Messadi DV^1,2 , Le A¹, Berg S¹, Huang G¹, Zhuang W¹ and Bertolami CN³

¹ School of Dentistry, ² Dental Research Institute, University of California, Los Angeles, California, ³ School of Dentistry,University of California, San Francisco, California, USA

Received 1/8/98 Accepted 2/3/98

5. DISCUSSION

TGF- beta 1 is a multifunctional regulatory factor exerting a diversity of different effects on cell and tissue differentiation, growth, and wound healing (20). Both PDGF and TGF-beta are released from the alpha granules of human platelets when these platelets aggregate and degranulate at the site of injury. Several investigators have shown that both PDGF and TGF-beta promote connective tissue deposition in vivo (21, 22), and can enhance the healing of dermal wounds in certain animal models (23, 24,25).

In this study, the effects of TGF- beta 1 on PDGF receptors (alpha and beta ) in human dermal fibroblasts were studied both at the transcriptional and posttranscriptional levels. The present data demonstrate that TGF- beta 1 upregulates the expression of PDGF alpha receptor for keloid fibroblasts only, with no discernible effect on normal skin fibroblasts. The differences in TGF- beta 1 modulation of PDGF alpha receptor membrane expression in the cell lines tested also corresponds to the effect of TGF- beta 1 on PDGF alpha receptor subunit mRNA levels. Recent studies indicate that selected growth factors have the capacity to modulate proliferating responses to PDGF isoforms by affecting the expression of PDGF receptor subunits. Investigators have shown that scleroderma fibroblasts experience a distinct upregulation of PDGF alpha receptor after treatment with TGF-beta as well as increased responsiveness to PDGF-AA (26). This upregulation was not seen in normal human adult and foreskin fibroblasts treated under the same conditions (27). The authors speculate that this characteristic of scleroderma fibroblasts may be important for the in vivo expansion of this cell population, the same maybe true for the expansion of keloid fibroblasts. In studying the regulation of TGF-beta 1 on PDGF beta receptors for normal skin, normal scar and keloid fibroblasts, both at the protein and mRNA levels, no modulatory effect for any of the cell lines was found. One possibility is that PDGF-beta receptor levels are already maximal, or that more than one growth factor is needed for the upregulation of the PDGF-beta receptors in these cells. Other studies of PDGF receptor expression in wounds, have found that the PDGF-beta receptor is elevated in both chronic wounds and psoriasis, with no increase in PDGF- alpha receptors (28), the same is true for normal healing wounds (29), and in systemic sclerosis (30). Elevation of PDGF-alpha receptor expression in keloid fibroblasts only and not in normal skin was also demonstrated by Haisa and coworkers (31), who speculate that elevated levels of PDGF-alpha receptor in the keloid fibroblasts present in the keloid-derived cells would make them more responsive to PDGF AA as a chemoattractant and mitogen. The presence of PDGF AA in the tissue could selectively recruit cells with elevated PDGF alpha receptors forming a site with distinct subpopulation of fibroblasts. The reason for this differential expression of the PDGF-alpha receptor expression after TGF- beta 1 treatment in keloid fibroblasts only is still unknown. It may be due to differences in TGF- beta 1 signal-transduction pathways in keloid and normal skin fibroblasts, or it may reflect differences between the two cell lines in the levels or activities of transcription factors implicated in the regulation of the PDGF- alpha receptor gene.

At present, mechanisms of fibrosis in keloid scars and other fibroproliferative diseases such as scleroderma and pulmonary fibrosis are not fully understood. Factors such as PDGF and TGF-beta which are consistently found in fibrotic lesions, may stimulate fibroblasts to proliferate and synthesize extracellular matrix (31). Distinctive properties of abnormal scar fibroblasts such as increased extracellular matrix synthesis and abnormal phenotypic proliferation may play an essential role in the development of fibrosis. At present, the origin of abnormal fibroblasts residing in these lesions is unknown. One can speculate that, proliferation of a subpopulation of fibroblasts occurs—a subset expressing genes promoting increased production of, for instance, matrix collagen and fibronectin. The selective amplification of such a substrain of fibroblasts maybe associated with increased responsiveness of growth factors present in the lesion and, correspondingly, continued propagation of the particular strain(s).

These results indicate that an intertwining network of growth factors present in the early phases of the wound healing process may play a role in the pathogenesis of fibrotic disorders such as keloid scarring. This work accentuates the critical role of TGF-beta in this process.