title: Bortezomib is cytotoxic to the human growth plate and permanently impairs bone growth in young mice.
abstract: Bortezomib, a novel proteasome inhibitor approved for the treatment of cancer in adults, has recently been introduced in pediatric clinical trials. Any tissue-specific side effects on bone development have to our knowledge not yet been explored. To address this, we experimentally studied the effects of bortezomib in vivo in young mice and in vitro in organ cultures of rat metatarsal bones and human growth plate cartilage, as well as in a rat chondrocytic cell line. We found that bortezomib while efficiently blocking the ubiquitin/proteasome system (UPS) caused significant growth impairment in mice, by increasing resting/stem-like chondrocyte apoptosis. Our data support a local action of bortezomib, directly targeting growth plate chondrocytes leading to decreased bone growth since no suppression of serum levels of insulin-like growth factor-I (IGF-I) was observed. A local effect of bortezomib was confirmed in cultured rat metatarsal bones where bortezomib efficiently caused growth retardation in a dose dependent and irreversible manner, an effect linked to increased chondrocyte apoptosis, mainly of resting/stem-like chondrocytes. The cytotoxicity of bortezomib was also evaluated in a unique model of cultured human growth plate cartilage, which was found to be highly sensitive to bortezomib. Mechanistic studies of apoptotic pathways indicated that bortezomib induced activation of p53 and Bax, as well as cleavage of caspases and poly-ADP-ribose polymerase (PARP) in exposed chondrocytes. Our observations, confirmed in vivo and in vitro, suggest that bone growth could potentially be suppressed in children treated with bortezomib. We therefore propose that longitudinal bone growth should be closely monitored in ongoing clinical pediatric trials of this promising anti-cancer drug.
authors.affiliation: Pediatric Endocrinology Unit, Department of Women's and Childreńs Health, Karolinska Institutet, Stockholm, Sweden. Emma.E.Eriksson@ki.se
authors.forename: Emma
authors.initials: E
authors.lastname: Eriksson
authors.forename: Farasat
authors.initials: F
authors.lastname: Zaman
authors.forename: Dionisios
authors.initials: D
authors.lastname: Chrysis
authors.forename: Henrik
authors.initials: H
authors.lastname: Wehtje
authors.forename: Terhi J
authors.initials: TJ
authors.lastname: Heino
authors.forename: Lars
authors.initials: L
authors.lastname: Sävendahl
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D017209:Apoptosis / Q000187:drug effects; D001846:Bone Development / Q000187:drug effects*; D001897:Boronic Acids / Q000009:adverse effects*; D000069286:Bortezomib; D002356:Cartilage / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D019902:Chondrocytes / Q000166:cytology / Q000187:drug effects; D020219:Chondrogenesis / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D006132:Growth Plate / Q000166:cytology* / Q000187:drug effects*; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D008682:Metatarsal Bones / Q000166:cytology / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D051379:Mice; D051336:Mitochondrial Membranes / Q000187:drug effects; D061988:Proteasome Inhibitors / Q000009:adverse effects*; D055550:Protein Stability / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011719:Pyrazines / Q000009:adverse effects*; D051381:Rats; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D061988:Proteasome Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D011719:Pyrazines; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D000069286:Bortezomib; D020169:Caspases