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Differentiating mouse 3T3-L1 preadipocytes have been used as a model system to study the ability of type P transforming growth factor (TGF-fi) to modulate cell devel- The cellular actions of TGF-3 include induction of anchorage-independent proliferation in mesenchymal cells (1-3), inhibition of the transformed phenotype in carcinoma cells (4), and inhibition of epithelial cell proliferation (5).

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Retrovirus-transformed rat cells that actively express transforming growth factor type a (TGF-a) release into the medium a soluble protein of 17-19 kDa that has been identified as a precursor for TGF-a. The identification of this protein as a TGF-a precursor is based on its recognition by specific antibodies and by the ability of elastase to convert this protein into a 6-kDa polypeptide with the properties of mature TGF-a. This TGF-a precursor binds to epidermal growth factor/TGF-a receptors and activates the receptor-associated tyrosine kinase activity in intact cells. The biological potency of this precursor is not markedly increased by conversion into mature TGF-a in vitro. These studies demonstrate the ability of transformed cells to release a TGF-a precursor capable of strong mitogenic action in vivo.

This study examines the mechanism by which TGF-beta 1, an important mediator of cell growth and differentiation, blocks the differentiation of normal rat diploid fetal osteoblasts in vitro. We have established that the inability for pre-osteoblasts to differentiate is associated with changes in the expression of cell growth, matrix forming, and bone related genes. These include histone, jun B, c-fos, collagen, fibronectin, osteocalcin, alkaline phosphatase, and osteopontin. Morphologically, the TGF-beta 1-treated osteoblasts exhibit an elongated, spread shape as opposed to the characteristic cuboidal appearance during the early stages of growth. This is followed by a decrease in the number of bone nodules formed and the amount of calcium deposition. These effects on differentiation can occur without dramatic changes in cell growth if TGF-beta 1 is given for a short time early in the proliferative phase. However, continuous exposure to TGF-beta 1 leads to a bifunctional growth response from a negative effect during the proliferative phase to a positive growth effect during the later matrix maturation and mineralization phases of the osteoblast developmental sequence. Extracellular matrix genes, fibronectin, osteopontin and alpha 1(I) collagen, are altered in their expression pattern which may provide an aberrant matrix environment for mineralization and osteoblast maturation and potentiate the TGF-beta 1 response throughout the course of osteoblast differentiation. The initiation of a TGF-beta 1 effect on cell growth and differentiation is restricted to the proliferative phase of the culture before the cells express the mature osteoblastic phenotype. Second passage cells that are accelerated to differentiate by the addition of dexamethasone or by seeding cultures at a high density are refractory to TGF-beta 1. These in vitro results indicate that TGF-beta 1 exerts irreversible effects at a specific stage of osteoblast phenotype development resulting in a potent inhibition of osteoblast differentiation at concentrations from 0.1 ng/ml.