Session Information
Title: Systemic Sclerosis, Fibrosing Syndromes and Raynaud's - Pathogenesis, Animal Models and Genetics I
Session Type: Abstract Submissions (ACR)
Background/Purpose :Systemic sclerosis (SSc) skin fibrosis is associated with attenuated cutaneous adipose tissue and adipogenic gene expression. Levels of the adipose-derived cytokine adiponectin (APN) and its receptors, are both reduced in SSc, and inversely correlated with extent of skin involvement. We investigated the role of APN in pathogenesis of skin fibrosis in mice with genetic APN gain- and loss-of-function, and determined the effects, mechanism and therapeutic potential of APN-derived synthetic peptides on the fibrotic process in vitro and in vivo.
Methods :Fibrotic responses were examined in human and mouse fibroblasts, skin organ cultures and 3D skin equivalents. Novel APN-derived peptides targeting APN receptors were designed and synthesized. Genetic and pharmacological manipulation of APN signaling was evaluated in mouse models of scleroderma.
Results :Mice lacking APN developed exaggerated cutaneous fibrosis and intradermal adipose loss upon bleomycin challenge. In contrast, ΔGly-APN mutant mice that have ~2-fold elevated levels of circulating APN were protected from fibrosis, and showed preferential expansion of intradermal adipose tissue. To directly evaluate the role of APN signaling in SSc fibrosis, recombinant APN, as well as synthetic APN-derived peptides were used. APN treatment of skin fibroblasts resulted in suppression of collagen synthesis, myofibroblast transformation and other fibrotic responses that were mediated via the energy-sensing enzyme AMP kinase. Synthetic APN-derived peptides targeting the APN receptors abrogated fibrotic responses in explanted fibroblasts, skin organ cultures and in 3D human skin equivalents. Daily treatment of mice with APN-derived peptides induced potent activation of AMP kinase in target organs in the absence of toxicity. Significantly, peptide treatment prevented, as well as reversed, bleomycin-induced cutaneous fibrosis.
Conclusion :We identified an important homeostatic role for the adipocyte-derived cytokine APN in negative regulation of collagen deposition and myofibroblast accumulation, highlighting a novel link between metabolism and skin fibrosis. Restoring impaired APN signaling in SSc (scleroderma) using synthetic APN-derived peptides might therefore represent a pharmacological approach to fibrosis therapy.
Disclosure:
F. Fang,
None;
R. G. Marangoni,
None;
X. Zhou,
None;
W. Hong,
None;
B. Ye,
None;
A. Yoshihide,
None;
S. Sato,
None;
Y. Masui,
None;
C. Zhang,
None;
K. Lakota,
None;
J. Wei,
None;
M. E. Hinchcliff,
None;
P. Scherer,
None;
L. Otvos,
None;
J. Varga,
None.
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