Identification of a Stimulator of Steroid Hormone Synthesis Isolated from Testis

Abstract

Gonadal steroidogenesis is regulated by pituitary gonadotropins and a locally produced, unidentified factor. A 70-kilodalton (kD) protein complex secreted from rat Sertoli cells was isolated. The complex, composed of 28- and 38-kD proteins, stimulated steroidogenesis by Leydig cells and ovarian granulosa cells in a dose-dependent and adenosine 3',5'-monophosphate-independent manner. The follicle-stimulating hormone-induced 28-kD protein appeared to be responsible for the bioactivity, but the 38-kD protein was indispensable for maximal activity. The 28- and 38-kD proteins were shown to be identical to the tissue inhibitor of metalloproteinase-1 (TIMP-1) and the proenzyme form of cathepsin L, respectively. Thus, a TIMP-1-procathepsin L complex is a potent activator of steroidogenesis and may regulate steroid concentrations and, thus, germ cell development in both males and females.

Contribution of Recent Transgenic Models and Transcriptional Profiling Studies to Our Understanding of the Mechanisms by which Androgens Control Spermatogenesis

“…Taken together these data suggest that Leydig cell development not only requires direct actions of androgens on developing Leydig cells [98,118] but also indirect signals most likely mediated by androgenregulated paracrine factors derived from Sertoli cells. These observations are reminiscent of earlier in vitro [119,120] and in vivo experiments [121,122] showing that FSH also stimulates Leydig cell development via paracrine agonists secreted by Sertoli cells. The nature of the paracrine mediators responsible for LeydigSertoli cell interaction remains uncertain.…”

Matrix metalloproteinases and tissue inhibitors of metalloproteinases in ovarian function

“…The production of mRNA encoding TIMP-1 (Hampton et al, 1995) and TIMP-1 (McIntush and Smith, 1997) by the corpus luteum is 30-3 000 times greater than that of other tissues. Although reports of growth- (Edwards et al, 1996) and steroidogenesispromoting (Boujrad et al, 1995) activities of TIMP-1 suggest that it may also modulate these processes within the corpus luteum, the potential role of these activities will not be addressed here. TIMP-1, TIMP-2 and PAI-1 are expressed specifically by one of the several types of luteal cell, and may be important in maintaining an ECM microenvironment conducive to the differentiation of follicular-derived cells into luteal cells, and the maintenance of the phenotype of luteal cells.…”

“…Factors regulating the function of TIMP-1 include: (1) endothelial-stimulating angiogenesis factor (ESAF), a low molecular mass substance that liberates active MMP-1 from MMP-1-TIMP-1 complexes (McLaughlin et al, 1991); (2) proteinases (Itoh and Nagase, 1995); and (3) peroxynitrite, a product of superoxide radicals and hydrogen peroxide (Frears et al, 1996). TIMPs are multifunctional molecules that, in addition to inhibiting MMP activity, stimulate proliferation of various cell types (Edwards et al, 1996), and stimulate progesterone production by steroidogenic cells (Boujrad et al, 1995). The mechanism by which TIMPs stimulate cell proliferation is unknown but may involve plasma membrane receptors (Edwards et al, 1996).…”

Differential expression of tissue inhibitor of metalloproteinases type 1 (TIMP‐1) during mouse gonad development

“…In addition, TIMP-1 controls apoptosis through a non-MMP inhibitory pathway in some lymphoma cell lines (Guedez et al, 1998), and a procathepsin L-TIMP-1 complex enhances steroidogenesis both in testis and ovary (Boujrad et al, 1995). Nonetheless, it remained that timp-1-deficient mice exhibit no specific phenotypes at the testis level with no compensation by TIMP-2 or TIMP-3 (testatin and protease nexin-1 were not studied).…”