Peroxisome proliferator-activated receptor γ: innate protection from excessive fibrogenesis and potential therapeutic target in systemic sclerosis.
OBJECTIVE
Progressive organ fibrosis and pulmonary arterial hypertension (PAH) are the leading causes of death in patients with systemic sclerosis (SSc). However, the pathogenesis and the link between these two processes remain obscure. A better understanding of these events is needed in order to facilitate the discovery and development of effective therapies for SSc.


RESULTS
Recent reports provide evidence that the orphan receptor peroxisome proliferator-activated receptor γ (PPARγ), better known for its pivotal role in metabolism, has potent effects on inflammation, fibrogenesis and vascular remodeling and is important in the pathogenesis of fibrosis and PAH, and as a potential therapeutic target in SSc. The studies discussed in this review indicate that ligands of PPARγ potently modulate connective tissue turnover and suggest that aberrant expression or function of PPARγ is associated with, and very likely contributes to, the progression of pathological fibrosis and vascular remodeling. These observations are of particularly relevance because FDA-approved drugs of the thiazolidinedione class currently used for the treatment of obesity-associated type 2 diabetes activate PPARγ signaling. Moreover, novel PPARγ ligands with selective activity are under development or in clinical trials for inflammatory diseases, asthma, Alzheimer disease and cancer.


CONCLUSIONS
Drugs targeting the PPARγ pathway might be effective for the control of fibrosis as well as pathological vascular remodeling underlying PAH and, therefore, might have a therapeutic potential in SSc. A greater understanding of the mechanisms underlying the antifibrogenic and vascular remodeling activities of PPARγ ligands will be necessary in order to advance these drugs into clinical use.
Wei
Jun
J
Division of Rheumatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
Bhattacharyya
Swati
S
Varga
John
J
D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000639:trends; D005355:Fibrosis; D006801:Humans; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors* / Q000502:physiology*; D047495:PPAR gamma / Q000037:antagonists & inhibitors* / Q000502:physiology*; D012595:Scleroderma, Systemic / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D018836:Inflammation Mediators; D047495:PPAR gamma