Peroxisome proliferator-activated receptor (PPAR)-beta as a target for wound healing drugs: what is possible?
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 PPARbeta, one of the three PPAR isotypes, during wound healing. While PPARbeta 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 PPARbeta, whose expression and activity as transcription factor are up-regulated by pro-inflammatory signals. The re-activation of PPARbeta 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 PPARbeta 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 PPARbeta, 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 PPARbeta 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 PPARbeta +/- mice and wound closure is retarded by 2-3 days. The multiple roles of PPARbeta 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.
Tan
Nguan Soon
NS
Unité CIG-Sciences, Centre Intégratif de Génomique, Université de Lausanne, Lausanne, Switzerland.
Michalik
Liliane
L
Desvergne
Beatrice
B
Wahli
Walter
W
D000818:Animals; D002465:Cell Movement; D015603:Keratinocytes / Q000502:physiology; D051379:Mice; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects* / Q000502:physiology; D012867:Skin / Q000293:injuries*; D014157:Transcription Factors / Q000187:drug effects* / Q000502:physiology; D014945:Wound Healing / Q000187:drug effects*; D016335:Zinc Fingers / Q000187:drug effects*
D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors