LIM-only protein Fhl2 impairs skin wound healing

In recent years, considerable progress has been made in understanding the role of growth factors and cytokines in wound healing. These factors are released from injured vessels and coagulated platelets and trigger an infl ammatory response that initiates the deposition of a provisional extracellular matrix. In parallel, mesenchymal and endothelial precursor cells invade the wound to form the granulation tissue and to contract the wounded area. Contraction of the granulation tissue by mesodermal fi broblasts is of high importance for sealing the wound, as it helps to bring the wound margins together. To be able to contract effi ciently, mesenchymal cells of the granulation tissue differentiate into myofi broblasts characterized by a well-developed cytoskeleton. Myofi broblasts express α-smooth muscle actin (α-SMA), which is incorporated into actin stress fi bers and enables them to develop much higher mechanical forces (Hinz and Gabbiani, 2003). Hence, induction of α-SMA expression in fi broblasts is a critical step in wound healing. Besides growth factors and cytokines, bioactive lipids have been identifi ed as important signal molecules, modulating infl ammatory responses, cell growth, and tissue formation. However, the role of lipid-induced signaling and its contribution to wound healing is still poorly understood. We previously showed that sphingosine-1-phosphate (S1P) triggers a signal transduction cascade mediating nuclear translocation of the LIM-only protein Fhl2 in response to activation of the RhoA GTPase (Muller et al., 2000, 2002). We and others further identifi ed the LIM-only protein Fhl2 as interacting with transcription factors, including androgen receptor (Muller et al., 2002), serum response factor (SRF; Philippar et al., 2004; Purcell et al., 2004), Jun, and Fos (Morlon and Sassone-Corsi, 2003), as well as with integrin receptors (Wixler et al., 2000; Samson et al., 2004) Defi ciency in the LIM-only protein Fhl2 impairs skin wound healing