Endocrine Abstracts (2002) 3 P235

Regulation of expression and activity of lysyl oxidase in developing ovarian follicles

MT Rae, CR Harlow, L Davidson & SG Hillier

Reproductive Medicine Laboratory, Reproductive and Developmental Sciences, The University of Edinburgh, Edinburgh, UK.

Introduction Tissue remodelling, and deposition of extracellular matrix and basement membrane are critical processes in the formation and development of ovarian follicles. Collagen is a major component of the ECM. Though there is substantial literature concerning the breakdown of collagen in the ovary, little attention has been given to the processes of collagen formation and deposition. Lysyl oxidase (LO) is critical in this process, being the enzyme responsible for the final formation of mature, insoluble collagen. Previous studies from our laboratory have indicated the presence, and regulation by FSH, of lysyl oxidase in the granulosa cells of ovarian follicles.

Methods We have examined LO mRNA and enzymatic activity in vitro in the immature rat ovary, in response to FSH and TGF-beta superfamily members. 21 day old female Wistar rats were treated with DES (2mg every 24 hours for 2 days) to induce formation of populations of pre- and peri-antral follicles in the ovary. Granulosa cells were recovered and cultured in vitro for 48 hours, in the presence and absence of FSH, TGF-beta1, GDF-9, activin, and combinations of FSH and the TGF-beta superfamily members. Lysyl oxidase mRNA was then measured by Nothern analysis, and lysyl oxidase activity secreted in culture media measured by an assay, utilising tritiated recombinant tropoelastin as substrate.

Results FSH dose dependently inhibited LO mRNA expression and activity (P<0.05). In contrast, TGF-beta dose dependently increased LO mRNA expression and LO activity (P<0.05). FSH also dose dependently inhibited the stimulation of LO enzyme activity by TGF-beta. GDF-9 and activin alone showed similar trends of stimulation of mRNA and LO activity, which, although not statistically significant, suggested a similar mode of action to TGF-beta. The stimulatory effects of GDF-9 and activin on LO mRNA expression of were reversed in the presence of FSH (P<0.05) in a similar fashion to TGF-beta combined with FSH.Conclusion These experiments demonstrate that the expression and activity of lysyl oxidase in the developing follicle is tightly controlled by both endocrine and paracrine factors, and suggest an important role in folliculogenesis.

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