Mechanical overloading induces GPX4-regulated chondrocyte ferroptosis in osteoarthritis via Piezo1 channel facilitated calcium influx

Introductions: Excessive mechanical stress is closely associated with cell death in various conditions. Exposure of chondrocytes to excessive mechanical loading leads to a catabolic response as well as exaggerated cell death. Ferroptosis is a recently identified form of cell death during cell aging and degeneration. However, it's potential association with mechanical stress remains to be illustrated. Objectives: To identify whether excessive mechanical stress can cause ferroptosis. To explore the role of mechanical overloading in chondrocyte ferroptosis. Methods: Chondrocytes were collected from loading and unloading zones of cartilage in patients with osteoarthritis (OA), and the ferroptosis phenotype was analyzed through transmission electron microscope and microarray. Moreover, the relationship between ferroptosis and OA was analyzed by GPX4-conditional knockout (Col2a1-CreERT: GPX4flox/flox) mice OA model and chondrocytes cultured with high strain mechanical stress. Furthermore, the role of Piezo1 ion channel in chondrocyte ferroptosis and OA development was explored by using its inhibitor (GsMTx4) and agonist (Yoda1). Additionally, chondrocyte was cultured in calcium-free medium with mechanical stress, and ferroptosis phenotype was tested. Results: Human cartilage and mouse chondrocyte experiments revealed that mechanical overloading can induce GPX4-associated ferroptosis. Conditional knockout of GPX4 in cartilage aggravated experimental OA process, while additional treatment with ferroptosis suppressor protein (FSP-1) and coenzyme Q10 (CoQ10) abated OA development in GPX4-CKO mice. In mouse OA model and chondrocyte experiments, inhibition of Piezo1 channel activity increased GPX4 expression, attenuated ferroptosis phenotype and reduced the severity of osteoarthritis. Additionally, high strain mechanical stress induced ferroptosis damage in chondrocyte was largely abolished by blocking calcium influx through calcium-free medium. Conclusions: Our findings show that mechanical overloading induces ferroptosis through Piezo1 activation and subsequent calcium influx in chondrocytes, which might provide a potential target for OA treatment

A systematic review of progranulin concentrations in biofluids in over 7,000 people—assessing the pathogenicity of GRN mutations and other influencing factors

Background: Pathogenic heterozygous mutations in the progranulin gene (GRN) are a key cause of frontotemporal dementia (FTD), leading to significantly reduced biofluid concentrations of the progranulin protein (PGRN). This has led to a number of ongoing therapeutic trials aiming to treat this form of FTD by increasing PGRN levels in mutation carriers. However, we currently lack a complete understanding of factors that affect PGRN levels and potential variation in measurement methods. Here, we aimed to address this gap in knowledge by systematically reviewing published literature on biofluid PGRN concentrations. Methods: Published data including biofluid PGRN concentration, age, sex, diagnosis and GRN mutation were collected for 7071 individuals from 75 publications. The majority of analyses (72%) had focused on plasma PGRN concentrations, with many of these (56%) measured with a single assay type (Adipogen) and so the influence of mutation type, age at onset, sex, and diagnosis were investigated in this subset of the data. Results: We established a plasma PGRN concentration cut-off between pathogenic mutation carriers and non-carriers of 74.8 ng/mL using the Adipogen assay based on 3301 individuals, with a CSF concentration cut-off of 3.43 ng/mL. Plasma PGRN concentration varied by GRN mutation type as well as by clinical diagnosis in those without a GRN mutation. Plasma PGRN concentration was significantly higher in women than men in GRN mutation carriers (p = 0.007) with a trend in non-carriers (p = 0.062), and there was a significant but weak positive correlation with age in both GRN mutation carriers and non-carriers. No significant association was seen with weight or with TMEM106B rs1990622 genotype. However, higher plasma PGRN levels were seen in those with the GRN rs5848 CC genotype in both GRN mutation carriers and non-carriers. Conclusions: These results further support the usefulness of PGRN concentration for the identification of the large majority of pathogenic mutations in the GRN gene. Furthermore, these results highlight the importance of considering additional factors, such as mutation type, sex and age when interpreting PGRN concentrations. This will be particularly important as we enter the era of trials for progranulin-associated FTD.</p

ADAMTS-12: A Multifaced Metalloproteinase in Arthritis and Inflammation

ADAMTS-12 is a member of a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) family of proteases, which were known to play important roles in various biological and pathological processes, such as development, angiogenesis, inflammation, cancer, arthritis, and atherosclerosis. In this review, we briefly summarize the structural organization of ADAMTS-12; concentrate on the emerging role of ADAMTS-12 in several pathophysiological conditions, including intervertebral disc degeneration, tumorigenesis and angioinhibitory effects, pediatric stroke, gonad differentiation, trophoblast invasion, and genetic linkage to schizophrenia and asthma, with special focus on its role in arthritis and inflammation; and end with the perspective research of ADAMTS-12 and its potential as a promising diagnostic and therapeutic target in various kinds of diseases and conditions

