Articular cartilage is composed by a unique cell population, the chondrocytes, embedded in an abundant extra-cellular matrix (ECM). Growth, differentiation and homeostasis of the cartilage are regulated by an intricate interplay between the chondrocytes and ECM, which allows the matrix to send signals to the chondrocytes and the chondrocytes to sense the changes from the surrounding microenvironment. Obviously, the knowledge of this inside-out/outside-in signaling is critical to understand the pathophysiology of cartilage. The interactions between chondrocytes and ECM are mediated by an array of membrane receptors, chiefly the integrins. However, besides the integrins, chondrocytes express other transmembrane molecules that act as receptors for ECM, such as annexin V that binds to type II collagen and CD44 and ICAM-I (intercellular adhesion molecule-1) that are hyaluronan receptors [5]. Notably, the binding of the N-telopeptide of type II collagen is through annexin V, whereas binding of the C-telopeptide and the triple helical peptide to the surface of chondrocytes occurs through integrins. The integrins are a wide family of transmebrane heterodimeric proteins with a cytoplasmic tail connected with the cytoskeleton and an extracellular domain that recognizes different ECM components. Until now 15α and 8β subunits have been identified that differently pair to form a large number of integrin receptors. In adult chondrocytes the most important integrin family is β1, others such as β4 and β5 are critical in regulating differentiation and apoptosis of growth plate chondrocytes [15]. Among β1 integrins, α1-β1 and α5-β1 that ligate type II collagen and fibronectin, respectively, are those more extensively studied on chondrocytes [15]. Both α1-β1 and α5-β1 act as mechanoreceptors that transduce the physiologic mechanical loads into cell-survival signals [13], whereas deprivation of chondrocytes from collagen [1] or fibronectin derived signals induces apoptosis [10]. In the last years two important concepts are emerging. To transmit functional positive signals integrins must cluster at the adhesion surface and a second signal, cooperating with integrins, is mandatory to activate chondrocyte anabolism. Intact fibronectin ligates α5-β1 integrin expressed on chondrocytes through the RGD sequence (arginine–glycine–aspartic acid) and stimulates survival signals, but fragments of fibronectin activate degradation pathways by enhancing the expression of MMPs (metalloproteinases) [3]. This seems to be due to the fact that fibronectin fragments contain a reduced number of RGD binding sites, insufficient to cluster α5-β1 integrins. In normal cartilage, intact fibronectin possesses multiple domains available for binding to integrins and the signaling to the cells is effective. In OA, fibronectin fragments are abundant with formation of smaller clusters of integrins engaged by fibronectin. This in turn leads to an alteration in signal transduction and promotion of catabolic gene expression [12].