Androgen conversion in osteoarthritis and rheumatoid arthritis synoviocytes--androstenedione and testosterone inhibit estrogen formation and favor production of more potent 5alpha-reduced androgens.
In synovial cells of patients with osteoarthritis (OA) and rheumatoid arthritis (RA), conversion products of major anti-inflammatory androgens are as yet unknown but may be proinflammatory. Therefore, therapy with androgens in RA could be a problem. This study was carried out in order to compare conversion products of androgens in RA and OA synoviocytes. In 26 OA and 24 RA patients, androgen conversion in synovial cells was investigated using radiolabeled substrates and analysis by thin-layer chromatography and HPLC. Aromatase expression was studied by immunohistochemistry. Dehydroepiandrosterone (DHEA) was converted into androstenediol, androstenedione (ASD), 16alphaOH-DHEA, 7alphaOH-DHEA, testosterone, estrone (E1), estradiol (E2), estriol (E3), and 16alphaOH-testosterone (similar in OA and RA). Surprisingly, levels of E2, E3, and 16alpha-hydroxylated steroids were as high as levels of testosterone. In RA and OA, 5alpha-dihydrotestosterone increased conversion of DHEA into testosterone but not into estrogens. The second androgen, ASD, was converted into 5alpha-dihydro-ASD, testosterone, and negligible amounts of E1, E2, E3, or 16alphaOH-testosterone. 5alpha-dihydro-ASD levels were higher in RA than OA. The third androgen, testosterone, was converted into ASD, 5alpha-dihydro-ASD, 5alpha-dihydrotestosterone, and negligible quantities of E1 and E2. 5alpha-dihydrotestosterone was higher in RA than OA. ASD and testosterone nearly completely blocked aromatization of androgens. In addition, density of aromatase-positive cells and concentration of released E2, E3, and free testosterone from superfused synovial tissue was similar in RA and OA but estrogens were markedly higher than free testosterone. In conclusion, ASD and testosterone might be favorable anti-inflammatory compounds because they decrease aromatization and increase anti-inflammatory 5alpha-reduced androgens. In contrast, DHEA did not block aromatization but yielded high levels of estrogens and proproliferative 16alpha-hydroxylated steroids. Androgens were differentially converted to pro- and anti-inflammatory steroid hormones via diverse pathways.
Schmidt
Martin
M
Institute of Biochemistry II, Hospital of the Friedrich-Schiller-University, Jena, Germany. schmidt@mti.uni-jena.de
Weidler
Claudia
C
Naumann
Heidrun
H
Anders
Sven
S
Schölmerich
Jürgen
J
Straub
Rainer H
RH
D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000378:metabolism*; D000728:Androgens / Q000096:biosynthesis*; D000735:Androstenedione / Q000378:metabolism / Q000494:pharmacology*; D001141:Aromatase / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000378:metabolism* / Q000473:pathology; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D016207:Cytokines / Q000378:metabolism; D003687:Dehydroepiandrosterone / Q000378:metabolism / Q000494:pharmacology*; D004967:Estrogens / Q000096:biosynthesis*; D005260:Female; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008954:Models, Biological; D010003:Osteoarthritis / Q000378:metabolism* / Q000473:pathology; D013583:Synovial Membrane / Q000378:metabolism* / Q000473:pathology; D013739:Testosterone / Q000378:metabolism / Q000494:pharmacology*
D000728:Androgens; D016207:Cytokines; D004967:Estrogens; D018836:Inflammation Mediators; D013739:Testosterone; D000735:Androstenedione; D003687:Dehydroepiandrosterone; D001141:Aromatase; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase