Small leucine-rich proteoglycans (SLRP) are a class of proteoglycans that are characterized by small protein cores and structures of leucine-rich repeats. SLRPs are expressed in most extracellular matrices and share many biological functions that are related to binding of collagens and cell surface receptors. Osteoadherin/osteomodulin is encoded by the Omd gene and is a keratan sulfate proteoglycan of the class II subfamily of SLRPs. Osteoadherin is highly expressed in mineralized tissues, including bone and dentin, but its precise roles remain unknown. In this study, we determined Omd expression levels and investigated the effects of over and under expression of osteoadherin in osteoblastic cells. Omd mRNA expression increased with osteoblast differentiation in MC3T3-E1 cells. In C2C12 cells, Omd mRNA expression was induced by bone morphogenetic protein (BMP) 2. Reporter assays similarly showed activation of the Omd gene promoter after co-transfection with Smad1 and Smad4, which are intracellular signaling molecules of the BMP2 signaling pathway. Overexpression of Omd increased viability and decreased caspase 3/7 activity in MC3T3-E1 cells. In contrast, following transfection with siRNA for Omd, viable cell numbers were decreased and caspase 3/7 activity was increased. Moreover, overexpression of Omd reduced the expression of CCN family 2 (CCN2) in these cells. These results show that Omd expression is regulated during osteoblast differentiation, and that the protein product osteoadherin plays roles in apoptosis and growth of osteoblast cells.