Profibrotic role of myostatin in Peyronie's disease.
BACKGROUND
The primary histologic finding in many urologic disorders, including Peyronie's disease (PD), is fibrosis, mainly mediated by the transforming growth factor beta1 (TGFbeta1).


OBJECTIVE
To determine whether another member of the TGFbeta family, myostatin, (i) is expressed in the human PD plaque and normal tunica albuginea (TA), their cell cultures, and the TGFbeta1-induced PD lesion in the rat model; (ii) is responsible for myofibroblast generation, collagen deposition, and plaque formation; and (iii) mediates the profibrotic effects of TGFbeta1 in PD.


METHODS
Human TA and PD tissue sections, and cell cultures from both tissues incubated with myostatin and TGFbeta1 were subjected to immunocytochemistry for myostatin and alpha-smooth muscle actin (ASMA). The cells were assayed by western blot, Real time-Polymerase chain reaction (RT-PCR), and ribonuclease protection. Myostatin cDNA and shRNA were injected, with or without TGFbeta1, in the rat penile TA, and plaque size was estimated by Masson.


METHODS
Myostatin expression in the human TA, the PD plaque, and their cell cultures, and myostatin effects on the PD-like plaque in the rat.


RESULTS
A threefold overexpression of myostatin was found in the PD plaque as compared with the TA. In PD cells, myostatin expression was mainly in the myofibroblasts, and in the TA cells, it increased upon passage paralleling myofibroblast differentiation and was up-regulated by TGFbeta1. Myostatin or its cDNA construct increased the myofibroblast number and collagen in TA cells. Myostatin was detected in the TGFbeta1-induced PD-like plaque of the rat partly in the myofibroblasts, and in the TA. Myostatin cDNA injected in the TA induced a plaque and intensified the TGFbeta1 lesion, which was not reduced by myostatin shRNA.


CONCLUSIONS
Myostatin is overexpressed in the PD plaque, partly because of myofibroblast generation. Although myostatin induces a plaque in the rat TA, it does not appear to mediate the one triggered by TGFbeta1, thus suggesting that both proteins act concurrently and that therapy should target their common downstream effectors.
Cantini
Liliana P
LP
Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Urology Research Laboratory, Los Angeles, CA, USA.
Ferrini
Monica G
MG
Vernet
Dolores
D
Magee
Thomas R
TR
Qian
Ansha
A
Gelfand
Robert A
RA
Rajfer
Jacob
J
Gonzalez-Cadavid
Nestor F
NF
D000818:Animals; D005347:Fibroblasts / Q000473:pathology; D005355:Fibrosis / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D055435:Myostatin; D010411:Penile Induration / Q000378:metabolism* / Q000503:physiopathology; D010413:Penis / Q000503:physiopathology*; D051381:Rats; D011916:Rats, Inbred F344; D013234:Stem Cells; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
C525911:MSTN protein, human; C525913:Mstn protein, rat; D055435:Myostatin; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1