Hydrostatic Compress Force Enhances the Viability and Decreases the Apoptosis of Condylar Chondrocytes through Integrin-FAK-ERK/PI3K Pathway

Abstract

Reduced mechanical stimuli in many pathological cases, such as hemimastication and limited masticatory movements, can significantly affect the metabolic activity of mandibular condylar chondrocytes and the growth of mandibles. However, the molecular mechanisms for these phenomena remain unclear. In this study, we hypothesized that integrin-focal adhesion kinase (FAK)-ERK (extracellular signal–regulated kinase)/PI3K (phosphatidylinositol-3-kinase) signaling pathway mediated the cellular response of condylar chondrocytes to mechanical loading. Primary condylar chondrocytes were exposed to hydrostatic compressive forces (HCFs) of different magnitudes (0, 50, 100, 150, 200, and 250 kPa) for 2 h. We measured the viability, morphology, and apoptosis of the chondrocytes with different treatments as well as the gene, protein expression, and phosphorylation of mechanosensitivity-related molecules, such as integrin α2, integrin α5, integrin β1, FAK, ERK, and PI3K. HCFs could significantly increase the viability and surface area of condylar chondrocytes and decrease their apoptosis in a dose-dependent manner. HCF of 250 kPa resulted in a 1.51 ± 0.02-fold increase of cell viability and reduced the ratio of apoptotic cells from 18.10% ± 0.56% to 7.30% ± 1.43%. HCFs could significantly enhance the mRNA and protein expression of integrin α2, integrin α5, and integrin β1 in a dose-dependent manner, but not ERK1, ERK2, or PI3K. Instead, HCF could significantly increase phosphorylation levels of FAK, ERK1/2, and PI3K in a dose-dependent manner. Cilengitide, the potent integrin inhibitor, could dose-dependently block such effects of HCFs. HCFs enhances the viability and decreases the apoptosis of condylar chondrocytes through the integrin-FAK-ERK/PI3K pathway.

Extracellular Signal-Regulated Kinase: A Regulator of Cell Growth, Inflammation, Chondrocyte and Bone Cell Receptor-Mediated Gene Expression

“…Of note, it had been previously shown that HDAC inhibitors suppressed uniaxial cyclic tensile strain-induced p38, ERK, and c-Jun amino terminal kinase (JNK) in human chondrocytes [109]. In fact, Ma et al [110] had previously shown that hydrostatic pressure significantly increased the activation of ERK1/2 without altering ERK content in cultured condylar chondrocytes. Hydrostatic pressure also resulted in the activation of focal adhesion kinase (FAK) and PI3K, as well as the mechanosensitive molecules integrin α2, integrin α5, and integrin β1.…”

“…The increase in ERK1 and ERK2 activation was accompanied by an increase in the expression of MMP-13, ADAMTS-5 and TNF-α genes. Thus, the significance of abnormal loading of joints via increasing hydrostatic pressure or sustained impact loading has long been proposed as a potential initiator of extracellular matrix damage and controlled chondrocyte death in articular cartilage, which would precede alterations in joint cartilage consistent with the development of OA [110,111,112].…”

Compressive Stimulation Enhances Ovarian Cancer Proliferation, Invasion, Chemoresistance, and Mechanotransduction via CDC42 in a 3D Bioreactor

“…Cells stimulated with compressive stress rely on mechanotransduction via modulation of cytoskeletal deformation [ 22 ], integrin binding complexes [ 23 ], ion channels [ 24 ], and lipid rafts [ 25 ]. Rho family GTPase cell division cycle 42 (CDC42) links mechanical sensitive focal adhesions to protrusive filopodia and acts as a molecular switch for a variety of cellular processes [ 26 , 27 ].…”

Crecimiento del cartílago condilar. Una revisión de la literatura

“…En la actualidad, la cantidad de crecimiento modulada por estímulos mecánicos es desconocida, probablemente debido a la ausencia de medidas cuantitativas del crecimiento mandibular y de conocimiento de los estímulos utilizados para modular el crecimiento mandibular. Sin aplicar métodos biológicos cuantitativos como marcación celular e histomorfometría computarizada; y sin determinar con exactitud las magnitudes, frecuencias de fuerzas aplicadas y la tensión inducida al tejido, no es posible dilucidar la cantidad de crecimiento mandibular en función de los cambios mecánicos 70,78 .…”