Smad3 is required for dedifferentiation of retinal pigment epithelium following retinal detachment in mice.
Retinal pigment epithelial (RPE) cells dedifferentiate and undergo epithelial-mesenchymal transition (EMT) following retinal detachment, playing a central role in formation of fibrous tissue on the detached retina and vitreous retraction (proliferative vitreoretinopathy (PVR)). We have developed a mouse model of subretinal fibrosis with implications for PVR in which retinal detachment is induced without direct damage to the RPE cells. Transforming growth factor-beta (TGF-beta) has long been implicated both in EMT of RPEs and the development of PVR. Using mice null for Smad3, a key signaling intermediate downstream of TGF-beta and activin receptors, we show that Smad3 is essential for EMT of RPE cells induced by retinal detachment. De novo accumulation of fibrous tissue derived from multilayered RPE cells was seen following experimental retinal detachment in eyes of wild type, but not Smad3-null mice. Expression of alpha-smooth muscle actin, a hallmark of EMT in this cell type, and extracellular matrix components, lumican and collagen VI, were also not observed in eyes of Smad3-null mice. Our data show that induction of PDGF-BB by Smad3-dependent TGF-beta signaling is likely an important secondary proliferative component of the disease process. The results suggest that blocking the Smad3 pathway might be beneficial in prevention/treatment of PVR.
Department of Ophthalmology, Wakayama Medical University, Kimiidera, Wakayama, Japan. shizuya@wakayama-med.ac.jp
Shizuya
S
Saika
Satoko
S
Kono-Saika
Takeshi
T
Tanaka
Osamu
O
Yamanaka
Yoshitaka
Y
Ohnishi
Misako
M
Sato
Yasuteru
Y
Muragaki
Akira
A
Ooshima
Jiyun
J
Yoo
Kathleen C
KC
Flanders
Anita B
AB
Roberts
D000199:Actins / Q000378:metabolism; D000818:Animals; D000077214:Becaplermin; D015415:Biomarkers / Q000032:analysis; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D011508:Chondroitin Sulfate Proteoglycans / Q000378:metabolism; D024142:Collagen Type VI / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000502:physiology*; D004195:Disease Models, Animal; D019084:Fluorescent Antibody Technique, Indirect; D006801:Humans; D007632:Keratan Sulfate / Q000378:metabolism; D000071234:Lumican; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D010857:Pigment Epithelium of Eye / Q000378:metabolism / Q000473:pathology*; D010982:Platelet-Derived Growth Factor / Q000096:biosynthesis / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis; D012163:Retinal Detachment / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction / Q000502:physiology; D051900:Smad3 Protein; D013552:Swine; D015534:Trans-Activators / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology / Q000502:physiology*; D053781:Transforming Growth Factor beta2; D018630:Vitreoretinopathy, Proliferative / Q000378:metabolism / Q000473:pathology*
D000199:Actins; D015415:Biomarkers; D011508:Chondroitin Sulfate Proteoglycans; D024142:Collagen Type VI; D004268:DNA-Binding Proteins; C000604306:LUM protein, human; C000604307:Lum protein, mouse; D000071234:Lumican; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; C497790:SMAD3 protein, human; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; C509041:TGFB2 protein, human; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D053781:Transforming Growth Factor beta2; D000077214:Becaplermin; D007632:Keratan Sulfate