Expression of pleiotrophin, an embryonic growth and differentiation factor, in rheumatoid arthritis.
OBJECTIVE
Pleiotrophin (PTN), a 15.3-kd heparin-binding peptide, is expressed in mesodermal and neuroectodermal cells during development, but rarely in adult tissues. Since developmentally regulated factors often reappear during disease, we sought to determine whether there was PTN expression in the synovial membranes of patients with rheumatoid arthritis (RA).


METHODS
PTN messenger RNA expression was assayed by quantitative reverse transcriptase-polymerase chain reaction. The protein was localized by immunohistochemistry and quantified by enzyme-linked immunosorbent assay (ELISA). Effects of PTN on cell proliferation in vitro were determined by DNA measurements.


RESULTS
PTN expression in normal adult synovial membranes and cartilage was barely detectable. However, PTN was strongly up-regulated in synovial tissues from patients with RA. In contrast, samples from patients with pyogenic arthritis had moderate PTN levels, and those from patients with osteoarthritis had only a slight increase in PTN, as measured by ELISA. In RA patients, PTN was localized primarily in synoviocytes but was also found in endothelial cells of blood vessels. In cultured mouse fibroblasts used as a model, PTN expression was up-regulated by tumor necrosis factor alpha and was more weakly up-regulated by epidermal growth factor. Recombinant PTN stimulated the proliferation of cultured human synoviocytes and the monocyte cell line THP-1, but not human dermal fibroblasts, in which PTN increased the synthesis of vascular endothelial growth factor.


CONCLUSIONS
In addition to certain types of cancer, the embryonic growth and differentiation factor PTN is expressed in adults with inflammatory diseases, in particular, RA. Proinflammatory cytokines enhance the expression of PTN. Thus, we propose that PTN is a further paracrine angiogenesis and growth factor for synovial cells in RA.
Pufe
Thomas
T
University of Kiel, Kiel, Germany.
Bartscher
Michaela
M
Petersen
Wolf
W
Tillmann
Bernhard
B
Mentlein
Rolf
R
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000378:metabolism*; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics / Q000494:pharmacology; D017931:DNA Primers / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D016228:Endothelial Growth Factors / Q000096:biosynthesis; D004797:Enzyme-Linked Immunosorbent Assay; D006133:Growth Substances / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D007124:Immunoenzyme Techniques; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis; D008222:Lymphokines / Q000096:biosynthesis; D009000:Monocytes / Q000187:drug effects / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012867:Skin / Q000187:drug effects / Q000473:pathology; D013583:Synovial Membrane / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D002352:Carrier Proteins; D016207:Cytokines; D017931:DNA Primers; D016228:Endothelial Growth Factors; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C066845:pleiotrophin