Peroxisome Proliferator-Activated Receptor (PPAR)-β as a Target for Wound Healing Drugs

Peroxisome proliferator-activated receptor (PPAR) dysfunction has been implicated in the manifestation of many diseases and illnesses, ranging from obesity to cancer. Herein, we discuss the role of PPARβ, one of the three PPAR isotypes, during wound healing. While PPARβ expression is undetectable in unchallenged and healthy adult interfollicular mouse skin, it is robustly re-activated in stress situations, such as upon phorbol ester treatment, hair plucking and cutaneous wounding. The inflammatory reaction associated with a skin injury activates the keratinocytes at the edges of the wound. This activation involves PPARβ, whose expression and activity as transcription factor are up-regulated by pro-inflammatory signals. The re-activation of PPARβ influences three important properties of the activated keratinocytes that are vital for rapid wound closure, namely, survival, migration and differentiation. The anti-apoptotic and, thus, survival role of PPARβ is mediated by the up-regulation of expression of integrin-linked kinase and 3-phosphoinositide-dependent kinase-1. Both kinases are required for the full activation of the Akt1 survival cascade. Therefore, the up-regulation of PPARβ, early after injury, appears to be important to maintain a sufficient number of viable keratinocytes at the wound edge. At a later stage of wound repair, the stimulation of keratinocyte migration and differentiation by PPARβ is also likely to be important for the formation of a new epidermis at the wounded area. Consistent with these observations, the entire wound healing process is delayed in PPARβ +/− mice and wound closure is retarded by 2–3 days. The multiple roles of PPARβ in the complex keratinocyte response after injury and during skin repair certainly justify a further exploration of its potential as a target for wound healing drugs.