FAK inhibition protects condylar cartilage under excessive mechanical stress

Abstract

Temporomandibular joint disorder (TMD) is a degenerative multifactorial disease. Temporomandibular joint (TMJ) osteoarthritis (OA) is severe form of TMD and characterized by cartilage degradation. Cartilage degradation leads to loss of the extracellular matrix (ECM). Some researchers have suggested excessive mechanical stress as a risk factor for TMJ-OA (Ikeda, Yonemitsu, Takei, Shibata, & Ono, 2014) (Asakawa-Tanne et al., 2015). An optimal level of mechanical stress is necessary for ECM maintenance in cartilage, but excessive mechanical stress can trigger destruction of the ECM (Su

Mechanical Loading Disrupts Focal Adhesion Kinase Activation in Mandibular Fibrochondrocytes During Murine Temporomandibular Joint Osteoarthritis

“…Thus, it would be predicted that the preclinical mouse model would have lower levels of FAK and pFAK at Tyr397. This is in contrast to reports that mechanical and inflammatory injury of cartilage in the mandible [25], cartilage of the intervertebral disc [60], and skin [13] are associated with an increase in the level of pFAK at Tyr397. Western blot analysis of the whole joint after TMJ OA illustrates the largest increase in FAK and pFAK at Tyr397 in sham control tissues and no significant difference between the TMJ OA and non-surgical control samples.…”

“…Further, iFAK treatment suppresses MMP13 in a loading independent manner and attenuates matrix proteolysis. This hypothesis is consistent with data from a rat mandibular condyle explant model loaded under static compression with and without FAK inhibitor PF0455487, illustrating FAK dependent suppression of inflammatory biomarkers, MMP13 mediated proteolysis, and TUNEL staining in the chondroblastic and hypertrophic cell layer [25]. The inhibition of pFAK at Tyr397 is also associated with an increase in TGFβ.…”

“…Other studies have proposed that FAK inhibition as a therapeutic strategy for fibrogenic disorders [13,41] and for TMJ OA [25]. To evaluate the role of FAK in the in vivo progression of TMJ OA, we treated surgically destabilized mice with a small molecule inhibitor of pFAK at Tyr397 through intra-articular injection.…”

“…In the TMJ, mechanical activation of FAK by phosphorylation at Tyr397 (pFAK) enhances cellular viability [16] and upregulates pro-inflammatory cytokines including COX-2, IL1β, and TNF-α [15]. Further, inhibition of pFAK at Tyr397 is chondroprotective in a static loading mandibular condylar cartilage, ex vivo organ culture loading model, suppressing IL-1β, MMP-13, and apoptosis in hypertrophic cells [25]. A similar chondroprotective effect was demonstrated using in vitro mechanical loading of mandibular fibrochondrocytes treated with and without an antagonist of integrin [26].…”

Osteoarthritis: pathogenic signaling pathways and therapeutic targets

“… 321 Pharmacological inhibition of FAK relieved the degradation of articular cartilage of the mandibular condyle under mechanical loading by inhibiting the expression of pro-inflammatory cytokines and ECM-degrading enzymes. 322 Miyauchi and coworkers showed that genetic deletion of the Hic-5 (hydrogen peroxide-inducible clone-5), a focal adhesion mechanosensitive adapter, alleviated the progression of OA through regulation of chondrocyte catabolism induced by mechanical stress. 323 …”