Transforming growth factor type (3 (TGF-f3), when injected subcutaneously in newborn mice, causes formation of granulation tissue (induction of angiogenesis and activation offibroblasts to produce collagen) at the site of injection.These effects occur within 2-3 days at dose levels of <1 jg. Parallel in vitro studies show that TGF-(3 causes marked increase of either proline or leucine incorporation into collagen in either an NRK rat fibroblast cell line or early passage human dermal fibroblasts. Epidermal growth factor (EGF) and platelet-derived growth factor (PDGF) do not cause these same in vivo and in vitro effects; in both rat and human fibroblast cultures, EGF antagonizes the effects of TGF-(3 on collagen formation. We have obtained further data to support a role for

Type .8 transforming growth factor is a two-chain polypeptide of 25,000 daltons isolated from many tissues, including bovine kidney, human placenta, and human platelets. It has been characterized by its ability to stimulate reversible transformation of nonneoplastic murine fibroblasts, as measured by the formation of colonies of these cells in soft agar (ED50 = 4 pM TGF-/3 for NRK fibroblasts). We now show that the response of cells to TGF-,8 is bifunctional, in that TGF-IJ inhibits the anchorage-dependent growth of NRK fibroblasts and of human tumor cells by increasing cell cycle time. Moreover, the anchorage-independent growth of many human melanoma, lung carcinoma, and breast carcinoma cell lines is inhibited by TGF-fJ at concentrations in the same range as those that stimulate colony formation of NRK fibroblasts (average ED50 = 10-30 pM TGF-36 for inhibition). Whereas epidermal growth factor and TGF-. synergize to induce anchorage-independent growth of NRK fibroblasts, their effects on the growth of A-549 human lung carcinoma cells are antagonistic. The bifunctional response of cells to TGF-(3 is further demonstrated in Fischer rat 3T3 fibroblasts transfected with a cellular myc gene. In these cells TGFf3 synergizes with platelet-derived growth factor to stimulate colony formation but inhibits the colony formation induced by epidermal growth factor. The data indicate that the effects of TGF-8 on cells are not a function of the peptide itself, but rather of the total set of growth factors and their receptors that is operant in the cell at a given time.

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Maternal sources of transforming growth factor-beta 1 (TGF-beta 1) are shown here to contribute to the normal appearance and perinatal survival of TGF-beta 1 null newborn mice. Labeled TGF-beta 1 crossed the placenta and was recovered intact from various tissues after oral administration to mouse pups. TGF beta-1 protein was also detected in cells recovered from breast milk. In immunohistochemical analyses, TGF-beta 1 null embryos and null newborn pups born to TGF-beta 1 heterozygotes stained positive for TGF-beta 1, whereas those born to a null female were negative and had severe cardiac abnormalities. These results suggest an important role for maternal sources of TGF-beta 1 during development and, more generally, provide evidence for maternal rescue of targeted gene disruption in the fetus.

Abstract. Transforming growth factor-type 13 has been identified as a constituent of bone matrix 261:5693-5695). We used both developing bone and bone-forming cells in vitro to demonstrate the cellular origin of this peptide. TGF-13 mRNA was detected by Northern analysis in both developing bone tissue and fetal bovine bone-forming cells using human cDNA probes. TGF-13 was shown to be synthesized and secreted by metabolically labeled bone cell cultures by immunoprecipitation from the medium. Further, TGF-13 activity was demonstrated in conditioned media from these cultures by competitive radioreceptor and growth promotion assays. Fetal bovine bone cells (FBBC) were found to have relatively few TGF-~ receptors (5,800/ce11) with an extremely low Kd of 2.2 pM (high binding affinity). In contrast to its inhibitory effects on the growth of many cell types including osteosarcoma cell lines, TGF-I3 stimulated the growth of subconfluent cultures of FBBC; it had little effect on the production of collagen by these cells. We conclude that bone-forming cells are a source for the TGF-I~ that is found in bone, and that these cells may be modulated by this factor in an autocrine fashion. TRANSFORMING growth factor-type 13 (TGF-13), ~ discovered and named for its ability to phenotypically transform nonneoplastic fibroblasts in vitro (30), is emerging as the prototype for a family of multifunctional regulatory peptides (38). Many cells, both nonneoplastic and neoplastic, synthesize TGF-13 and most of these cells have receptors for the peptide. The diverse effects of TGF-[~ on cell function have been further illuminated by the recent finding that TGF-[i is similar, if not identical, to cartilageinducing factor-A (36), a protein isolated from demineralized bone that induces the formation of cartilage proteoglycan and type II collagen from undifferentiated mesenchymal cells in vitro (35). Although platelets are the most concentrated source of TGF-13 in the body (2), the high yield of TGF-I~ from bone (14) (,,ol00-fold greater than from soft tissues such as placenta [10] and kidney [32]) suggests that bone has the greatest total amount of TGF-13. Since the level of serum-derived proteins in bone is high (e.g., ¢t2 HSglycoprotein, which is synthesized in the liver, can account for >2 % of the total bone matrix [40]), the origin of TGF-13 found in bone is not entirely clear, and some of it may simply be absorbed to the tissue from serum. Although recent studies of the production of growth factors by fetal rat calvaria have demonstrated secretion of TGF-13 into bone organ culture medium (5), this developing tissue contains both Abbreviations used in thispaper:FBBC, fetal bovine bone cells; TGF-I~, transforming growth factor-type 13; NRK, normal rat kidney fibroblasts. mineralized and nonmineralized regions, with ceils in nonmineralized regions exhibiting distinctly fibroblastic characteristics (i.e., production of types I and III collagen). Consequently, the cellular origin of TGF-I~ in this organ culture system also is unclear. In th...

Anti-inflammatory corticosteroids significantly impair wound healing. Retinoids partially, but significantly, reverse this effect. Little is known about the mechanism of steroid retardation or retinoid reversal. We hypothesized that corticosteroids lower transforming growth factor-␤ (TGF-␤) and insulinlike growth factor-I (IGF-I) levels and tissue deposition in wounds and that retinoids stimulate corticosteroid-impaired TGF-␤ and IGF-I release and collagen production.

To assess the effect of transforming growth factor (,3 on the skin in vivo, we have targeted its expression to the epidermis of transgenic mice. To ensure that active TGF-P1 was expressed, we used a porcine TGF-fji cDNA with mutations of Cys-223 --Ser and Cys-225 --Ser, which allow constitutive activation. Mice expressing the mutant transforming growth factor ,13 transgene exhibited a marked phenotype at birth. The skin was very shiny and tautly stretched. These animals were rigid and appeared to be restricted in their ability to move and breathe; death occurred within 24 hr. Histologically, the most prominent features of the skin were a compact orthohyperkeratosis and a reduction in the number of hair follicles. Pulse-labeling studies with 5-bromodeoxyuridine demonstrated a marked reduction in the number of replicating cells in the epidermis and hair follicles. Thus, the macro-and microscopic appearance of these mice, as well as their neonatal lethality, most likely result from inhibition of normal skin development and suppression of epithelial cell proliferation by the overexpression of transforming growth factor Pi.