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.