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Since M6P acts at the same receptor as TGF-[beta]1 on fibroblasts, it is possible that treatment with M6P may inhibit fibrosis.
Cell Culture for M6P Concentration Studies: Once confluent, the cells were plated on 24-well plates where row A served as a control, row B served as 0.
05 [micro]M (Medium) M6P (Sigma-Aldrich) treatment, row C served as 200 ng (Low) TGF-[beta]1 (Sigma-Aldrich) treatment, and row D served as the M6P/TGF-[beta]1 combination treatment.
Cell Counts for M6P Study: Fibroblast cells treated with low (0.
05 [micro]M dose of M6P was the lowest dose that did not show evidence of significantly decreasing mitotic activity or increasing cellular damage and the 200 ng dose of TGF-[beta]1, at 48 hours, showed the most significant increase in mitotic activity over Control, these doses and the 48 hour time point were chosen for the competitive study.
Cell Count for Competitive Study: The cell count for the group treated with TGF-[beta]1 alone revealed significantly greater mitotic activity than that of the control cells whereas the mitotic activity of the groups treated with M6P alone and with both TGF-Pi and M6P were not significantly different from the untreated control group (Figure 3).
Since both TGF-[beta]1 and M6P bind reversibly at the M6P/IGF-II receptor, M6P may competitively inhibit the binding of TGF-[beta]1.
Previous studies in our lab have shown that F6P but not M6P under hypoxic conditions is capable of decreasing HIF-1[alpha] and CTGF, suggesting M6P has a mechanism of action unrelated to isomerization to F6P.
Overall, our results show that M6P is capable of reducing TGF-[beta]1-induced fibroblast proliferation and suggest that this is accomplished through competitive inhibition of the M6P/IGF-II receptor of fibroblasts.
Toronto, Ontario Canada M6P 3T1 416)-762-1111 Fax: 416)-762-0888 George Keller, Mgr.
Toronto, Ontario Canada M6P 3T1 (416)-762-1111 Fax: (416)-762-0888 George Keller, Mgr.