Syndecans are cell surface heparan sulfate proteoglycans that serve as 
co-receptors and modulate the actions of a number of extracellular ligands. 
Syndecans thereby regulate cell adhesion, proliferation, and differentiation. 
Studies in cancer cells suggest that syndecans may also modulate cell viability. 
We previously showed that syndecan-2 controls the growth of normal human 
osteoblastic cells. In this study, we examined the role of syndecan-2 in 
osteosarcoma cell proliferation and apoptosis. To this goal, MG63 osteosarcoma 
cells which express low syndecan-2 levels were transfected to overexpress 
full-length syndecan-2 or truncated syndecan-2 lacking its cytoplasmic domain. 
Determination of cell growth by cell counting and 3H-thymidine incorporation 
showed that truncated syndecan-2 inhibited MG63 cell proliferation. Flow 
cytometry analysis of DNA content and colony forming test revealed that 
syndecan-2, but not truncated syndecan-2, induced MG63 cell death. We show that 
characteristic features of apoptosis such as caspase activation, PARP cleavage, 
cytochrome c release, increased Bax expression, and DNA fragmentation were 
associated with syndecan-2-induced cell death. We further show that expression 
of full-length or truncated syndecan-2 induced differential activation of MAPK 
phosphorylation in MG63 cells. Notably, syndecan-2 but not truncated syndecan-2 
overexpression increased JNK phosphorylation. Moreover, SP600125, a specific 
inhibitor of JNK, suppressed Bax expression induced by syndecan-2 
overexpression, indicating that JNK activation mediates syndecan-2-induced 
apoptosis. The results show that syndecan-2 induces osteoblastic cell apoptosis 
through the JNK/Bax apoptotic pathway and that the cytoplasmic domain of 
syndecan-2 is required for this action. This supports a role for syndecan-2 in 
the regulation of osteosarcoma cell fate and identifies one signaling pathway by 
which syndecan-2 induces apoptosis in osteosarcoma cells.