[Pathophysiological relevance of peroxisome proliferators activated receptors (PPAR) to joint diseases - the pro and con of agonists].
Peroxisome proliferators activated receptors (PPAR) are ligand-inducible nuclear transacting factors comprising three subtypes, PPARalpha, PPARbeta/delta and PPARgamma, which play a key role in lipids and glucose homeostasis. All PPAR subtypes have been identified in joint or inflammatory cells and their activation resulted in a transcriptional repression of pro-inflammatory cytokines (IL-1, TNFalpha), early inflammatory genes (NOS(2), COX-2, mPGES-1) or matrix metalloproteases (MMP-1, MMP-13), at least for the gamma subtype. PPAR full agonists were also shown to stimulate IL-1 receptor antagonist (IL-1Ra) production by cytokine-stimulated articular cells in a subtype-dependent manner. These anti-inflammatory and anti-catabolic properties were confirmed in animal models of joint diseases where PPAR agonists reduced synovial inflammation while preventing cartilage destruction or inflammatory bone loss, although many effects required much higher doses than needed to restore insulin sensitivity or to lower circulating lipid levels. However, these promising effects of PPAR full agonists were hampered by their ability to reduce the growth factor-dependent synthesis of extracellular matrix components or to induce chondrocyte apoptosis, by the possible contribution of immunosuppressive properties to their anti-arthritic effects, by the increased adipocyte differentiation secondary to prolonged stimulation of PPARgamma, and by a variable contribution of PPAR subtypes depending on the system. Clinical data are scarce in rheumatoid arthritis (RA) patients whereas thousands of patients worldwilde, treated with PPAR agonists for type 2 diabetes or dyslipidemia, are paradoxically prone to suffer from osteoarthritis (OA). Whereas high dosage of full agonists may expose RA patients to cardiovascular adverse effects, the proof of concept that PPAR agonists have therapeutical relevance to OA may benefit from an epidemiological follow-up of joint lesions in diabetic or hyperlipidemic patients treated for long periods of time with glitazones or fibrates. Additionally, cellular and animal studies are required to assess whether partial agonists of PPAR (SPPARMs) may preserve therapeutical properties with potentially less safety concern.
Jouzeau
Jean-Yves
JY
UMR CNRS-Nancy Université, France. Jean-Yves.Jouzeau@pharma.uhp-nancy.fr
Moulin
David
D
Koufany
Meriem
M
Sebillaud
Sylvie
S
Bianchi
Arnaud
A
Netter
Patrick
P
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000188:drug therapy; D002839:Chromans / Q000494:pharmacology / Q000627:therapeutic use; D019281:Dimerization; D005109:Extracellular Matrix / Q000502:physiology; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use; D007592:Joint Diseases / Q000503:physiopathology*; D010003:Osteoarthritis / Q000188:drug therapy; D047493:PPAR alpha / Q000502:physiology; D048068:PPAR-beta / Q000187:drug effects / Q000502:physiology; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists* / Q000235:genetics / Q000502:physiology*; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology / Q000627:therapeutic use; D000077288:Troglitazone
D002839:Chromans; D007004:Hypoglycemic Agents; D047493:PPAR alpha; D048068:PPAR-beta; D047492:Peroxisome Proliferator-Activated Receptors; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D000077288:Troglitazone; C039671:ciglitazone