Gene expression profiling in Paget's disease of bone: upregulation of interferon signaling pathways in pagetic monocytes and lymphocytes.
We examined the gene expression profile of genes involved in bone metabolism in 23 patients with PD compared with 23 healthy controls. We found a significant overexpression of the genes of the IFN pathway along with a downregulation of tnf-alpha. Our result suggest that IFN-mediated signaling may play important roles in aberrant osteoclastogenesis of PD.


BACKGROUND
Paget's disease of bone (PD) is characterized by focal regions of highly exaggerated bone remodeling and aberrant osteoclastogenesis. Under physiological conditions, circulating monocytes may serve as early progenitors of osteoclasts and along with peripheral blood lymphocytes produce a wide variety of factors important in bone metabolism. Nevertheless, little is known about the roles of circulating monocytes and lymphocytes in relation to the pathological bone turnover in PD.


METHODS
In this study, we aimed at investigating the gene expression pattern of PD using quantitative real-time PCR in monocytes and lymphocytes isolated from peripheral blood mononuclear cells (PBMCs). Fifteen genes known to be involved in osteoclastogenesis were studied in cells from 23 patients with PD and in cells from 23 healthy controls. Eight human genes including ifn-alpha (3.48-fold, p < 0.001), ifn-beta (2.68-fold, p < 0.001), ifn-gamma (1.98-fold, p = 0.002), p38 beta2 mapk (2.47-fold, p = 0.002), ifn-gammar1 (2.03-fold, p = 0.01), ifn-gammar2 (1.81-fold, p = 0.02), stat1 (1.57-fold, p = 0.037), and tnf-alpha (-2.34, p < 0.001) were found to be significantly altered in pagetic monocytes compared with monocytes of healthy controls.


RESULTS
In pagetic lymphocytes, significant changes in the expression of ifn-alpha (2.17-fold, p < 0.001), ifn-beta (2.13-fold, p = 0.005), ifn-gamma (1.89-fold, p < 0.001), ifn-gammar1 (1.02-fold, p = 0.04), ifn-gammar2 (1.01-fold, p = 0.031), stat2 (1.79-fold, p < 0.001), and tnf-alpha (-1.49, p < 0.001) were found compared with lymphocytes of healthy controls. Furthermore, IFN-gamma protein was significantly elevated in the sera of PD patients (18.7 +/- 6.69 pg/ml) compared with healthy controls (3.87 +/- 6.48 pg/ml, p = 0.042).


CONCLUSIONS
In conclusion, our data suggest that novel pathways mainly related to the IFN-mediated signaling may play important roles in the aberrant osteoclastogenesis of PD.
Nagy
Zsolt B
ZB
National Institute of Rheumatology and Physiotherapy, Budapest, Hungary.
Gergely
Péter
P
Donáth
Judit
J
Borgulya
Gábor
G
Csanád
Mónika
M
Poór
Gyula
G
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007371:Interferon-gamma / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D008214:Lymphocytes / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009000:Monocytes / Q000473:pathology*; D010001:Osteitis Deformans / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics* / Q000276:immunology
D007371:Interferon-gamma