A major constituent in focal adhesions, mediating downstream intracellular signaling is focal adhesion kinase (FAK). Focal adhesions are known to be involved in mechanosensation and downstream signaling in various cell types, and external mechanical forces have a direct role in their formation [65]. Paxillin proteins are predominantly “localized” to upper and lower “poles” of fibular osteocyte cell bodies, whereas they are evenly distributed across the osteocyte cell bodies in calvaria suggesting that focal adhesions are formed in osteocytes along the direction of principle strains within the bone [64]. FAK is essential for mechanotransduction in osteoblasts [68], and FAK has a similar role

in osteocyte mechanotransduction [69]. It was found that mechanical stimulation by means of a pulsatile fluid flow induced stabilization

of β-catenin in osteocytes ABT-888 in a FAK-dependent mechanism [69]. Interestingly, knockdown of membrane-type matrix metalloproteinase-1 (MT1-MMP) increased the number and size of focal adhesions in cultured MLO-Y4 osteocytes concomitantly with an enhanced NO production and c-jun and c-fos mRNA expression in response to mechanical stimulation [70]. This indicates that MT1-MMP knockdown osteocytes have an increased sensitivity to mechanical loading and demonstrates a novel and unexpected potential role for MT1-MMP in mechanosensing. Primary cilia are single cytoplasmic organelles found in virtually all eukaryotic cells. They protrude into the extracellular space this website from the cell surface and function as mechanosensors in tissues such as kidney. Osteocytes also possess a single primary cilium [71]. PKD1/PC1, a mechanosensory protein in the kidney that localizes to primary cilia, is known to

play a role in normal bone structure. It is not yet established if PKD1 functions via the primary cilia or it has a function in another location in the cell. Interestingly, Idelalisib supplier MC3T3-E1 osteoblasts and MLO-Y4 osteocytes possess primary cilia that project from the cell surface and deflect during fluid flow [72]. These primary cilia are required for the osteocyte response to dynamic fluid flow in vitro. However, the location of the primary cilium, i.e. on the osteocyte cell body, makes it difficult to envision a role for the primary cilium as a flow sensor for osteocytes in vivo, because physical laws dictate that loading-induced fluid flow will primarily occur around the osteocyte cell processes and it is difficult to envision how a primary cilia could fit into the lacuno-canalicular space without being already severely bent [58] and [36]. An alternative hypothesis, postulated by Bell, suggests that cells sense hydraulic pressure by using the primary cilium as a sensor of hydrostatic pressure, but no experimental evidence to support this hypothesis currently exists [73].