Physiological mineralization in growth plate cartilage is highly regulated and restricted to terminally differentiated chondrocytes. Because mineralization occurs in the extracellular matrix, we asked whether major extracellular matrix components (collagens) of growth plate cartilage are directly involved in regulating the mineralization process. Our findings show that types II and X collagen interacted with cell surface-expressed annexin V. ] i , alkaline phosphatase activity, and mineralization. In conclusion, the interactions between collagen and annexin V regulate mineralization of growth plate cartilage. Because annexin V is up-regulated during pathological mineralization events of articular cartilage, it is possible that these interactions also regulate pathological mineralization.The extracellular matrix not only plays a major role in maintaining the function of a tissue but it also interacts and communicates directly with the cell via cell receptor/matrix interactions. These interactions play crucial roles in cell adhesion, migration, proliferation, and differentiation. Various types of collagens are the main organic components of extracellular matrices of many tissues. For example, in bone the main organic extracellular matrix component is type I collagen, whereas the main collagenous component in growth plate cartilage is type II collagen (1). Type II collagen is highly expressed in the proliferative and prehypertrophic zones of growth plate cartilage. Just before mineralization starts, type II collagen synthesis is reduced and the hypertrophic growth plate chondrocytes produce type X collagen (2, 3).Several cell surface receptors that mediate cell/matrix interactions have been identified in growth plate chondrocytes. Among these receptors are integrin receptors and non-integrin receptors, like annexin V and CD44. Several integrins have been identified to be expressed by growth plate chondrocytes. Among these integrins are ␣1, ␣2, ␣5, ␣6, ␣V, 1, and 5. Most of these integrins are expressed in all growth plate zones, whereas some integrins are restricted to certain zones. For example, 5 integrin is restricted to the hypertrophic zone (1, 4). The main collagen receptors in growth plate cartilage are ␣11 and ␣21 integrins (5). Annexin V was identified as another protein binding to types II and X collagen, and it has been demonstrated that chondrocytes attach to type II collagen using annexin V (6). It was originally isolated from the chondrocyte membrane fractions as a type II collagen-binding protein (7,8). We and others have shown that annexin V, among other annexins, is highly expressed by hypertrophic and terminally differentiated growth plate chondrocytes (9, 10). Annexins are normally located in the cytoplasm or at the inner plasma membrane surface. However, several annexins have been detected extracellularly or surface-exposed. In addition, several annexins have been shown to act as receptors for a variety of molecules, including extracellular matrix proteins, fetuin A, vitamin D, and other ce...