title: Folinic acid attenuates methotrexate chemotherapy-induced damages on bone growth mechanisms and pools of bone marrow stromal cells.
abstract: Chemotherapy often induces bone growth defects in pediatric cancer patients; yet the underlying cellular mechanisms remain unclear and currently no preventative treatments are available. Using an acute chemotherapy model in young rats with the commonly used antimetabolite methotrexate (MTX), this study investigated damaging effects of five once-daily MTX injections and potential protective effects of supplementary treatment with antidote folinic acid (FA) on cellular activities in the tibial growth plate, metaphysis, and bone marrow. MTX suppressed proliferation and induced apoptosis of chondrocytes, and reduced collagen-II expression and growth plate thickness. It reduced production of primary spongiosa bone, volume of secondary spongiosa bone, and proliferation of metaphyseal osteoblasts, preosteoblasts and bone marrow stromal cells, with the cellular activities being most severely damaged on day 9 and returning to or towards near normal levels by day 14. On the other hand, proliferation of marrow pericytes was increased early after MTX treatment and during repair. FA supplementation significantly suppressed chondrocyte apoptosis, preserved chondrocyte proliferation and expression of collagen-II, and attenuated damaging effects on production of calcified cartilage and primary bone. The supplementation also significantly reduced MTX effects on proliferation of metaphyseal osteoblastic cells and of bone marrow stromal cells, and enhanced pericyte proliferation. These observations suggest that FA supplementation effectively attenuates MTX damage on cellular activities in producing calcified cartilage and primary trabecular bone and on pools of osteoblastic cells and marrow stromal cells, and that it enhances proliferation of mesenchymal progenitor cells during bone/bone marrow recovery.
authors.affiliation: Department of Orthopaedic Surgery, Women's and Children's Hospital, Adelaide, South Australia. cory.xian@adelaide.edu.au
authors.forename: Cory J
authors.initials: CJ
authors.lastname: Xian
authors.forename: Johanna C
authors.initials: JC
authors.lastname: Cool
authors.forename: Michaela A
authors.initials: MA
authors.lastname: Scherer
authors.forename: Chiaming
authors.initials: C
authors.lastname: Fan
authors.forename: Bruce K
authors.initials: BK
authors.lastname: Foster
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D001846:Bone Development / Q000187:drug effects*; D001854:Bone Marrow Cells / Q000187:drug effects* / Q000473:pathology*; D001842:Bone and Bones / Q000166:cytology / Q000187:drug effects; D001973:Bromodeoxyuridine / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D019902:Chondrocytes / Q000166:cytology / Q000187:drug effects; D024043:Collagen Type II / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006132:Growth Plate / Q000187:drug effects / Q000473:pathology; D002955:Leucovorin / Q000494:pharmacology*; D008297:Male; D008727:Methotrexate / Q000009:adverse effects*; D009929:Organ Size / Q000187:drug effects; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects; D020286:Pericytes / Q000166:cytology / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017154:Stromal Cells / Q000187:drug effects* / Q000473:pathology*