title: Substrain-specific differences in bone parameters, alpha-2-macroglobulin circulating levels, and osteonecrosis incidence in a rat model.
abstract: Osteonecrosis of the femoral head (ONFH) is a potentially devastating complication that occurs in up to 40% of young adults receiving chronic glucocorticoid (GC) therapy. Through a validated GC therapy rat model, we have previously shown that Wistar Kyoto (WK) rats exhibit a genetic susceptibility to GC-induced ONFH compared to Sasco Fischer (F344) rats. We have undertaken this study in order to investigate differences between these two strains for their bone parameters, alpha-2-macroglobulin (A2M) circulating levels and incidence of GC-induced osteonecrosis of the femoral head. WK and F344 rats were treated either with 1.5 mg/kg/day of prednisone or placebo for 6 months. Blood was taken every month. The femoral heads were harvested for histological examination to detect ONFH and analyzed with micro-computed tomography. After 3 months of GC-therapy, plasma A2M was elevated in treated rats only. GC-treated WK rats exhibited histological evidence of early ONFH through higher rates of cellular apoptosis and empty osteocyte lacunae in the subchondral bone compared to placebos and to F344 rats. Furthermore, micro-CT analysis exhibited femoral head collapse only in GC-treated WK rats. Interestingly, GC-treated F344 rats exhibited significant micro-CT changes, but such changes were less concentrated in the articular region and were accompanied histologically with increased marrow fat. These µCT and histological findings suggest that elevated A2M serum level is not predictive and suitable as an indicative biomarker for early GC-induced ONFH in rodents. Elevated A2M levels observed during GC treatment suggests that it plays role in the host reparative response to GC-associated effects. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1183-1194, 2017.
authors.affiliation: Vascular, Biology Research Lab, Research Institute, McGill University Health Centre, C9 Montreal General Hospital, 1650 Cedar Avenue, Montreal, QC H3G 1A4, Canada.|Bone Engineering Labs, Surgical Research, Research Institute, McGill University Health Centre, Montreal General Hospital, 1650 Cedar Avenue, Montreal, QC H3G 1A4, Canada.|Department of Surgery, Division of Orthopaedic Surgery, McGill University Health Centre, B5 Montreal General Hospital, 1650 Cedar Avenue, Montreal, QC H3G 1A4, Canada.
authors.forename: Alberto V
authors.initials: AV
authors.lastname: Carli
authors.affiliation: Vascular, Biology Research Lab, Research Institute, McGill University Health Centre, C9 Montreal General Hospital, 1650 Cedar Avenue, Montreal, QC H3G 1A4, Canada.|Bone Engineering Labs, Surgical Research, Research Institute, McGill University Health Centre, Montreal General Hospital, 1650 Cedar Avenue, Montreal, QC H3G 1A4, Canada.|Department of Surgery, Division of Orthopaedic Surgery, McGill University Health Centre, B5 Montreal General Hospital, 1650 Cedar Avenue, Montreal, QC H3G 1A4, Canada.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Harvey
authors.affiliation: Vascular, Biology Research Lab, Research Institute, McGill University Health Centre, C9 Montreal General Hospital, 1650 Cedar Avenue, Montreal, QC H3G 1A4, Canada.
authors.forename: Bouziane
authors.initials: B
authors.lastname: Azeddine
authors.affiliation: Bone Engineering Labs, Surgical Research, Research Institute, McGill University Health Centre, Montreal General Hospital, 1650 Cedar Avenue, Montreal, QC H3G 1A4, Canada.
authors.forename: Chan
authors.initials: C
authors.lastname: Gao
authors.affiliation: Vascular, Biology Research Lab, Research Institute, McGill University Health Centre, C9 Montreal General Hospital, 1650 Cedar Avenue, Montreal, QC H3G 1A4, Canada.
authors.forename: Yongbiao
authors.initials: Y
authors.lastname: Li
authors.affiliation: Bone Engineering Labs, Surgical Research, Research Institute, McGill University Health Centre, Montreal General Hospital, 1650 Cedar Avenue, Montreal, QC H3G 1A4, Canada.
authors.forename: Ailian
authors.initials: A
authors.lastname: Li
authors.affiliation: Vascular, Biology Research Lab, Research Institute, McGill University Health Centre, C9 Montreal General Hospital, 1650 Cedar Avenue, Montreal, QC H3G 1A4, Canada.
authors.forename: Mireille
authors.initials: M
authors.lastname: Sayegh
authors.affiliation: Bone Engineering Labs, Surgical Research, Research Institute, McGill University Health Centre, Montreal General Hospital, 1650 Cedar Avenue, Montreal, QC H3G 1A4, Canada.
authors.forename: Huifen
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Pathology, McGill University Health Centre (MUHC), C3 Montreal General Hospital, 1650 Cedar Avenue, Montreal, QC H3G 1A4, Canada and McGill University Health Centre (MUHC), Glen site, 1001 Décarie Blvd, Montreal, QC H4A 3J1, Canada.
authors.forename: Ayoub
authors.initials: A
authors.lastname: Nahal
authors.affiliation: Department of Pathology, McGill University Health Centre (MUHC), C3 Montreal General Hospital, 1650 Cedar Avenue, Montreal, QC H3G 1A4, Canada and McGill University Health Centre (MUHC), Glen site, 1001 Décarie Blvd, Montreal, QC H4A 3J1, Canada.
authors.forename: René P
authors.initials: RP
authors.lastname: Michel
authors.affiliation: Bone Engineering Labs, Surgical Research, Research Institute, McGill University Health Centre, Montreal General Hospital, 1650 Cedar Avenue, Montreal, QC H3G 1A4, Canada.
authors.forename: Janet E
authors.initials: JE
authors.lastname: Henderson
authors.affiliation: Vascular, Biology Research Lab, Research Institute, McGill University Health Centre, C9 Montreal General Hospital, 1650 Cedar Avenue, Montreal, QC H3G 1A4, Canada.|Department of Medicine, Division of Hematology and Oncology, McGill University Health Centre, Glen site, 1001 Décarie Blvd, room D02-7519, Montreal, QC H4A 3J1, Canada.
authors.forename: Chantal
authors.initials: C
authors.lastname: Séguin
mesh_terms: D000818:Animals; D001786:Blood Glucose; D001835:Body Weight; D004195:Disease Models, Animal; D005270:Femur Head / Q000000981:diagnostic imaging / Q000473:pathology*; D005271:Femur Head Necrosis / Q000097:blood / Q000139:chemically induced / Q000000981:diagnostic imaging / Q000473:pathology*; D008297:Male; D011241:Prednisone; D011916:Rats, Inbred F344; D011921:Rats, Inbred WKY; D013045:Species Specificity; D055114:X-Ray Microtomography; D000511:alpha-Macroglobulins / Q000032:analysis*
chemical_list: D001786:Blood Glucose; D000511:alpha-Macroglobulins; D011241:Prednisone
keywords: alpha-2-macroglobulin; endothelium; glucocorticoid; osteoblast; rat model