Genistein-mediated inhibition of glycosaminoglycan synthesis, which corrects storage in cells of patients suffering from mucopolysaccharidoses, acts by influencing an epidermal growth factor-dependent pathway

• DOI: 10.1186/1423-0127-16-26
• Publication Date: 2009-05-28T19:17:50Z
• Authors: Joanna Jakóbkiewi...; Ewa Piotrowska; Magdalena Narajczyk; Sylwia Barańska; Grzegorz Węgrzyn
• Keywords: 0301 basic medicine; substrate deprivation therapy; mouse model; receptor; Endocrinology, Diabetes and Metabolism; Clinical Biochemistry; open-label; I Patiens; Cell Line; Rhoamine-B; 03 medical and health sciences; Humans; Pharmacology (medical); Phosphorylation; Molecular Biology; Glycosaminoglycans; Biochemistry, medical; Epidermal Growth Factor; Estradiol; enzyme-replacement therapy; Research; R; prediction; Cell Biology; Fibroblasts; Mucopolysaccharidoses; Genistein; laronidase; 3. Good health; ErbB Receptors; Medicine; Signal Transduction

Mucopolysaccharidoses (MPS) are inherited metabolic disorders caused by mutations leading to dysfunction of one enzymes involved in degradation glycosaminoglycans (GAGs). Due their impaired degradation, GAGs accumulate cells patients, which results tissues and organs. Substrate reduction therapy is potential treatment these diseases. It was demonstrated previously that genistein (4', 5, 7-trihydroxyisoflavone) inhibits synthesis reduces levels cultures fibroblasts MPS patients. Recent pilot clinical study indicated such a may be effective III (Sanfilippo syndrome).To learn on details the molecular mechanism genistein-mediated inhibition GAG synthesis, efficiency this process studied measuring incorporation labeled sulfate, storage lysosomes estimated using electron microscopic techniques, phosphorylation epidermal growth factor (EGF) receptor determined an ELISA-based assay with fluorogenic substrates.Effects accumulation from patients suffering various types were abolished presence excess EGF, partially reversed increased concentration genistein. No effects observed when 17beta-estradiol used instead EGF. Moreover, EGF-mediated stimulation phsophorylation EGF both wild-type fibroblasts.The presented report indicate operates through (EGF)-dependent pathway.