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Purpose Prolonged bed rest and microgravity in space cause intervertebral disc (IVD) degeneration. However, the underlying molecular mechanisms are not completely understood. Transient receptor potential canonical (TRPC) channels are implicated in mechanosensing of several tissues, but are poorly explored in IVDs. Methods Primary human IVD cells from surgical biopsies composed of both annulus fibrosus and nucleus pulposus (passage 1-2) were exposed to simulated microgravity and to the TRPC channel inhibitor SKF-96365 (SKF) for up to 5days. Proliferative capacity, cell cycle distribution, senescence and TRPC channel expression were analyzed. Results Both simulated microgravity and TRPC channel antagonism reduced the proliferative capacity of IVD cells and induced senescence. While significant changes in cell cycle distributions (reduction in G1 and accumulation in G2/M) were observed upon SKF treatment, the effect was small upon 3days of simulated microgravity. Finally, downregulation of TRPC6 was shown under simulated microgravity. Conclusions Simulated microgravity and TRPC channel inhibition both led to reduced proliferation and increased senescence. Furthermore, simulated microgravity reduced TRPC6 expression. IVD cell senescence and mechanotransduction may hence potentially be regulated by TRPC6 expression. This study thus reveals promising targets for future studies.
Oxygen isotope compositions are reported for the first time for the Himalayan metabasites of the Kaghan Valley, Pakistan in this study. The highest metamorphic grades are recorded in the north of the valley, near the India-Asia collision boundary, in the form of high-pressure (HP: Group I) and ultrahigh-pressure (UHP: Group II) eclogites. The rocks show a step-wise decrease in grade from the UHP to HP eclogites and amphibolites. The protoliths of these metabasites were the Permian Panjal Trap basalts (ca. 267 +/- 2.4 Ma), which were emplaced along the northern margin of India when it was part of Gondwana. After the break-up of Gondwana, India drifted northward, subducted beneath Asia and underwent UHP metamorphism during the Eocene (ca. 45 +/- 1.2 Ma). At the regional scale, amphibolites, Group I and II eclogites yielded delta O-18 values of +5.84 and +5.91 parts per thousand, +1.66 to +424 parts per thousand, and -2.25 to +0.76 parts per thousand, respectively, relative to VSMOW. On a more local scale, within a single eclogite body, the delta O-18 values were the lowest (-2.25 to-1.44%.) in the central, the best preserved (least retrograded) parts, and show a systematic increase outward into more retrograded rocks, reaching up to +0.12 parts per thousand. These values are significantly lower than the typical mantle values for basalts of + 5.7 +/- 0.3 parts per thousand. The unusually low or negative delta O-18 values in Group II eclogites potentially resulted from hydrothermal alteration of the protoliths by interactions with meteoric water when the Indian plate was at southern high latitudes (similar to 60 degrees S). The stepwise increase in delta O-18 values, among different eclogite bodies in general and at single outcrop-scales in particular, reflects differing degrees of resetting of the oxygen isotope compositions during exhumation-related retrogression. (C) 2014 Elsevier B.V. All rights reserved.