Studies on chondrocyte integrins and mechanical signaling

Abstract: Integrins are a family of cell surface receptors known to bind matrix proteins and to mediate signals such as mechanical signals between the cell and the surrounding matrix. We have studied integrins that are expressed by chondrocytes, with specific focus on the integrins that interact with the cartilage matrix protein collagen type II. It was found that chondrocytes isolated from articular cartilage express the collagen-binding integrins alpha1beta1, alpha10beta1 and small amounts of alpha2beta1. By investigating the expression of integrins in cultured chondrocytes, we could demonstrate that expression of alpha10beta1 is correlated with chondrocyte phenotype. To further understand the role of the collagen-binding integrin alpha10beta1 during the formation of cartilage, its distribution during cartilage development was investigated. Expression of alpha10 was found in the early stages of chondrogenesis and strong expression was observed throughout the development and maturation of the cartilage. These results indicate that alpha10beta1 is a major collagen-binding integrin in articular cartilage and it is likely to play an important role as a link between the chondrocyte and the surrounding matrix. We have also studied the effect of mechanical stimulation on the expression of matrix molecules and integrins. Cyclic mechanical stimulation of cultured chondrocytes upregulated expression of the cartilage matrix components collagen II and aggrecan. In addition we found that extracellular signal-regulated kinase (ERK) was activated in response to mechanical load. A specific inhibitor of ERK prevented the mechanically induced collagen synthesis indicating that this signaling molecule has an important role in the signaling cascade resulting in collagen production in response to mechanical load. Cyclic stimulation also increased the expression of integrin subunits in chondrosarcoma cells. Interestingly, the integrin subunit alpha2 was mainly upregulated when the cells were cultured on collagen II, which indicates that matrix molecules can modulate the expression of integrins during mechanical load. It is possible that this upregulation/modulation of integrins in response to mechanical load changes the adhesive and/or signaling properties of the chondrocyte which could be of functional importance in the remodeling of the tissue.