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Connective tissue growth factor/cysteine-rich 61
- Regulation of Wound Healing by Growth Factors and Cytokines

The CNN family comprises as yet six different members, includingconnective 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 cysteineresidues 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). Inaddition, CTGF and cyr61 have been suggested to play a rolein wound repair. CTGF is expressed in many different tissuesand organs and stimulates proliferation and chemotaxis of fibroblastsdirectly (31). Most interestingly, it is a potent inducer ofextracellular matrix proteins, such as collagen type I andfibronectin and their integrin receptors (93), and it actsas a mediator of TGF-{beta}1 in these processes (150). Due to thisfunction and to the fact that it is overexpressed in varioustypes of fibrotic disease, CTGF has been suggested to be amajor 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{beta}-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).

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