Paclitaxel modulates TGFβ signaling in scleroderma skin grafts in immunodeficient mice

Xialin Liu, Shoukang Zhu, Tao Wang, Laura Hummers, Fredrick M. Wigley, Pascal Goldschmidt-Clermont, Chunming Dong

Research output: Contribution to journalArticle

47 Citations (Scopus)

Abstract

Background: Systemic sclerosis (SSc) is characterized by excessive fibrosis and obliterative vascular lesions. Abnormal TGFβ activation is implicated in the pathogenesis of SSc. Aberrant TGFβ/Smad signaling can be controlled by stabilization of microtubules with paclitaxel. Methods and Findings: SSc and healthy human skin biopsies were incubated in the presence or absence of paclitaxel followed by transplantation into severe combined immunodeficient mice. TGFβ signaling, fibrosis, and neovessel formation were evaluated by quantitative RT-PCR and immunohistochemical staining. Paclitaxel markedly suppressed Smad2 and Smad3 phosphorylation and collagen deposition in SSc grafts. As a result, the autonomous maintenance/reconstitution of the SSc phenotype was prevented. Remarkably, SSc grafts showed a 2-fold increase in neovessel formation relative to normal grafts, regardless of paclitaxel treatment. Angiogenesis in SSc grafts was associated with a substantial increase in mouse PECAM-1 expression, indicating the mouse origin of the neovascular cells. Conclusion: Low-dose paclitaxel can significantly suppress TGFβ/Smad activity and lessen fibrosis in SCID mice. Transplantation of SSc skin into SCID mice elicits a strong angiogenesis - an effect not affected by paclitaxel. Although prolonged chemotherapy with paclitaxel at higher doses is associated with pro-fibrotic and anti-angiogenic changes, the findings described here indicate that low-dose paclitaxel may have therapeutic benefits for SSc via modulating TGFβ signaling.

Original languageEnglish
Article numbere354
Pages (from-to)1334-1342
Number of pages9
JournalPLoS Medicine
Volume2
Issue number12
DOIs
StatePublished - Dec 1 2005
Externally publishedYes

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Systemic Scleroderma
Paclitaxel
Grafts
Skin
Transplants
SCID Mice
Fibrosis
CD31 Antigens
Transplantation
Phosphorylation
Chemotherapy
Biopsy
Angiogenesis Inducing Agents
Microtubules
Collagen
Blood Vessels
Stabilization
Chemical activation
Maintenance
Staining and Labeling

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Liu, X., Zhu, S., Wang, T., Hummers, L., Wigley, F. M., Goldschmidt-Clermont, P., & Dong, C. (2005). Paclitaxel modulates TGFβ signaling in scleroderma skin grafts in immunodeficient mice. PLoS Medicine, 2(12), 1334-1342. [e354]. https://doi.org/10.1371/journal.pmed.0020354

Paclitaxel modulates TGFβ signaling in scleroderma skin grafts in immunodeficient mice. / Liu, Xialin; Zhu, Shoukang; Wang, Tao; Hummers, Laura; Wigley, Fredrick M.; Goldschmidt-Clermont, Pascal; Dong, Chunming.

In: PLoS Medicine, Vol. 2, No. 12, e354, 01.12.2005, p. 1334-1342.

Research output: Contribution to journalArticle

Liu, X, Zhu, S, Wang, T, Hummers, L, Wigley, FM, Goldschmidt-Clermont, P & Dong, C 2005, 'Paclitaxel modulates TGFβ signaling in scleroderma skin grafts in immunodeficient mice', PLoS Medicine, vol. 2, no. 12, e354, pp. 1334-1342. https://doi.org/10.1371/journal.pmed.0020354
Liu X, Zhu S, Wang T, Hummers L, Wigley FM, Goldschmidt-Clermont P et al. Paclitaxel modulates TGFβ signaling in scleroderma skin grafts in immunodeficient mice. PLoS Medicine. 2005 Dec 1;2(12):1334-1342. e354. https://doi.org/10.1371/journal.pmed.0020354
Liu, Xialin ; Zhu, Shoukang ; Wang, Tao ; Hummers, Laura ; Wigley, Fredrick M. ; Goldschmidt-Clermont, Pascal ; Dong, Chunming. / Paclitaxel modulates TGFβ signaling in scleroderma skin grafts in immunodeficient mice. In: PLoS Medicine. 2005 ; Vol. 2, No. 12. pp. 1334-1342.
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