title: Potential Effects of Phytoestrogen Genistein in Modulating Acute Methotrexate Chemotherapy-Induced Osteoclastogenesis and Bone Damage in Rats.
abstract: Chemotherapy-induced bone damage is a frequent side effect which causes diminished bone mineral density and fracture in childhood cancer sufferers and survivors. The intensified use of anti-metabolite methotrexate (MTX) and other cytotoxic drugs has led to the need for a mechanistic understanding of chemotherapy-induced bone loss and for the development of protective treatments. Using a young rat MTX-induced bone loss model, we investigated potential bone protective effects of phytoestrogen genistein. Oral gavages of genistein (20 mg/kg) were administered daily, for seven days before, five days during, and three days after five once-daily injections (sc) of MTX (0.75 mg/kg). MTX treatment reduced body weight gain and tibial metaphyseal trabecular bone volume (p < 0.001), increased osteoclast density on the trabecular bone surface (p < 0.05), and increased the bone marrow adipocyte number in lower metaphyseal bone (p < 0.001). Genistein supplementation preserved body weight gain (p < 0.05) and inhibited ex vivo osteoclast formation of bone marrow cells from MTX-treated rats (p < 0.001). However, MTX-induced changes in bone volume, trabecular architecture, metaphyseal mRNA expression of pro-osteoclastogenic cytokines, and marrow adiposity were not significantly affected by the co-administration of genistein. This study suggests that genistein may suppress MTX-induced osteoclastogenesis; however, further studies are required to examine its potential in protecting against MTX chemotherapy-induced bone damage.
authors.affiliation: Sansom Institute for Health Research, School of Pharmacy and Medical Science, University of South Australia, Adelaide, SA 5001, Australia. tristan.king@unisa.edu.au.|Department of Physiology, School of Medical Sciences, University of Adelaide, Adelaide, SA 5001, Australia. tristan.king@unisa.edu.au.
authors.forename: Tristan J
authors.initials: TJ
authors.lastname: King
authors.affiliation: Sansom Institute for Health Research, School of Pharmacy and Medical Science, University of South Australia, Adelaide, SA 5001, Australia. tetyanas@geneworks.com.au.
authors.forename: Tetyana
authors.initials: T
authors.lastname: Shandala
authors.affiliation: Sansom Institute for Health Research, School of Pharmacy and Medical Science, University of South Australia, Adelaide, SA 5001, Australia. alice.lee@unisa.edu.au.
authors.forename: Alice M
authors.initials: AM
authors.lastname: Lee
authors.affiliation: Department of Orthopaedic Surgery, Women's and Children's Hospital, North Adelaide, SA 5006, Australia. Bruce.Foster@health.sa.gov.au.
authors.forename: Bruce K
authors.initials: BK
authors.lastname: Foster
authors.affiliation: Institute of Orthopaedics, Lanzhou General Hospital, Lanzhou Command of Chinese People's Liberation Army, Lanzhou 730050, China. chenkm@lut.cn.
authors.forename: Ke-Ming
authors.initials: KM
authors.lastname: Chen
authors.affiliation: Nutritional Physiology Research Centre, School of Health Sciences, University of South Australia, Adelaide, SA 5001, Australia. peter.howe@newcastle.edu.au.|Clinical Nutrition Research Centre, University of Newcastle, Callaghan, NSW 2308, Australia. peter.howe@newcastle.edu.au.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Howe
authors.affiliation: Sansom Institute for Health Research, School of Pharmacy and Medical Science, University of South Australia, Adelaide, SA 5001, Australia. cory.xian@unisa.edu.au.
authors.forename: Cory J
authors.initials: CJ
authors.lastname: Xian
mesh_terms: D017667:Adipocytes / Q000187:drug effects / Q000473:pathology; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects*; D001835:Body Weight / Q000187:drug effects; D015519:Bone Density / Q000187:drug effects; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology; D001862:Bone Resorption / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D001842:Bone and Bones / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D019833:Genistein / Q000627:therapeutic use*; D008297:Male; D008727:Methotrexate / Q000009:adverse effects*; D048789:Phytoestrogens / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000964:Antimetabolites, Antineoplastic; D048789:Phytoestrogens; D019833:Genistein; D008727:Methotrexate
keywords: chemotherapy; genistein; methotrexate; osteoporosis