabolic activities of chondrocytes, and is a potential target in the treatment of osteoarthritis (OA).Methods. CnA expression was examined in cartilage tissue samples and cultured chondrocytes from OA patients, using immunohistochemistry and Western blot analysis, respectively. Concentrations of matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases 1 (TIMP-1) in the culture supernatants were determined using enzyme-linked immunosorbent assay. Levels of nitric oxide (NO) and type II collagen (CII) were measured using the Griess reaction and Western blot analysis, respectively. In addition, the pathologic role of Cn was examined in an in vivo model in which experimental OA was induced in mice by injecting type VII collagenase into the knee joints.Results. CnA was highly expressed in the chondrocytes of lesional OA cartilage. Cyclosporin A (CSA), a Cn inhibitor, inhibited spontaneous and interleukin-1␤-stimulated production of NO, MMP-1, and MMP-3 in chondrocytes. However, CSA increased the levels of production of CII, TIMP-1, and transforming growth factor ␤. Similar changes in MMP-1, NO, and CII expression levels in chondrocytes were observed after the targeted inhibition of Cn by overexpression of calcineurin binding protein 1, a natural Cn antagonist. Moreover, in the mouse model, animals treated with CSA showed a significant decrease in both the extent and the severity of cartilage damage, which were assessed macroscopically and microscopically, compared with vehicle-treated animals.Conclusion. These results suggest that CnA is critically involved in the catabolic and anabolic activities of chondrocytes as well as in the progression of experimental OA. Targeted inhibition of CnA may be an effective treatment strategy for OA.The failure of chondrocytes to maintain cartilage integrity is a key event leading to joint destruction in many arthritic conditions, including rheumatoid arthritis (RA), osteoarthritis (OA), and septic arthritis (1,2). Chondrocytes respond to a variety of stimuli, including proinflammatory cytokines and mechanical loading, by increasing the concentration of cartilage degradative enzymes and catabolic mediators. A disturbance in the regulation of the anabolic and catabolic activities of chondrocytes can result in a net loss of cartilage matrix components. Regardless of the initiating stimuli, the key process in cartilage degradation is similar, involving specific matrix metalloproteinases (MMPs), nitric oxide (NO), and aggrecanases, which are members of the ADAMTS family (3). Previous studies have demonstrated that interleukin-1␤ (IL-1␤) and tumor necrosis factor ␣ (TNF␣) also play key roles in cartilage degradation by stimulating their own production and inducing chondrocytes to produce MMPs and NO (4,5).

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“…Similar gene induction for TGF␤ and TIMP-1 in CSA-treated fibroblasts has been reported (30,31). The precise molecular mechanism of TGF␤ induction in chondrocytes is unclear.…”

Section: Discussionsupporting

confidence: 51%

Calcineurin modulates the catabolic and anabolic activity of chondrocytes and participates in the progression of experimental osteoarthritis

Yoo

Park

Yoon

et al. 2007

Arthritis & Rheumatism

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“…These results show that CsA has a stimulating effect on HGF, which was consistent with report that CsA increases the proliferation of human gingival fibroblasts in vitro. 12) Proteomics analysis has emerged as most sensitive detector of gene alterations and aberrant gene expression, protein modification as results of physio-pathogenesis. In the present study, proteomic method was employed to detect possible changes at a protein level after CsA treatment in HGF.…”

Section: Resultsmentioning

confidence: 99%

“…5) Moreover, some previous studies have demonstrated that CsA stimulates the proliferation of human gingival fibroblasts (HGF). 3,12) On the other hand, there has been still controversy over the pathology of CsAGO with conflicting reports as to whether it represents a true hyperplasia. It would appear that CsA has the potential to alter the metabolism HGF in several ways.…”

mentioning

confidence: 99%

Proteomic Analysis in Cyclosporin A-Induced Overgrowth of Human Gingival Fibroblasts

Jung

Kang

Jeong

et al. 2009

Biological & Pharmaceutical Bulletin

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“…Additionally, CSA has been shown to have direct transformative effects on keratinocytes and may induce phenotypic changes that can increase cell invasiveness and unregulated tumor growth (13,14). CSA has also been associated with the promotion and stimulation of cellular proliferation in normal human fibroblasts (15). Currently, however, the precise mechanism underlying the tumorigenic effect of CSA on SCCs -and its association with catastrophic SCC, as defined above -remains largely unknown.…”

Section: Introductionmentioning

confidence: 99%

Cyclosporine A immunosuppression drives catastrophic squamous cell carcinoma through IL-22

Abikhair¹,

Mitsui²,

Yanofsky³

et al. 2016

JCI Insight

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Cyclosporin A Induces Proliferation in Human Gingival Fibroblasts via Induction of Transforming Growth Factor‐β1

Abstract: The results presented here suggest that CsA stimulatory induction of NG fibroblast proliferation is mediated via TGF-beta1 in an autocrine fashion.

Cited by 73 publications

References 46 publications

Calcineurin modulates the catabolic and anabolic activity of chondrocytes and participates in the progression of experimental osteoarthritis

Calcineurin modulates the catabolic and anabolic activity of chondrocytes and participates in the progression of experimental osteoarthritis

Proteomic Analysis in Cyclosporin A-Induced Overgrowth of Human Gingival Fibroblasts

Cyclosporine A immunosuppression drives catastrophic squamous cell carcinoma through IL-22

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