Periostin facilitates skin sclerosis via PI3K/Akt dependent mechanism in a mouse model of scleroderma.
OBJECTIVE
Periostin, a novel matricellular protein, is recently reported to play a crucial role in tissue remodeling and is highly expressed under fibrotic conditions. This study was undertaken to assess the role of periostin in scleroderma.


METHODS
Using skin from patients and healthy donors, the expression of periostin was assessed by immunohistochemistry and immunoblotting analyses. Furthermore, we investigated periostin(-/-) (PN(-/-)) and wild-type (WT) mice to elucidate the role of periostin in scleroderma. To induce murine cutaneous sclerosis, mice were subcutaneously injected with bleomycin, while untreated control groups were injected with phosphate-buffered saline. Bleomycin-induced fibrotic changes were compared in PN(-/-) and WT mice by histological analysis as well as by measurements of profibrotic cytokine and extracellular matrix protein expression levels in vivo and in vitro. To determine the downstream pathway involved in periostin signaling, receptor neutralizing antibody and signal transduction inhibitors were used in vitro.


RESULTS
Elevated expression of periostin was observed in the lesional skin of patients with scleroderma compared with healthy donors. Although WT mice showed marked cutaneous sclerosis with increased expression of periostin and increased numbers of myofibroblasts after bleomycin treatment, PN(-/-) mice showed resistance to these changes. In vitro, dermal fibroblasts from PN(-/-) mice showed reduced transcript expression of alpha smooth actin and procollagen type-I alpha 1 (Col1α1) induced by transforming growth factor beta 1 (TGFβ1). Furthermore, recombinant mouse periostin directly induced Col1α1 expression in vitro, and this effect was inhibited by blocking the αv integrin-mediated PI3K/Akt signaling either with anti-αv functional blocking antibody or with the PI3K/Akt kinase inhibitor LY294002.


CONCLUSIONS
Periostin plays an essential role in the pathogenesis of Bleomycin-induced scleroderma in mice. Periostin may represent a potential therapeutic target for human scleroderma.
Department of Dermatology, Osaka University Graduate School of Medicine, Osaka, Japan.
Lingli
L
Yang
Satoshi
S
Serada
Minoru
M
Fujimoto
Mika
M
Terao
Yorihisa
Y
Kotobuki
Shun
S
Kitaba
Saki
S
Matsui
Akira
A
Kudo
Tetsuji
T
Naka
Hiroyuki
H
Murota
Ichiro
I
Katayama
D000328:Adult; D000368:Aged; D000818:Animals; D001761:Bleomycin; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D024042:Collagen Type I / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D004195:Disease Models, Animal; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005260:Female; D005355:Fibrosis; D055786:Gene Knockout Techniques; D006801:Humans; D039564:Integrin alphaV / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D058628:Myofibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012595:Scleroderma, Systemic / Q000201:enzymology* / Q000473:pathology*; D012598:Sclerosis; D012867:Skin / Q000187:drug effects / Q000473:pathology*; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects; D055815:Young Adult
D001761:Bleomycin; D015815:Cell Adhesion Molecules; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D016326:Extracellular Matrix Proteins; D039564:Integrin alphaV; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D053773:Transforming Growth Factor beta1; C000716128:Col1a1 protein, mouse; C082838:Postn protein, mouse