The application of 2000

microstrain macroscopically to a

The application of 2000

microstrain macroscopically to a piece of bone resulted in a much greater microscopic strain surrounding the osteocyte lacunae of over 30,000 microstrain [53]. Taken together, it might be considered that osteocytes embedded in living bone tissue receive larger strain as compared with those in bone. The major cellular components involved in mechanotransduction are integrins, cytoskeletal proteins, GTP-binding check details regulatory proteins (G proteins), receptor tyrosine kinases (RTKs), mitogen-activated protein kinases (MAPKs), and stretch-activated channels [57]. Signals originating from mechanical stimulation can lead to gene expression and protein synthesis through the MAPK pathway [57]. Mechanical stretching also rapidly activates extracellular signal-regulated kinase (ERK)1/2 in human pulmonary epithelial cells [58]. In addition, p38 MAPK and c-Jun NH2-terminal kinase/stress activated protein kinase (JNK/SAPK) are activated by various cellular mechanical stresses [57]. Moreover, p38 MAPK, SAPK, and ERK1/2 phosphorylation are activated by compressive loading in the chondrocytes of articular cartilages [21]. Through these signaling cascades, mechanical compression regulates the activity of transcriptional factors and gene expression [59].

A second route of activation by mechanical stress seems to be via the NF-κB AG-014699 datasheet pathway [60]. Various stresses are known to induce phosphorylation and degradation of IκB, the cytoplasmic inhibitor of the transcription factor NF-κB, which becomes activated and translocates to the nucleus [60]. This has been demonstrated to occur in endothelial cells under shear stress [61]. Activation of NF-κB via protein kinase C-ζ is also required for the integrin-dependent ability of fibroblasts Epothilone B (EPO906, Patupilone) to contract in collagen gels [62]. A number of studies have demonstrated load-related responses in osteocytes

in vivo and in vitro, supporting their proposed roles as mechanotransducers in bone. Changes in the expression levels of certain genes in osteocytes during bone modeling and/or remodeling have been investigated, suggesting complex and interdependent signaling networks are probably involved in their response to loading. CCN2 (also termed connective tissue growth factor, CTGF), is a 38 kDa, cysteine-rich, extracellular matrix protein that belongs to the CCN family of proteins. CCN2 has been implicated in numerous cellular events including angiogenesis, skeletogenesis and wound healing [63]. CCN2 regulates different cellular events, including adhesion, proliferation, migration, and differentiation [64], [65], [66] and [67], and it may be an important growth factor in the control and regulation of osteogenesis [68] and [69] possibly in the regulation of mechanosensing in osteocytes.

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