Annexin 2 and bone: A pathway to mineralization

Osteosarcoma, the most common form of primary bone cancer, is highly aggressive and often metastatic. As is the case with many types of cancer, the metastatic aspect of the disease is most devastating. Therefore, in order to obtain a better understanding of the genes involved in the metastatic process of osteosarcoma, our laboratory utilized a representational difference analysis screen to identify genes differentially expressed between primary human osteosarcoma tumors and subsequent metastatic lung lesions. One of the interesting genes identified in this screen was annexin 2.;Annexin 2 has been described in several cellular localizations with various functional implications, many of which may be relevant to metastatic potential. Overexpression of annexin 2 in osteosarcoma cells did not appear to affect several in vitro metastatic parameters. However, annexin 2 overexpression did result in an increase in mineralization capacity of osteoblastic cells.;In addition to an increased mineralization in osteosarcoma cells and primary osteoblasts, overexpression of annexin 2 led to an increase in alkaline phosphatase activity. It was determined that both annexin 2 and alkaline phosphatase activity were localized to membrane microdomains called lipid rafts in osteoblastic cells, and annexin 2 overexpression resulted an increase in alkaline phosphatase activity associated with lipid microdomains. Furthermore, disruption of lipid rafts or reduction of annexin 2 expression each resulted in diminished mineralization. Therefore, intact lipid rafts containing annexin 2 appear to be important for alkaline phosphatase activity and may facilitate the osteoblastic mineralization process.;One mechanism by which osteoblastic cells can mineralize is mediated by matrix vesicles. Interestingly, annexin 2 overexpression resulted in an increased production of vesicular structures on the surface of the osteoblastic cells. The contents of these vesicles were determined to be consistent with matrix vesicles, and overexpression of annexin 2 resulted in an increase in alkaline phosphatase activity detected within the matrix vesicles. Therefore, annexin 2 may increase the rate of osteoblastic mineralization by increasing alkaline phosphatase activity associated with matrix vesicles at early times points in the differentiation process.