INSULIN-LIKE-GROWTH-FACTOR BINDING-PROTEIN-1 - RECENT FINDINGS AND NEW DIRECTIONS

In 1988, insulin-like growth factor-binding protein-1 (IGFBP-1) became the first characterized member of a group of structurally related sol uble proteins which specifically bind and modulate the actions of the IGFs. Since then, a wealth of information has accumulated regarding th e physiology of this dynamic serum protein. In this review, we update our 1993 summary (Lee PDK et al. Proc Soc Exp Biol Med 204:4-29) of th e status of IGFBP-1 research. The IGFBP-1 protein sequence contains 12 N-terminal and 6 C-terminal cysteine residues which are conserved in other mammalian IGFBP-1 sequences and amongst other IGFBPs; both of th e cysteine-rich regions are required for optimal IGF binding. The nonc onserved IGFBP-1 midregion may act as both a hinge which defines ligan d binding characteristics and as a specific target for protease activi ty. Integrin-binding and phosphorylation sites within the IGFBP-1 sequ ence have functional significance in vitro, but their physiologic rele vance in vivo have not been defined. The human IGFBP-1 and IGFBP-3 gen es are contiguous and located in close proximity to the homeobox A (HO XA) gene cluster on chromosome 7. The other IGFBP genes, located on ch romosomes 2, 12, and 17, are also associated with HOX clusters, sugges ting evolutionary linkage of the IGFBP and HOX gene families. Similari ties between the hlGFBP-1 and phosphoenolpyruvate kinase (PEPCK) promo ters, including regions conferring insulin, glucocorticoid, and cyclic adenosine-monophosphate responses, are consistent with our previous h ypothesis that IGFBP-1 is involved in regulation of glucose metabolism . The tissue-specific patterns of IGFBP-1 gene expression in liver, ki dney, decidua, and ovary may be due to stimulation of IGFBP-1 transcri ption by hepatic nuclear factor 1 (HNF1) proteins. Clinical and basic studies of IGFBP-1 physiology have been aided by several recently deve loped assay methods. Numerous investigations have confirmed that insul in, via inhibition of IGFBP-1 transcription, is the primary determinan t of IGFBP-1 expression both in vitro and in vivo. IGF-I and IGF-II al so have specific inhibitory effects on IGFBP-1 expression. Glucocortic oids and cAMP stimulate IGFBP-1 transcription, but these effects are o bserved only in conditions of low or absent insulin effect, Other stim ulants of IGFBP-1 expression include thyroid hormones and epidermal gr owth factor. Phorbol ester stimulation of IGFBP-1 expression can super sede the effects of insulin in vitro;however, the mechanism and in viv o correlates of this effect have not been determined. Cytokines and? p erhaps, growth hormones may affect IGFBP-1 expression, perhaps by alte ring the regulatory actions of insulin; this effect may have important clinical relevance. IGFBP-1 expression is upregulated in liver and (n onhuman) kidney during postinjury regeneration. The IGF-inhibitory act ions of IGFBP-1 has been confirmed by numerous in vitro studies and se veral in vivo animal investigations, including administration of recom binant IGFBP-1 and IGFBP-1 transgenic models. IGFBP-1 has been shown t o inhibit somatic linear growth, weight gain, tissue growth, and gluco se metabolism. Moreover, IGFBP-1 appears to be a primary determinant o f free IGF-I levels in serum. Excess levels of IGFBP-1 may contribute to growth failure in intrauterine growth restriction and in pediatric chronic renal failure, while low IGFBP-1 levels are associated with ob esity and with cardiovascular risk factors In insulin resistance syndr omes, Serum IGFBP-1 measurements may be useful biochemical marker in t hese pathologic conditions. IGFBP-1 is expressed in decidualized strom al cells of the uterine endometrium and in ovarian granulosa cells. IG FBP-1,together with IGFs, insulin, ovarian steroids, cytokines, and ot her factors, is Involved in a complex system which regulates menstrual cycles, ovulation, decidualization, blastocyst implantation, and feta l growth. Models for the? Pole of IGFBP-1 in female reproductive physi ology are presented, and evidence for pathophysiologic roles in pre-ec lampsia, polycystic ovarian syndrome, and uterine malignancy are revie wed. Very recent: data indicates that IGFBP-1 undergoes regulated expr ession in human osteoblasts. Limited information also suggests that IG FBP-1 may be present in peripheral neurons, and that serum IGFBP-1 may increase during exercise and in critical illness. In summary, two maj or roles far IGFBP-1 in normal physiology can be constructed from curr ent data: (i) As an ''endocrine'' factor, IGFBP-1 regulates the bioava ilability of serum IGF-I, thereby modulating IGF-mediated tissue metab olism. The dominant regulation of IGFBP-1 expression by meal-related c hanges in hepatic insulin concentrations provides a dynamic link to su bstrate availability. (ii) As an autocrine/paracrine:factor, IGFBP-1 a ppears to play a crucial role in the female reproductive system and, i n particular, the sequence of events leading from ovulation to implant ation to successful fetal outcome. Future investigations will further delineate the manner in which IGFBP-1 participates in these and other physiologic processes, and the mechanisms by which IGFBP-1 may be invo lved in clinical pathophysiology.