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

2. INTRODUCTION

Abnormal healing after traumatic injury is often manifested as excessive fibrosis and is recognized clinically as hypertrophic scars or keloids. These conditions represent debilitating derangement in remodeling and are associated with impaired function and significant dysmorphea. They are defined largely by an abnormal accumulation of extracellular matrix (1). Previous studies have independently suggested a role for transforming growth factor beta1 (TGF-beta1) (2), and platelet derived growth factors (PDGF) in tissue repair (3); however their involvement in abnormal healing has not been adequately explored nor has the specific relationship between TGF-beta1and PDGF receptors, in orofacial tissue repair been studied.

TGF-beta1 is a well known and potent biological response modifier implicated in a wide array of biologic processes, including tissue repair and modulation of extracellular matrix accumulation (4).

PDGF isoforms are potent mitogens and chemoattractants for fibroblasts. They have been suggested to play an important role in wound healing and have been implicated in several fibroproliferative disorders such as systemic sclerosis, pulmonary fibrosis and atherosclerosis (5). Three different isoforms of PDGF have been identified (AA, AB, BB). These isoforms bind and dimerize two PDGF receptor subtypes (alpha and beta) (6). PDGF-AA binds only PDGF alpha-receptor subtype (PDGF-alpha R), whereas PDGF-AB and PDGF-BB bind both PDGF-receptors subtypes (alpha and beta) Matsui and coworkers (7), also Seppa and coworkers (8) have reported that both PDGF receptors -(alpha and beta) transduce the signals for both mitogenesis and chemotaxis. It has been previously demonstrated that TGF-beta1 can upregulate or downregulate the PDGF-alpha R fibroblasts depending on the cell type (9). TGF-beta1 has been reported to downregulate the PDGF- alpha R on human smooth muscle cells and human foreskin fibroblasts (10) and also on human periodontal ligament fibroblasts (11). It upregulates PDGF- alpha R on fibroblasts derived from scleroderma patients with no effect on PDGF-beta receptor (12) . The reason for these contradictory results is not clear, but may be due to TGF-beta modulating PDGF receptors in both cell and species specific manner.

We have previously shown (13) that fibroblasts derived from scar tissues (normal scar and keloid) secrete TGF-beta1 in active form, while normal skin fibroblasts (NSk) secrete fibroblasts in latent form. Moreover, we have shown that scar fibroblasts exhibit greater autocrine responsiveness to TGF-beta1 than do skin fibroblasts. Such findings suggest that TGF-beta1 functions differently in normal skin than it does in scar tissues. The aim of this study is to clarify the roles of TGF-beta1 and PDGF in abnormal scar formation after traumatic injury. To do so, we examined the effect of TGF-beta1 on fibroblasts derived from normal skin (NSk) and scar tissues (both normal scar [NSc] and abnormal scar [keloid]), with regard to PDGF alpha and beta receptor cell surface production and gene expression.