507. TGFβ REGULATES ENDOMETRIOSIS-LIKE LESION DEVELOPMENT IN MICE INDEPENDENTLY OF THE RUNX-2/OPN PATHWAY

Abstract

TGFβ is likely to significantly influence endometriotic lesion development, as TGFβ KO/SCID mice with no host-derived TGFβ activity have smaller human ectopic endometrial lesions than control mice. TGFβ potentially acts via RUNX2, a transcription factor that directly upregulates OPN transcription in osteoblasts, as we have identified RUNX-2 and OPN gene expression at high levels in nude mouse endometriosis-like lesions, in human endometrial stomal cell cultures and in the stroma of endometriotic tissues. We hypothesised that inhibition of RUNX-2 would suppress OPN production and result in reduction of endometriotic lesion formation and size. As P38/MAPK inhibitors suppress TGF-β mediated RUNX-2 transcription, we utilised the nude mouse model to test whether the P38/MAPK inhibitor FR167653 would suppress OPN production in endometriotic tissues resulting in smaller lesions.FR167653 (30 mg/kg twice a day) or placebo was administered for either 10 or 14 days to nude mice (16 in each group) implanted with human endometrial tissue xenografts from 4 different women. The size and weight of the lesions were measured and immunohistochemical analysis of OPN, αSMA (myofibroblasts) and F4/80 (macrophages) was carried out. There was no difference in size or weight of the lesions, and there was no overt difference in any of the staining parameters explored. The inhibition of p38/MAPK did not alter the size of the nude mouse lesions nor OPN staining within these lesions despite being administered at a maximal therapeutic dose. This suggests that TGFβ regulation of endometriotic lesion development is mediated by an alternate molecular pathway.