Integrins in osteoarthritis and cartilage repair

Beta 1 integrins, a/b receptors that transmit mechano-chemical signals across the cell membrane, are implicated in articular cartilage (AC) development, remodelling and repair. The collagen-binding a10b1 integrin is abundantly expressed on chondrocytes and is present in a sub-population of human mesenchymal stem cells (hMSCs). Our previous studies with genetically modified mice showed that b1 and a10 integrins are required for skeletal development and the lack of the b1 subunit on chondrocytes leads to osteoarthritis (OA)-like changes of the AC. Our recent work identified mechanosensitive signalling pathways downstream of b1 integrin; emphasised the importance of b1 in the mechanical stability of the AC and revealed that priming of a10 in hMSCs enhances chondrogenesis in vitro. To explore a10 integrin in AC degeneration (Aim 1), a10-null and control mice will be investigated in experimental situations reflecting risk factors of OA (aging, injury). The combined role of risk factors and a10-deficiency on the mechanical properties of the AC will be investigated by atomic force microscopy, the impact of a10 and b1 deficient AC on subchondral bone will be assessed by nanoCT and osteoclast/neurotransmitter profiling. To decipher the role of a10 and b1 integrins in mechano-transduction (Aim 2), control and mutant chondrocytes will be mechanically stimulated using an in vitro hip injury model and in chondrocyte-gel plugs. Protein and gene expression profiles including miRNAs will be analyzed upon mechanical stimulation. To challenge AC regeneration (Aim 3), a10 overexpressing hMSCs will be assessed for chondrogenic differentiation and cartilage repair using ex vivo and in vivo repair models