Microscopic Damage to Limestone under Acidic Conditions: Phenomena and Mechanisms

In an acidic environment, the mineral components in rock begin to break down. As a result, the microstructure will be damaged, and then the mechanical properties will deteriorate, which will eventually have a negative effect on engineering stability. In order to study acid damage’s effect on this kind of rock, limestone samples were acidified for 0 days, 5 days, 10 days, 15 days, and 20 days. The microstructure changes in the limestone after acidification were studied via the wave velocity test and electron microscope scanning, and the damage deterioration mechanism was revealed. The results show that the acoustic signal of acidified samples has an obvious absorption effect at high frequency, and the surface pore structure of acidified samples shows fractal characteristics. The P-wave velocity, main peak amplitude, and fractal dimension of the acidified samples did not gradually decrease with time; however, there was a short-term strengthening phenomenon during immersion, which was mainly caused by the formation of CaSO4 crystals

Time-Varying Characteristics of Granite Microstructures after Cyclic Dynamic Disturbance Using Nuclear Magnetic Resonance

To investigate the variation in the characteristics of rock microstructure after cyclic dynamic disturbances, a split Hopkinson pressure bar (SHPB) was used to carry out cyclic dynamic impact tests on granite, and the P-wave velocity was used as the characteristic parameter representing the microstructural change. Using the nuclear magnetic resonance (NMR) technique, the porosity and the T2 distribution of rock samples were obtained. The results show that, after the cyclic dynamic disturbance, the P-wave velocity within the rock specimen decreases but rebounds with time. At the elastic phase, when the axial loading increases, the P-wave velocity declines. The T2 limit is shortened, and the cyclic dynamic disturbance process promotes the formation of small pores and decreases the size and quantity of large pores. After the cyclic dynamic disturbance, the porosity of the rock samples was reduced

XBP1S associates with RUNX2 and regulates chondrocyte hypertrophy.

Detail of support beam for balcony on north facade; The Neue Nationalgalerie (dedicated to art of the 20th century) was opened in 1968 and is the last major construction completed by Ludwig Mies van der Rohe. The architect’s long-term preoccupation with creating fluid, open spaces culminated in the design of the glazed upper pavilion of the gallery (most of the museum is on an underground level). The upper story serves as an entrance hall as well as the primary special exhibit gallery, totaling 2,683 square meters of space. It is elevated from street level and only accessible by three flights of steps. Though it only comprises a small portion of the total gallery space, the exhibition pavilion stands as the building’s primary architectural expression. Eight cruciform columns, two on each length placed so as to avoid corners, support a square pre-stressed steel roof plate 1.8 meters thick and painted black. An eighteen-meter cantilever allows for ample space between the gallery’s glazed façade and eight supporting columns. Mies also designed the outdoor sculpture gardens. It was constructed as one of the vital cornerstones of the Kulturforum, as planned by another great architect of the postwar period, Hans Scharoun. In 1967, Mies attended the hydraulic raising into place of the gigantic steel roof. The Neue Nationalgalerie is slated for renovation by architect David Chipperfield and will be closed 2015-2018. Source: Staatliche Museen zu Berlin, SMB Digital Database [website]; http://www.smb-digital.de/ (accessed 6/19/2014

A Disintegrin and Metalloprotease with Thrombospondin Type I Motif 7 A New Protease for Connective Tissue Growth Factor in Hepatic Progenitor/Oval Cell Niche

Hepatic progenitor/oval cell (OC) activation occurs when hepatocyte proliferation is inhibited and is tightly associated with the fibrogenic response during severe liver damage. Connective tissue growth factor (CTGF) is important for OC activation and contributes to the pathogenesis of liver fibrosis. By using the Yeast Two-Hybrid approach, we identified a disintegrin and metalloproteinase with thrombospondin repeat 7 (ADAMTS7) as a CTGF binding protein. In vitro characterization demonstrated CTGF binding and processing by ADAMTS7. Moreover, Adamts7 mRNA was induced during OC activation, after the implantation of 2-acetylaminofluorene with partial hepatectomy in rats or on feeding a 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet in mice. X-Gal staining showed Adamts7 expression in hepatocyte nuclear factor 4α+ hepatocytes and desmin+ myofibroblasts surrounding reactive ducts in DDC-treated Adamts7−/− mice carrying a knocked-in LacZ gene. Adamts7 deficiency was associated with higher transcriptional levels of Ctgf and OC markers and enhanced OC proliferation compared to Adamts7+/+ controls during DDC-induced liver injury. We also observed increased α-smooth muscle actin and procollagen type I mRNAs, large fibrotic areas in α-smooth muscle actin and Sirius red staining, and increased production of hepatic collagen by hydroxyproline measurement. These results suggest that ADAMTS7 is a new protease for CTGF protein and a novel regulator in the OC compartment, where its absence causes CTGF accumulation, leading to increased OC activation and biliary fibrosis