Fluid pressurization is the dominant load-bearing mechanism of the in vivo joint environment, supporting up to 90% of compressive loads in cartilage[1]. In accordance with its prominence in cartilaginous tissues, hydrostatic pressure (HP) significantly enhances the chondrogenic differentiation of mesenchymal stem cells (MSCs) [2,3]. However, surprisingly little is known about the mechanisms by which cells sense HP and translate it into a biochemical signal. This is partly due to the fact that HP generates a state of stress with little deformation, as hydrated tissues and cells are nearly incompressible. Because of this, it has been assumed that HP mechanotransduction differs from that of other mechanical loads which deform the cells [4]. Recently, we demonstrated that integrin binding to the pericellular matrix (PCM) regulates the cytoskeletal organization of MSCs, and this in turn determines their response to HP [5]. Another proposed mechanism of HP mechanotransduction is fluctuations in intracellular ion concentrations, which are altered by the application of HP [6–8]. In particular, calcium signaling has been implicated as a key regulator of cellular response in other mechanical loading modalities, yet no studies have examined the role of calcium in the response of MSCs to HP. Therefore the objective of this study was to examine the cellular proliferation and chondrogenic matrix accumulation of MSCs in response to HP in the presence of pharmacological inhibitors of calcium ion mobility in order to elucidate the role of calcium signaling in the mechanotransduction of HP.

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