Growth factors in human disease: the realities, pitfalls, and promise.

T HE LITERATURE related to growth factors increases at such a rapid rate that the cynical might postulate factors governing the development of new growth factors. In an effort to put a manageable perimeter around the subject, this review focuses primary attention on well characterized growth factors, known or suspected to exist in man. While a universally accepted definition of a growth factor does not exist, usage accepts growth factors as relatively small proteins that induce increased cell synthesis of nucleic acids, protein, and increased cellular mass. Conventionally, growth factors are considered to be agents with mitogenic activity. However, in connective tissues where a disproportionately small number of cells participate in the formation of a large extracellular matrix, growth may be manifested not only by increased cell numbers, but also by increases in one or several components of the extracellular matrix. The physiologic import of this distinction is not trivial when one recalls that approximately 75% of the human body is of mesenchymal origin, and that skeletal tissues, skin, and fascia (excluding muscular components) account for >33% of the body mass.‘** Also, it is pertinent to note that one of the first known growth factors, sulfation factor, was measured by its growth promoting activity as judged by the increased sulfated glycosaminoglycan (GAG) content of cartilage extracellular matrix. Sulfation factor was subsequently shown to be several proteins constituting a group of human growth hormone dependent proteins, members of the somatomedin family; knowledge of their mitogenic properties was a later development. The same principle applies to epithelial tissues; for example, epidermal growth factor (EGF) stimulates not only replication of cells, but formation of extracellular material such as keratin. Similarly, connective tissue cells exposed to EGF respond with both increased cell replication and increased synthesis and secretion of hyaluronic acid, an extracellular matrix component. Although the notion of growth promotion evokes the impression that growth factors are primarily concerned with anabolic events, it may be wise to visualize growth as a net increment in cells and certain of their extracellular products. Some growth factors also promote events whose primary impact is catabolic; connective tissue activating peptide(CTAP-III), primarily known for its mitogenic and GAG stimulating properties, also stimulates synthesis and secretion of a degradative protease, plasminogen activator.3 Similarly, interleukin1 (Il1). a potent stimulator of anabolic processes, also promotes synthesis and secretion of collagenase and prostaglandins by many types of sensitive cells. It seems likely that some growth factors evoke both anabolic and catabolic behavior by a single cell. The mechanism(s) for organized integration of these opposing metabolic vectors in intact organisms will be a focus of investigative effort in the future. Earlier debate aimed at classifying growth factors as hormones or autacoids now seems moot in the face of new data and the recognition of the depth of our ignorance. For instance, it seems likely that the several growth factors released from platelet alpha granules after platelet aggregation exert a potent local effect, thus behaving as autacoid mediators. Yet, there are no data to rule out significant distant (hormonal) biological effects from these substances, at least some of which are found in plasma. In the case of