Paclitaxel modulates TGFbeta signaling in scleroderma skin grafts in immunodeficient mice.
BACKGROUND
Systemic sclerosis (SSc) is characterized by excessive fibrosis and obliterative vascular lesions. Abnormal TGFbeta activation is implicated in the pathogenesis of SSc. Aberrant TGFbeta/Smad signaling can be controlled by stabilization of microtubules with paclitaxel.


RESULTS
SSc and healthy human skin biopsies were incubated in the presence or absence of paclitaxel followed by transplantation into severe combined immunodeficient mice. TGFbeta 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.


CONCLUSIONS
Low-dose paclitaxel can significantly suppress TGFbeta/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 TGFbeta signaling.
Liu
Xialin
X
Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States of America.
Zhu
Shoukang
S
Wang
Tao
T
Hummers
Laura
L
Wigley
Fredrick M
FM
Goldschmidt-Clermont
Pascal J
PJ
Dong
Chunming
C
D000328:Adult; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000494:pharmacology*; D001706:Biopsy; D004305:Dose-Response Relationship, Drug; D005260:Female; D005355:Fibrosis; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008875:Middle Aged; D009389:Neovascularization, Pathologic; D017239:Paclitaxel / Q000008:administration & dosage / Q000494:pharmacology*; D010641:Phenotype; D012595:Scleroderma, Systemic / Q000188:drug therapy* / Q000503:physiopathology*; D015398:Signal Transduction / Q000187:drug effects*; D051785:Smad Proteins / Q000187:drug effects / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000187:drug effects / Q000502:physiology*; D014183:Transplantation, Heterologous
D000972:Antineoplastic Agents, Phytogenic; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D017239:Paclitaxel