Specific inhibition of FAK signaling attenuates subchondral bone deterioration and articular cartilage degeneration during osteoarthritis pathogenesis.
Alendronate
/ pharmacology
Animals
Anterior Cruciate Ligament
/ pathology
Bone Remodeling
/ drug effects
Bone and Bones
/ pathology
Cartilage, Articular
/ metabolism
Chondrocytes
/ metabolism
Disease Models, Animal
Endothelial Cells
/ drug effects
Focal Adhesion Kinase 1
/ antagonists & inhibitors
Focal Adhesion Protein-Tyrosine Kinases
/ drug effects
Male
Osteoarthritis
/ drug therapy
Rats, Sprague-Dawley
FAK
H-type vessels
Y15
osteoarthritis
subchondral bone
Journal
Journal of cellular physiology
ISSN: 1097-4652
Titre abrégé: J Cell Physiol
Pays: United States
ID NLM: 0050222
Informations de publication
Date de publication:
11 2020
11 2020
Historique:
received:
09
08
2019
revised:
31
03
2020
accepted:
02
04
2020
pubmed:
24
4
2020
medline:
17
3
2021
entrez:
24
4
2020
Statut:
ppublish
Résumé
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.
Substances chimiques
Focal Adhesion Kinase 1
EC 2.7.10.2
Focal Adhesion Protein-Tyrosine Kinases
EC 2.7.10.2
Ptk2 protein, rat
EC 2.7.10.2
Alendronate
X1J18R4W8P
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
8653-8666Informations de copyright
© 2020 Wiley Periodicals, Inc.
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