Kindlin-2 inhibits Nlrp3 inflammasome activation in nucleus pulposus to maintain homeostasis of the intervertebral disc

Intervertebral disc (IVD) degeneration (IVDD) is the main cause of low back pain with major social and economic burdens; however, its underlying molecular mechanisms remain poorly defined. Here we show that the focal adhesion protein Kindlin-2 is highly expressed in the nucleus pulposus (NP), but not in the anulus fibrosus and the cartilaginous endplates, in the IVD tissues. Expression of Kindlin-2 is drastically decreased in NP cells in aged mice and severe IVDD patients. Inducible deletion of Kindlin-2 in NP cells in adult mice causes spontaneous and striking IVDD-like phenotypes in lumbar IVDs and largely accelerates progression of coccygeal IVDD in the presence of abnormal mechanical stress. Kindlin-2 loss activates Nlrp3 inflammasome and stimulates expression of IL-1β in NP cells, which in turn downregulates Kindlin-2. This vicious cycle promotes extracellular matrix (ECM) catabolism and NP cell apoptosis. Furthermore, abnormal mechanical stress reduces expression of Kindlin-2, which exacerbates Nlrp3 inflammasome activation, cell apoptosis, and ECM catabolism in NP cells caused by Kindlin-2 deficiency. In vivo blocking Nlrp3 inflammasome activation prevents IVDD progression induced by Kindlin-2 loss and abnormal mechanical stress. Of translational significance, adeno-associated virus-mediated overexpression of Kindlin-2 inhibits ECM catabolism and cell apoptosis in primary human NP cells in vitro and alleviates coccygeal IVDD progression caused by mechanical stress in rat. Collectively, we establish critical roles of Kindlin-2 in inhibiting Nlrp3 inflammasome activation and maintaining integrity of the IVD homeostasis and define a novel target for the prevention and treatment of IVDD.

Nrf2 Activation Is Involved in Cyclic Mechanical Stress-Stimulated Osteogenic Differentiation in Periodontal Ligament Stem Cells via PI3K/Akt Signaling and HO1-SOD2 Interaction

Nuclear factor erythroid-2-related factor-2 (Nrf2), the major transcriptional regulator in antioxidant response and cellular defense, had the vital effect on regulating osteogenic differentiation. Our previous study revealed that Nrf2 activation was involved in cyclic mechanical stress-stimulated osteogenic differentiation in the human periodontal ligament stem cells (PDLSCs). However, the mechanisms of Nrf2 underlying this process remained unclear. The goal of the study was to explore the mechanisms of Nrf2 in PDLSCs during cyclic mechanical stress-stimulated osteogenic differentiation via the tandem mass tag (TMT)-based liquid chromatography tandem-mass spectrometry (LC-MS/MS) analysis. And we applied tert-Butylhydroquinone (t-BHQ), the Nrf2 activator, to the orthodontic rats and detected the expression levels of the osteogenesis markers by immunohistochemistry (IHC) staining. Our results showed that Nrf2 activation in PDLSCs was involved in cyclic mechanical stress-stimulated osteogenic differentiation via phosphoinositide 3 kinase (PI3K)/protein kinase B (Akt) pathway. The protein-protein interaction between Akt and Nrf2 was detected. And the protein-protein interaction between heme oxygenase 1 (HO1) and superoxide dismutase 2 (SOD2), the downstream antioxidants of Nrf2, was associated with cyclic mechanical stress-stimulated osteogenic differentiation. T-BHQ enhanced the expression levels of the osteogenesis markers in orthodontic rats. Nrf2 might possess the potential to be a feasible molecular target in orthodontics.

Heavy Loaded Parts of Petrochemical Equipment Destruction Cause Investigation

The problem of using specialized passivating metals and alloys lies in a rather narrow range of the protecting film performance. With a slight change in operating conditions, the film is destroyed and an avalanche-like process of local corrosion begins at the place of film breakdown. A sequence has been developed for determining parts destruction causes, including a sequential analysis of operating conditions; nature of the part destruction; corrosion products composition; phase inversion in the alloy during overheating or mechanical stress in the part.

Mechanical stress affects dynamics and rheology of the human genome

Using a novel noninvasive approach, we measure dynamics and rheology of the genome in live human cells before and after applying mechanical stress. We find that mechanical stress alters both dynamics and material properties of the genome.

Reusable Piezocatalytic Water Disinfection Activity of CVD Grown WS2 Few-layer on Sapphire Substrate

Piezocatalysis of semiconductors is an arising technology that transforms mechanical stress into chemical energy to enhance reaction rate with piezo-generated free charge carriers. In the present work, CVD-grown few-layer WS2...

Исследование взаимосвязи механических напряжений, оптической неоднородности и концентрации кислорода в кристаллах германия

The radial distribution of mechanical stress, optical inhomogeneity and oxygen concentration in Sb-doped germanium crystals grown by the Czochralski method with diameter of 200 mm and resistivity from 10.5 to 18.5 Ω·cm were studied. It was found that residual stress calculated from the data of X-ray structural analysis correlates with results of numerical simulation of thermoelastic stress and interrelates with optical inhomogeneity and concentration of oxygen presented in the atomically dispersed state in germanium.