Possible implication of midkine in the development of endometriosis

BACKGROUND: The present study was conducted to assess whether midkine (MK), a multifunctional molecule known to stimulate tumor growth, may be involved in the development of endometriosis. METHODS: The mitogenic activity of MK on cultured endometriotic stromal cells was examined by measuring 5-bromo-2'-deoxyuridine (BrdU) incorporation. Concentrations of MK in the peritoneal fluid (PF) of women without or with endometriosis and those under GnRH agonist treatment were measured using a specific enzyme immunoassay. The expression of MK mRNA in peritoneal bone marrow-derived cells, peritoneum and endometriotic tissues was evaluated by RT-PCR. RESULTS: MK significantly increased BrdU incorporation into the DNA of cultured endometriotic stromal cells. The MK concentrations in the PF of the women with advanced endometriosis (stages II, III and IV) Median: 1.21 ng/ml; interquartile range 0.80-2.27 were significantly higher than those of the women without endometriosis and with stage I endometriosis (0.06 ng/ml, 0.67-1.26, P < 0.05). As for the menstrual phase, the MK concentration in PF in the inteal phase (1.32 ng/ml. 0.72-2.21) were significantly higher than those in the follicular phase (0.95 ng/ml, 0.68-1.24, P < 0.05). In addition, women with adnexal adhesions had higher concentrations of MK in PF than those without adhesions (P < 0.05). The MK concentrations of the women under GnRH agonist treatment were significantly lower than those of the other groups (P < 0.001). The expression of MK mRNA was detected in peritoneal bone marrow-derived cells, peritoneum and endometriotic tissues. CONCLUSIONS: The present findings suggest that MK may play roles, such as stimulation of endometriotic cell proliferation, in the development of endometriosis.