Estrogen and progesterone regulation of human fibroblast-like synoviocyte function in vitro: implications in rheumatoid arthritis.
OBJECTIVE
Despite increasing evidence regarding the significance of sex hormones in rheumatoid arthritis (RA), their etiopathological role and potential longterm effect on joint destruction remain unclear. We hypothesized that estrogen receptors (ER-alpha) are present in fibroblast-like synoviocytes, and 17beta-estradiol can modulate the production and activity of matrix degrading enzymes produced by these cells. Thus, depending on the endocrine balance, fibroblast-like synoviocyte activity can be suppressed or enhanced, leading to amelioration or exacerbation of the disease process, respectively.


METHODS
By utilizing an in vitro cartilage invasion model, in combination with the molecular analyses of hormone receptors, matrix metalloproteinases (MMP) and their respective inhibitors, we investigated the effect of hormones (i.e., estrogen and progesterone) on fibroblast-like synoviocyte phenotypic changes, with particular emphasis on their functional interactions with cartilage.


RESULTS
Our studies reveal the presence of functional ER-alpha in fibroblast-like synoviocytes. The findings indicate that estrogen exerts a stimulatory effect, while progesterone has an inhibitory effect on the expression of MMP, their tissue inhibitors (TIMP), and enzymatic activity of MMP produced by these cells. Furthermore, transfection of fibroblast-like synoviocytes with the ER-alpha gene resulted in the increased degradation and invasion of cartilage.


CONCLUSIONS
We identified the presence of functional ER-alpha in fibroblast-like synoviocytes. This renders fibroblast-like synoviocytes as target cells for hormonal regulation. The regulatory effect of estrogen is partly targeted to the MMP and their respective inhibitors associated with fibroblast-like synoviocytes. Such studies provide a link between hormonal status and disease activity in RA and open new venues for future therapeutic intervention to combat this debilitating disease.
Khalkhali-Ellis
Z
Z
Department of Anatomy and Cell Biology, University of Iowa, Iowa City 52242, USA.
Seftor
E A
EA
Nieva
D R
DR
Handa
R J
RJ
Price
R H
RH
Kirschmann
D A
DA
Baragi
V M
VM
Sharma
R V
RV
Bhalla
R C
RC
Moore
T L
TL
Hendrix
M J
MJ
D000293:Adolescent; D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology*; D002356:Cartilage / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D002478:Cells, Cultured; D047628:Estrogen Receptor alpha; D004967:Estrogens / Q000009:adverse effects / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D008297:Male; D020782:Matrix Metalloproteinases / Q000235:genetics; D008875:Middle Aged; D011374:Progesterone / Q000009:adverse effects / Q000378:metabolism*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D011960:Receptors, Estrogen / Q000187:drug effects / Q000378:metabolism; D013583:Synovial Membrane / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology*; D019714:Tissue Inhibitor of Metalloproteinases / Q000235:genetics
D047628:Estrogen Receptor alpha; D004967:Estrogens; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D019714:Tissue Inhibitor of Metalloproteinases; D011374:Progesterone; D020782:Matrix Metalloproteinases