We succeeded in developing a novel rabbit model of nonsteroid and nontrauma
tic osteonecrosis (ON) by use of a single- and low-dose lipopolysaccharide
(LPS) injection. This model is simple and highly reproducible for the frequ
ent development of multifocal and widespread ON lesions. Male adult Japanes
e white rabbits intravenously injected with a single injection of 10 mug/kg
body weight of LPS were histopathologically examined in the early phase (3
[n = 3], 5 [n = 3], and 24 h [n = 3]) and at 4 weeks (n = 22), Seventy-sev
en percent of the rabbits developed multifocal ON 4 weeks after LPS injecti
on. ON was also observed in the femoral and humeral condyle, The average pe
rcentage of necrotic area/total area examined was 86.7 +/- 29.1% and 78.8 /- 16.7% in the proximal one third of both the femoral and humeral bones, r
espectively, Organized thrombi in the intraosseous small-sized arteries and
arterioles were frequently seen in and around the necrotic tissues. In the
early phase, LPS treatment prominently induced thrombocytopenia, hyperlipi
demia, and increased plasma levels of plasminogen activator inhibitor-1 (PA
I-1), The plasma level of PAI-1 was significantly higher in the rabbits wit
h ON than in those without ON (p < 0.01). The immunohistochemical expressio
n of tissue factor was exaggerated in monocytes/macrophages and adipocytes
in both the femoral and humeral bones of the LPS-treated rabbits. Hisstolog
ically, marrow necrosis and fibrin thrombi could be observed at 24 h, In ad
dition, pretreatment with an anticoagulant, warfarin potassium, significant
ly decreased the incidence of LPS-induced ON (33%, n = 9, p < 0.05) associa
ted with elongation of prothrombin time. The results of our study show that
a single administration of low-dose lipopolysaccharide induces multifocal
and widespread ON characterized by the pathophysiological participation of
hypercoagulability in ON development. Therefore, this model would be useful
for elucidating the pathogenesis of nonsteroid ON in humans especially inf
lammatory hypercoagulability-induced as well as for developing preventive a
nd therapeutic strategies, (C) 2001 by Elsevier Science Inc, All rights res
erved.