Upregulation of monocyte/macrophage HGFIN (Gpnmb/Osteoactivin) expression in end-stage renal disease.
OBJECTIVE
Hematopoietic growth factor-inducible neurokinin 1 (HGFIN), also known as Gpnmb and osteoactivin, is a transmembrane glycoprotein that is expressed in numerous cells, including osteoclasts, macrophages, and dendritic cells. It serves as an osteoblast differentiation factor, participates in bone mineralization, and functions as a negative regulator of inflammation in macrophages. Although measurable at low levels in monocytes, monocyte-to-macrophage transformation causes substantial increase in HGFIN expression. HGFIN is involved in systemic inflammation, bone demineralization, and soft tissue vascular calcification.


METHODS
We explored HGFIN expression in monocytes and monocyte-derived macrophages in 21 stable hemodialysis patients and 22 control subjects.


RESULTS
Dialysis patients exhibited marked upregulation of colony-stimulating factor and IL-6 and significant downregulation of IL-10 in intact monocytes and transformed macrophages. HGFIN expression in intact monocytes was negligible in control subjects but conspicuously elevated (8.6-fold) in dialysis patients. As expected, in vitro monocyte-to-macrophage transformation resulted in marked upregulation of HGFIN in cells obtained from both groups but much more so in dialysis patients (17.5-fold higher). Upregulation of HGFIN and inflammatory cytokines in the uremic monocyte-derived macrophages occurred when grown in the presence of either normal or uremic serum, suggesting the enduring effect of the in vivo uremic milieu on monocyte/macrophage phenotype and function.


CONCLUSIONS
Uremic macrophages exhibit increased HGFIN gene and protein expression and heightened expression of proinflammatory and a suppressed expression of anti-inflammatory cytokines. Further studies are needed to determine the role of heightened monocyte/macrophage HGFIN expression in the pathogenesis of ESRD-induced inflammation and vascular and soft tissue calcification.
Pahl
Madeleine V
MV
Department of Medicine, Division of Nephrology and Hypertension, UCI Medical Center, 101 The City Drive, Building 53, Room 125, Rt 81, Orange, CA 92868, USA. mpahl@uci.edu
Vaziri
Nosratola D
ND
Yuan
Jun
J
Adler
Sharon G
SG
D002478:Cells, Cultured; D006801:Humans; D007676:Kidney Failure, Chronic / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D008562:Membrane Glycoproteins; D008565:Membrane Proteins / Q000096:biosynthesis*; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism*; D015854:Up-Regulation
C503042:GPNMB protein, human; D008562:Membrane Glycoproteins; D008565:Membrane Proteins