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Mammalian Hyaluronidase Induces Ovarian Granulosa Cell Apoptosis and Is Involved in Follicular Atresia

Maisonneuve-Rosemont Hospital Research Center (A.M.O., K.D.-D., E.C.), Montreal, Quebec, Canada H1T 2M4; Department of Medicine (E.C.), University of Montreal, Montreal, Quebec, Canada H3T 1J4; Chronic Disease Program (J.-Y.J., N.T., B.K.T.), Ottawa Health Research Institute, Ottawa, Canada K1Y 4E9; and Departments of Obstetrics and Gynecology (N.T., B.K.T.), Cellular and Molecular Medicine (B.K.T.), and Biochemistry, Microbiology, and Immunology (N.T.), University of Ottawa, Ottawa, Canada K1H 8M5

Address all correspondence and requests for reprints to: Euridice Carmona, Hôpital Maisonneuve-Rosemont, Centre de Recherche, 5415, boulevard de l’Assomption, Montreal, Quebec, Canada H1T 2M4. E-mail: ecarmona.hmr{at}ssss.gouv.qc.ca.

During ovarian folliculogenesis, the vast majority of follicles will undergo atresia by apoptosis, allowing a few dominant follicles to mature. Mammalian hyaluronidases comprise a family of six to seven enzymes sharing the same catalytic domain responsible for hyaluronan hydrolysis. Interestingly, some of these enzymes have been shown to induce apoptosis. In the ovary, expression of three hyaluronidases (Hyal-1, Hyal-2, and Hyal-3) has been documented. However, their precise cellular localization and role in ovarian regulation have not yet been defined. We herein investigated the possible involvement of these enzymes in ovarian atresia. First, we established a mouse model for ovarian atresia (gonadotropin withdrawal by anti-equine chorionic gonadotropin treatment) and showed that the mRNA levels of Hyal-1, Hyal-2, and Hyal-3 were significantly increased in apoptotic granulosa cells as well as in atretic follicles. Second, using ovaries of normally cycling mice, we demonstrated the correlation of Hyal-1 mRNA and protein expression with cleavage of caspase-3. In addition, we showed that expression of all three hyaluronidases induced apoptosis in transfected granulosa cells. Significantly, the induction of apoptosis by hyaluronidases was independent of catalytic activity, because enzymatically inactive Hyal-1 mutant (D157A/E159A) was as efficient as the wild-type enzyme in apoptosis induction. The activation of the extrinsic apoptotic signaling pathway was involved in this induction, because increased levels of cleaved caspase-8, caspase-3, and poly-ADP-ribose polymerase (PARP) were observed upon hyaluronidase ectopic expression. Our present findings provide a better understanding of the role of hyaluronidases in ovarian functions, showing for the first time their involvement in follicular atresia.

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