Effects of pleiotrophin, a heparin-binding growth factor, on human primary and immortalized chondrocytes.
OBJECTIVE
Pleiotrophin (PTN) is a secreted heparin-binding peptide expressed in mesodermal and neuroectodermal cells during development, but rarely in adult tissues. In fetal and juvenile, but not in mature cartilage, PTN is abundant. Furthermore, PTN is re-expressed in chondrocytes in early stages of osteoarthritis (OA). Since little is known about the functions of PTN in cartilage, we investigated the occurrence of PTN receptors in human articular cartilage in situ and PTN effects on human primary and immortalized chondrocytes in vitro.


METHODS
Receptor expression and regulation was monitored by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemistry. PTN effects and signal transduction were studied by electrophoretic mobility shift, Boyden chamber cell migration and proliferation assays, effects on gene expression by real time RT-PCR and that on nitric oxide (NO) by the Griess reaction.


RESULTS
Of the putative PTN signaling receptors, immortalized and primary chondrocytes (pc) expressed the anaplastic lymphoma kinase (ALK), less the receptor-type protein tyrosine phosphatase zeta/beta (PTPzeta). ALK expression was upregulated upon ligand exposure. PTN stimulation activated the AP-1 (activator protein-1) transcription factor and altered gene expression. Prolonged stimulation induced PTN mRNA expression slightly, reduced vascular endothelial growth factor (VEGF) mRNA as well as NO production. Whereas mRNA expression of matrix metalloproteinases (MMPs) MMP-1 and MMP-13 was reduced, their inhibitors TIMP-1 and TIMP-2 were induced. Furthermore, PTN stimulated chondrocyte migration and proliferation.


CONCLUSIONS
These results show that PTN is an autocrine growth factor in cartilage. We suggest that PTN may be involved in the clustering and proliferation of chondrocytes observed in the early stages of OA.
Pufe
T
T
Department of Anatomy, University of Kiel, D-24098 Kiel, Germany.
Groth
G
G
Goldring
M B
MB
Tillmann
B
B
Mentlein
R
R
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics*; D002358:Cartilage, Articular / Q000378:metabolism*; D002417:Cattle; D019902:Chondrocytes / Q000378:metabolism*; D016207:Cytokines / Q000235:genetics*; D006133:Growth Substances / Q000235:genetics*; D006801:Humans; D010003:Osteoarthritis / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
D002352:Carrier Proteins; D016207:Cytokines; D006133:Growth Substances; C066845:pleiotrophin