The CNN family comprises as yet six different members, including
connective tissue growth factor (CTGF), cysteine-rich 61 (cyr61),
nephroblastoma overexpressed (nov), WISP-1, WISP-2, and WISP-3.
They are secreted proteins that contain 38 conserved cysteine
residues that are organized into 4 distinct structural modules.
Members of this family appear to be involved in embryonic development,
differentiation, as well as pathological processes (36
addition, CTGF and cyr61 have been suggested to play a role
in wound repair. CTGF is expressed in many different tissues
and organs and stimulates proliferation and chemotaxis of fibroblasts
). Most interestingly, it is a potent inducer of
extracellular matrix proteins, such as collagen type I and
fibronectin and their integrin receptors (93
), and it acts
as a mediator of TGF-
1 in these processes (150
). Due to this
function and to the fact that it is overexpressed in various
types of fibrotic disease, CTGF has been suggested to be a
major player in the pathogenesis of fibrotic processes (36
A. Expression of CTGF in Skin Wounds
First evidence for a role of CTGF in cutaneous wound repaircame from studies by Igarashi et al. (129). Using a rat woundmodel consisting of a subcutaneously implanted stainless steelmesh chamber, they demonstrated the presence of CTGF mRNA inwounded but not in normal skin. Highest levels of CTGF transcriptswere observed at day 9 after injury that coincides with theinitial ingrowth of granulation tissue (129). In another studyCTGF mRNA levels were analyzed in full-thickness excisionalmouse wounds in mice. In this model, CTGF mRNA was most abundantat day 1 after injury and declined to basal levels within thenext 5 days (67). Due to the potent effect of CTGF on fibroblastproliferation and matrix deposition by these cells, the upregulationof CTGF expression after injury is likely to be important forgranulation tissue formation and subsequent scar formation.In addition, it was recently demonstrated that CTGF promotesendothelial proliferation, migration, survival, and adhesionin vitro and angiogenesis in vivo (14, 248), suggesting thatthis protein might also be involved in wound angiogenesis.
B. Expression of Cyr61 in Skin Wounds
In addition to CTGF, Cyr61 is likely to play a role in cutaneouswound healing. Cyr61 was shown to promote chemotaxis of fibroblastsand to enhance the mitogenic effect of other growth factorsfor these cells (147). Furthermore, it was identified as anangiogenic inducer in vivo (15). To determine the expressionpattern of the cyr61 gene in healing skin wounds, the expressionof this gene was examined in full-thickness incisional woundsof transgenic mice that express the bacterial lacZ gene encoding-galactosidase under the control of the endogenous cyr61 genepromoter (49). These studies revealed a strong expressionof Cyr61 in dermal fibroblasts of the granulation tissue. Invitro, Cyr61 activated a genetic program for wound repair incultured skin fibroblasts, indicating that Cyr61 regulatesinflammation, angiogenesis, cell-matrix interactions, and matrixremodeling after skin injury (49).