Vitamin D receptor regulates TGF-β signalling in systemic sclerosis.
BACKGROUND
Vitamin D receptor (VDR) is a member of the nuclear receptor superfamily. Its ligand, 1,25-(OH)2D, is a metabolically active hormone derived from vitamin D3. The levels of vitamin D3 are decreased in patients with systemic sclerosis (SSc). Here, we aimed to analyse the role of VDR signalling in fibrosis.


METHODS
VDR expression was analysed in SSc skin, experimental fibrosis and human fibroblasts. VDR signalling was modulated by siRNA and with the selective agonist paricalcitol. The effects of VDR on Smad signalling were analysed by reporter assays, target gene analyses and coimmunoprecipitation. The effects of paricalcitol were evaluated in the models of bleomycin-induced fibrosis and fibrosis induced by overexpression of a constitutively active transforming growth factor-β (TGF-β) receptor I (TBRI(CA)).


RESULTS
VDR expression was decreased in fibroblasts of SSc patients and murine models of SSc in a TGF-β-dependent manner. Knockdown of VDR enhanced the sensitivity of fibroblasts towards TGF-β. In contrast, activation of VDR by paricalcitol reduced the stimulatory effects of TGF-β on fibroblasts and inhibited collagen release and myofibroblast differentiation. Paricalcitol stimulated the formation of complexes between VDR and phosphorylated Smad3 in fibroblasts to inhibit Smad-dependent transcription. Preventive and therapeutic treatment with paricalcitol exerted potent antifibrotic effects and ameliorated bleomycin- as well as TBRI(CA)-induced fibrosis.


CONCLUSIONS
We characterise VDR as a negative regulator of TGF-β/Smad signalling. Impaired VDR signalling with reduced expression of VDR and decreased levels of its ligand may thus contribute to hyperactive TGF-β signalling and aberrant fibroblast activation in SSc.
Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany.
Pawel
P
Zerr
Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany.
Stefan
S
Vollath
Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany.
Katrin
K
Palumbo-Zerr
Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany Department of Rheumatology of the First Faculty of Medicine, Institute of Rheumatology, Charles University, Prague, Czech Republic.
Michal
M
Tomcik
Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany.
Jingang
J
Huang
Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany.
Alfiya
A
Distler
Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany.
Christian
C
Beyer
Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany.
Clara
C
Dees
Department of Orthopedic Trauma Surgery, University of Erlangen-Nuremberg, Erlangen, Germany.
Kolja
K
Gela
Center of Experimental Rheumatology and Zurich Center of Integrative Human Physiology, University Hospital Zurich, Zurich, Switzerland.
Oliver
O
Distler
Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany.
Georg
G
Schett
Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany.
Jörg H W
JH
Distler
D000328:Adult; D000368:Aged; D000818:Animals; D001761:Bleomycin / Q000633:toxicity; D004195:Disease Models, Animal; D004872:Ergocalciferols / Q000494:pharmacology; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D005355:Fibrosis / Q000139:chemically induced / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D034741:RNA, Small Interfering / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000819:agonists / Q000378:metabolism*; D012595:Scleroderma, Systemic / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D012867:Skin / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051785:Smad Proteins / Q000187:drug effects / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000187:drug effects / Q000378:metabolism*; D055815:Young Adult
D004872:Ergocalciferols; D034741:RNA, Small Interfering; D018167:Receptors, Calcitriol; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; C579457:VDR protein, human; D001761:Bleomycin; C084656:paricalcitol
Fibroblasts; Systemic Sclerosis; Treatment