Primary epiphyseal arteriopathy in a mouse model of steroid-induced osteonecrosis.

Janke LJ, Liu C, Vogel P, Kawedia J, Boyd KL, Funk AJ, Relling MV
Am J Pathol. 2013 183 (1): 19-25

PMID: 23673001 · PMCID: PMC3702740 · DOI:10.1016/j.ajpath.2013.03.004

Patients undergoing glucocorticoid therapy for a variety of disorders, including autoimmune diseases and hematological malignancies, are at risk of developing osteonecrosis. Despite extensive research in both patients and animal models, the underlying pathogenesis remains unclear. Proposed inciting mechanisms include intravascular thrombotic occlusion, marrow fat hypertrophy, osteocyte and/or endothelial cell apoptosis, hypercoagulability, and vasoconstriction of specific arteries and arterioles supplying bone. Our laboratory has developed a model of steroid-induced osteonecrosis in BALBcJ mice which reflects clinically relevant exposures to glucocorticoids in which treated mice develop osteonecrosis of the distal femoral epiphysis when administered 4 to 8 mg/L dexamethasone in drinking water for 6 weeks. We identified lesions in arterioles supplying this area, with the mildest occurring in knees without any evidence of osteonecrosis. However, arteriopathy was more common among mice that did versus did not develop osteonecrosis (P < 0.0001); in mice with osteonecrosis, the associated vessels showed transmural necrosis and thickening of the vessel wall progressing to the point of luminal obstruction. In the most severe cases of osteonecrosis, end-stage lesions consisted of fully occluded vessels with marrow and bone necrosis involving the entire epiphysis. We propose that a primary arteriopathy is the initiating event in the genesis of steroid-induced osteonecrosis and provides a basis for future investigation of this disease process.

Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

MeSH Terms (13)

Administration, Oral Animals Arterioles Dexamethasone Disease Models, Animal Drug Administration Schedule Epiphyses Femur Glucocorticoids Male Mice Mice, Inbred BALB C Osteonecrosis

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