BONE MORPHOGENETIC PROTEIN-2 INDUCES SCAR FORMATION AND SKIN MATURATION IN THE 2ND-TRIMESTER FETUS

Fetal mammals heal skin wounds through the second trimester of develop ment without evidence of scar. We have investigated the role of bone m orphogenetic protein 2 (BMP-2), which is a member of the TGF-beta supe rfamily,, in normal skin development and fetal wound healing. We first used RNA in situ hybridization to demonstrate that BMP-2 was expresse d at low levels in the developing hair follicles and in the epidermis of normal human fetal skin. We then created an in vivo model to test h ow exogenous BMP-2 would affect fetal skin development and wound heali ng. Fifty micrograms of BMP-2 was implanted into the subcutis of five 70-day-old fetal lambs through a full-thickness linear incision. The B MP-2 was placed beneath the right half of the wound, whereas the left half sen ed as an untreated control. In two of the five animals 1 mu g of TGF-beta was placed into the same position in addition to the 50 m u g of BMP-2. Twenty days later (90 days gestation, term = 140 days) a ll the fetal wounds were examined for evidence of cellular hyperprolif eration and scar formation. BMP-2 induced massive dermal and epidermal growth when compared with controls. This finding was characterized by marked epidermal thickening and keratinization, a dramatic increase i n the number of hair follicles, and more than 50 percent thickening of the dermis. The dermal thickening was the result of both increased ce llularity and deposition of large irregular collagen bundles. Wounds t reated with both BMP-2 and TGF-beta healed also with an adult-like pat tern of scar formation. Surprisingly, the wounds with BMP-2 alone heal ed with an equal pattern of scar, indicating that there was not an add itive effect of combining BMP-2 and TGF-beta, We conclude that BMP-2 i s a pleomorphic growth factor that induces cellular growth, maturation , and fibroplasia in both the dermis and epidermis. Further analysis o f this growth factor in both fetal and adult wound healing may lead to important discoveries regarding the control of scar formation and fib rosis in many adult tissues.