Osteopontin is an RGDS-containing protein that acts as a ligand for the ␣ v ␤ 3 integrin, which is abundantly expressed in osteoclasts, cells responsible for bone resorption in osteopenic diseases such as osteoporosis and hyperparathyroidism. However, the role of osteopontin in the process of bone resorption has not yet been fully understood. Therefore, we investigated the direct function of osteopontin in bone resorption using an organ culture system. The amount of 45 Ca released from the osteopontin-deficient bones was not significantly different from the basal release from wild type bones. However, in contrast to the parathyroid hormone (PTH) enhancement of the 45 Ca release from wild type bones, PTH had no effect on 45 Osteoclastic bone resorption is a key event in the pathophysiology of osteopenic diseases such as osteoporosis and hyperparathyroidism. Osteoclastic bone resorption involves a number of sequential events, including differentiation and activation of osteoclasts. These processes are regulated both by key cytokines and hormones interacting with various cell surface receptors and by interactions of osteoclast precursors with osteoblasts/stromal cells (1-3). The ␣ v ␤ 3 integrin is a major receptor on the osteoclast that can interact with RGD sequence-containing ligands such as osteopontin and vitronectin (4). It possibly promotes osteoclast attachment to bone and, when engaged by either immobilized or soluble ligands, stimulates signaling pathways that regulates osteoclast migration and function. Bone matrix consists of about 90% type I collagen and about 5% noncollagenous proteins. Among these noncollagenous proteins, at least five proteins, osteopontin, bone sialoprotein, thrombospondin, fibronectin, and vitronectin, contain RGD sequences that can be recognized by some integrins (5-8). These noncollagenous bone proteins are candidate ligands for the ␣ v ␤ 3 integrin expressed on the osteoclasts. In vitro data suggest that the ␤ 3 integrin subunit is involved in the attachment of osteoclasts to osteopontin and bone sialoprotein, whereas the ␤ 1 integrin subunit is responsible for the attachment of these cells to fibronectin (9). With regard to osteoclastic bone resorption in vitro, interactions between osteopontin and/or bone sialoprotein and the ␣ v ␤ 3 integrin (10, 11) have been proposed to play a crucial role. The signaling pathways stimulated by the integrin lead to modulation of cytoskeletal reorganization via regulatory molecules such as gelsolin (12). A recent study also indicates that the ␤ 3 integrin is important in osteoclastic bone resorption in vivo. (13) Osteopontin (14), is a mineralized matrix protein and a cytokine that has been suggested to act in several types of organs and systems, including bone (15), the immune system (16), the vascular system (17), and kidney (18). In addition, osteopontin is expressed at sites of inflammation. Osteopontin modifies cell behavior (19,20) and alters gene expression. In mineralized tissues, osteopontin is produced by osteoblasts and osteocla...