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Inhibition of Osteoporosis in Autoimmune Disease Prone MRL/Mpj-Fas^lpr Mice by N-3 Fatty Acids

Department of Medicine, Division of Clinical Immunology (A.B., M.M.R., J.L.B., R.A.L., M.F., G.F.), San Antonio, Texas
Department of Pathology (H.S.M.), San Antonio, Texas
University of Texas Health Science Center, OsteoScreen, Inc. (I.R.G.), San Antonio, Texas

Address reprint requests to: Gabriel Fernandes, Ph.D., Division of Clinical Immunology, mail code 7874, Department of Medicine, The University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900. E-mail: fernandes{at}uthscsa.edu

Objective: Rheumatoid arthritis (RA) is a systemic autoimmune inflammatory disease involving the breakdown of cartilage and juxta-articular bone, which is often accompanied by decreased bone mineral density (BMD) and increased risk of fracture. Anti-inflammatory omega-3 fatty acids may prevent arthritis and bone loss in MRL/lpr mice model of arthritis and in humans.

Methods: In this study, the effect of long term feeding of 10% dietary n-3 (fish oil (FO)) and n-6 (corn oil (CO)) fatty acids begun at 6 weeks of age on bone mineral density (BMD) in different bone regions in an MRL/lpr female mouse model of RA was measured at 6, 9, and 12 months of age by dual energy x-ray absorptiometry (DEXA). After sacrificing the mice at 12 months of age, antioxidant enzyme activities were measured in spleen, mRNA for receptor activator of NF-B ligand (RANKL) and osteoprotegerin (OPG) was measured by RT-PCR in lymph nodes, and synovitis was measured in leg joints.

Results: At 6, 9 and 12 months of age, BMD was significantly higher (p < 0.05) in distal femur, proximal tibia, and lumbar spine of FO fed mice than those of CO fed mice. Spleen catalase (CAT) and superoxide dismutase (SOD) activities were also significantly higher (p < 0.01) in FO fed mice than in CO fed mice. Histology of knee joints revealed mild synovitis in CO fed mice, which was not present in FO fed mice. RT-PCR analysis of lymph nodes revealed decreased RANKL mRNA (p < 0.001) expression and enhanced OPG mRNA expression (p < 0.01) in FO fed mice compared to CO fed mice.

Conclusions: These results suggest beneficial effects of long-term FO feeding in maintaining higher BMD and lower synovitis in this mouse model. These beneficial effects may be due, in part, to increased activity of antioxidant enzymes, decreased expression of RANKL, and increased expression of OPG in FO fed mice thereby altering the RANKL/OPG ratio. These significant beneficial effects on BMD suggest that FO may serve as an effective dietary supplement to prevent BMD loss in patients with RA.

Key words: rheumatoid arthritis, osteoporosis, RANKL/OPG, fish oil, antioxidants

Abbreviations: BHT = butylated hydroxy toluene • BMD = bone mineral density • CAT = catalase • CDNB = 1-chloro-2,4-dinitrobenzene • CLF = central left femur • CLT = central left tibia • CO = corn oil • DEXA = dual energy x-ray absorptiometry • DHA = docosahexaenoic acid • DLF = distal end of left femur • EPA = eicosapentaenoic acid • FID = flame ionization detector • FO = fish oil • GPx = glutathione peroxidase • GST = glutathione S-transferase • MUFA = monounsaturated fatty acids • NOS = Nitric oxide synthetase • OPG = osteoprotegerin • PI = peroxidizability index • PLT = proximal left tibia • P/S = polyunsaturated/saturated fatty acid ratio • PUFA = polyunsaturated fatty acids • RA = Rheumatoid arthritis • RANKL = receptor activator of NF-B ligand • SLE = systemic lupus erythematosus • SOD = superoxide dismutase • TBHQ = tertiary butyl hydroxy quinone

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