Specific inhibition of FAK signaling attenuates subchondral bone deterioration and articular cartilage degeneration during osteoarthritis pathogenesis.
Osteoarthritis (OA), a disease of the entire joint, is characterized by abnormal bone remodeling and coalescent degradation of articular cartilage. We have previously found that elevated levels of H-type vessels in subchondral bone correlate with OA and that focal adhesion kinase (FAK) is critical for H-type vessel formation in osteoporosis. However, the potential role of FAK in OA remains unexplored. Here, we demonstrate that the p-FAK level was dramatically elevated in subchondral bone following anterior cruciate ligament transection (ACLT) in rats. Specific inhibition of FAK signaling with Y15 in subchondral bone resulted in the suppression of subchondral bone deterioration and this effect was mediated by H-type vessel-induced ectopic bone formation. Further, articular cartilage degeneration was also alleviated after Y15 treatment. In vitro, the p-FAK level was significantly elevated in mesenchymal stem cells (MSCs) from vehicle-treated ACLT rats as compared to that in MSCs from sham controls and Y15-treated ACLT rats. Elevated p-FAK level in MSCs promoted vascular endothelial growth factor (VEGF) expression, as demonstrated from the high VEGF level in the blood, subchondral bone, and conditioned medium (CM) of MSCs from vehicle-treated ACLT rats. The CM of MSCs from vehicle-treated ACLT rats might promote the angiogenesis of endothelial cells and the catabolic response of chondrocytes through the FAK-growth factor receptor-bound protein 2-mitogen-activated protein kinase-mediated expression of VEGF. The effect of the CM from MSCs of Y15-treated ACLT rats or that treated with a VEGF-neutralizing antibody on vessel formation and the catabolic response was lowered. Thus, the specific inhibition of FAK signaling may be a promising avenue for the prevention or early treatment of OA.
['Wu|Hangtian|H|', 'Xu|Ting|T|0000-0002-8485-119X', 'Chen|Zhigang|Z|', 'Wang|Yutian|Y|', 'Li|Kaiqun|K|0000-0003-3322-4345', 'Chen|Pei-Sheng|PS|0000-0002-2472-2898', 'Yao|Zilong|Z|', 'Su|Jianwen|J|', 'Cheng|Caiyu|C|', 'Wu|Xiaohu|X|', 'Zhang|Hongan|H|', 'Chai|Yu|Y|', 'Zhang|Xianrong|X|', 'Hu|Yanjun|Y|', 'Yu|Bin|B|', 'Cui|Zhuang|Z|0000-0002-1061-0190']
D019386:Alendronate D000818:Animals D016118:Anterior Cruciate Ligament D016723:Bone Remodeling D001842:Bone and Bones D002358:Cartilage, Articular D019902:Chondrocytes D004195:Disease Models, Animal D042783:Endothelial Cells D051417:Focal Adhesion Kinase 1 D051416:Focal Adhesion Protein-Tyrosine Kinases D008297:Male D010003:Osteoarthritis D017207:Rats, Sprague-Dawley
FAK subchondral bone osteoarthritis H-type vessels Y15