Prostaglandins are released through hemi-channels and purinergic receptors in response to mechanical stimuli [105]. The Wnt family of proteins find more has been recently added to the repertoire of mediators of mechanotransduction in bone. Wnt signaling might be an important modulator of the process of mechano-regulated bone adaptation. Wnt signaling can be mediated by the β-catenin pathways, through kinases or through activation of GTPases, thereby modulating cytoskeletal organization [106] and [107]. Activation of β-catenin signaling in response to fluid shear stress is likely mediated by PGE2 in MLO-Y4 osteocytes

[108]. In light of the role of the cytoskeleton in mechanosensing, it is noteworthy that Wnts may modulate cytoskeletal organization, and that β-catenin links cadherins to the actin cytoskeleton. In vitro studies have

shown that MC3T3-E1 osteoblasts increase Wnt gene expression after mechanical stimulation by substrate deformation [47], and that pulsating fluid flow up-regulates mRNA expression of β-catenin, APC, and Wnt3a, as well as the Wnt antagonist SFRP4 in MLO-Y4 osteocytes [46], showing that osteocytes respond to mechanical loading with a modulation of expression of molecules involved in the wnt sinalling cascade. Recently it was shown that LRP5, a co-receptor for Wnt signaling, functions locally in osteocytes. Mice with osteocyte-specific expression of inducible Lrp5 mutations had bone properties comparable to those in mice with inherited mutations, demonstrating AG-014699 supplier the importance of wnt signalling for osteocytes [109]. Sclerostin appears to be highly expressed in mature osteocytes compared to immature osteocytes [48]. Sclerostin protein may be transported through canaliculi to the bone surface, where it inhibits bone formation by osteoblasts. Studies in sclerostin-deficient transgenic mice suggest that sclerostin inhibits bone mass accrual. The mice lacking sclerostin exhibit an increased bone mass resembling the human condition of sclerosteosis, which is due to a premature

termination of the Sost gene [110] that transcribes Sulfite dehydrogenase sclerostin. Sclerostin acts as a Wnt antagonist by binding the Wnt co-receptor Lrp5 [111], Lrp5 being an important anabolic regulator of bone mass [109] and [112]. Interestingly, Sost transcripts and sclerostin protein levels were dramatically reduced in osteocytes after loading of mouse ulnae in vivo. The magnitude of the strain stimulus was associated with Sost staining intensity and number of sclerostin-positive osteocytes. Hindlimb unloading on the other hand yielded a significant increase in Sost expression in the mouse tibia [113]. Other molecules have been identified whose expression is modulated by mechanical loading and seem to be more or less osteocyte-specific. MEPE is highly expressed in osteocytes as compared to osteoblasts. MEPE plays an inhibitory role in bone formation in mice [114].