Original articleOsteonecrosis induced by a single administration of low-dose lipopolysaccharide in rabbits
Introduction
There has been much clinical progress in the therapeutic and diagnostic aspects of nontraumatic osteonecrosis (ON) of the femoral head (ONFH). In particular, use and applications of magnetic resonance imaging (MRI) for ONFH have now made possible early detection of lesions and accurate classication of clinical stage of disease.31 Although several theories regarding the pathogenesis of ONFH, including increased bone marrow pressure at the femoral head,18, 29 enlargement of fat cell size,43 accumulation of lipid within osteocytes,22 fat embolism,7, 20, 43 obstruction of venous outflow,15 intravascular coagulation20, 41 and altered fibrinolysis10, 41 have been proposed, the pathogenesis of ONFH remains unclear. In fact, ONFH has often been known to develop following such various morbid conditions as the use of corticosteroids, especially pulse therapy or high-dose therapy for systemic lupus erythematosus1, 35 and renal transplantation,25 alcohol abuse,11, 19, 28 sickle-cell anemia,3, 14, 44 Gaucher disease,21 antiphospholipid antibody syndrome,5, 30 and others.31
The major problem in studying the pathogenesis of human ONFH results from the lack of any clinicopathological information during its earliest events, because it is very difficult to make a clinical diagnosis immediately after the occurrence of ONFH. Secondary bone deformity has normally already occurred by the time patients complain of such clinical symptoms as hip pain, gait disturbance, or limitations in the range of motion of the hip. Therefore, it is necessary to develop useful animal models for human ONFH of various etiologies. Some experimental animal models for nontraumatic ONFH have been reported and proved beneficial in pathophysiological studies of ONFH. Matsui et al.27 reported steroid-induced ON in rabbits with Arthus reaction that was provoked by repeated intravenous injections of horse serum. We previously developed a rabbit model by combining the Shwartzman reaction and corticosteroid injections and thus found steroid treatment to enhance the incidence of ON not only in the metaphysis and diaphysis but also in the epiphysis.41 We also recently reported that a single injection of high-dose corticosteroid could induce multifocal ON in rabbits, which were also associated with thrombocytopenia, hypofibrinogenemia, and hyperlipemia.42
Although steroid-independent ON is known to represent half of all patients with ONFH,2 to our knowledge, only a few animal models have been developed for nontraumatic and nonsteroid ON.34 We therefore attempted to generate a new, highly reproducible rabbit ON model using a single intravenous injection of low-dose LPS, but without steroid treatment. We herein report the histopathological characteristics of ON lesions and refer to the pathogenesis based on the coagulation/fibrinolysis system and lipid metabolism in this animal model.
Section snippets
Animals
Adult male Japanese white rabbits (Kyudo, Tosu, Japan), weighing 3.0–4.0 kg 30–34 weeks old, when growth plates of the femoral and humeral bones had already been closed, were used as experimental animals. All animals tested were kept under routine laboratory conditions at the Animal Center of Kyushu University. They received a standard laboratory diet and had free access to food and water in their cages. All experiments were reviewed by the ethics committee on animal experiments at the Graduate
Body weight
The body weight in the rabbits without ON showed the lowest value at 48 h and recovered to the basal level at 4 weeks, whereas the rabbits with ON continued their reduction in weight up to 2 weeks, with an average weight loss of 0.79 ± 0.28 kg (22.0% of prior body weight at 2 weeks), and 0.60 ± 0.34 kg (16.7% of prior body weight) at 4 weeks. Weight loss was more prominent in rabbits with ON than in those without ON from 72 h through 4 weeks (p < 0.01). The control group showed no remarkable
Discussion
LPS is a constituent of the cell wall of Gram-negative bacilli and has been well known to possess various biological activities, including activation of the immune system and the induction of inflammation-circulatory disturbance, and thus LPS participates intimately in the development of such morbid conditions as intravascular coagulation24 with or without LPS shock, fat embolism,13 multiple-organ dysfunction,40 hyperlipidemia,8 and others.36 In particular, LPS activates vascular endothelial
Acknowledgements
The authors thank Hiroshi Fujii, Shizuko Yugawa, and Yuko Fukai for their very helpful technical assistance and Dr. Brian Quinn for his review of the manuscript. This work was supported in part by a research grant for intractable diseases from the Ministry of Health and Welfare of Japan.
References (45)
- et al.
Hyperlipidemia, fatty liver, and bromosulfophthalein retention in rabbits injected intravenously with bacterial endotoxins
J Lipid Res
(1964) - et al.
Gram-negative bacteremiaIV. Re-evaluation of clinical features and treatment in 612 patients
Am J Med
(1980) - et al.
Inducible osteonecrosis in a rabbit serum sickness modelDeposition of immune complexes in bone marrow
Bone
(1996) - et al.
Phase II trial of intravenous endotoxin in patients with colorectal and non-small cell lung cancer
Eur J Cancer
(1996) - et al.
Aseptic necrosis of bone in systemic lupus erythematosus. Relationship to corticosteroid therapy
Arch Intern Med
(1978) - et al.
- et al.
Aseptic necrosis of the femoral head in sickle-cell disease
Br J Rheumat
(1986) - et al.
Cellular immune and cytokine pathways resulting in tissue factor expression and relevance to septic shock
Nouvelle Revue Francaise d Hematologie
(1992) - et al.
Catastrophic antiphospholipid antibody syndrome presenting with multiple thromboses and sites of avascular necrosis
J Rheumatol
(1994) - et al.
Interleukin 1 and lipopolysaccharide induce an inhibitor of tissue-type plasminogen activator in vivo and in cultured endothelial cells
J Exp Med
(1986)
The role of fat embolism in the etiology of corticosteroid-induced avascular necrosisClinical and experimental results
Clin Orthop
The acute splanchnic and peripheral tissue metabolic response to endotoxin in humans
J Clin Invest
The plasminogen activator inhibitor-1 gene, hypofibrinolysis, and osteonecrosis
Clin Orthop
Familial idiopathic osteonecrosis mediated by familial hypofibrinolysis with high levels of plasminogen activator inhibitor
Thromb Haemost
Incidence and pathogenesis of alcohol-induced osteonecrosis of the femoral head
Clin Orthop
Chondro-osseous growth abnormalities after meningococcemia. A clinical and histopathological study
J Bone Jt Surg [Am]
Fat embolism and intravascular coagulation
Acta Pathol Microbiol Scand A
Haematological factors associated with avascular necrosis of the femoral head in homozygous sickle cell disease
Br J Haematol
Histopathologic alterations of retinacular vessels and osteonecrosis
Clin Orthop
Use of avidin-biotin-peroxidase complex (ABC) in immunoperoxidase techniquesA comparison between ABC and unlabeled antibody (PAP) procedures
J Histochem Cytochem
Pathogenetic considerations in ischemic necrosis of bone
Can J Surg
Alcoholism-induced bone necrosis
NY State J Med
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Advances in experimental models of osteonecrosis of the femoral head
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