Dissecting the role of ß1 integrins in articular cartilage function and pathology

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Articular cartilage, the load-bearing tissue of the joints, has poor healing potential thus age-related metabolic changes or traumatic lesions frequently lead to its degeneration and osteoarthritis, a prevalent cause of disability worldwide. Beta1 integrins comprise the largest subfamily of the heterodimeric (alpha/beta) integrin receptors that transmit both chemical and mechanical signals from the extracellular matrix into chondrocytes through adhesion complexes and initiate divers signalling cascades that are believed to be important for cartilage function. Despite their anticipated importance, our knowledge about the in vivo role of integrins in articular cartilage physiology and pathophysiology is limited. The primary purpose of this proposal is to gain mechanistic insights into the function of beta1 integrins in the articular cartilage; the pathomechanisms of osteoarthritis and the process of cartilage regeneration using genetically-modified mouse strains. To achieve this aim, mice with conditional inactivation of the beta1 integrin gene either in limb bud mesenchyme precursors or in adult articular cartilage chondrocytes will be examined in 1) ex vivo hip injury, 2) spontaneous osteoarthritis; 3) surgically induced osteoarthritis and 4) regeneration models. These complementary experimental approaches will provide a better understanding of cartilage degenerative diseases and may identify novel molecular targets that facilitate and improve articular cartilage repair.