The intracellular signaling cascade triggered as a result of the surface chemistry of the bone mineral hydroxyapatite (HA) remains largely unknown. In this study, we found that the ERK signaling molecule is activated in response to HA. Moreover, we have performed the first systemic analysis of expression profiles using microarray technology. Eleven genes, including those involved in calcium regulation and bone matrix formation, showed a greater than 2.0-fold change in expression level in response to HA. Among those genes upregulated by HA was the gene encoding SOX9, whose expression we confirmed by real-time PCR analysis with a 5.7-fold increase in expression. Taken together, our results suggest that the activation of ERK and SOX9 by HA could have important implications for understanding the mechanisms by which cells respond on a molecular level to HA.