β-catenin also induces expression of Cx43, which increases osteocyte communication through gap junctions [97]. Taken together, these results demonstrate that there is cross talk between PGE2, PI3K/Akt, and Wnt signaling and that PGE2 can activate Wnt signaling independent of Lrp5/6. Studies in conditional

knockout mice have demonstrated the importance of the Wnt/β-catenin pathway in regulating the osteoclast inhibitor osteoprotegerin (OPG). Increased OPG through β-catenin promotes osteoblast differentiation and prevents the SCH772984 order differentiation of osteoclasts [98]. The conditional deletion of β-catenin in osteoblast precursors (using collagen I alpha I-; Col1a1-Cre) mature osteoblasts (osteocalcin-; Ocn-Cre), and osteocytes (dentin matrix acidic phosphoprotein 1-; DMP1-Cre) leads to a decreased level of OPG and an increased number of osteoclasts [98], [99] and [100]. These conditional knockouts demonstrate the importance

of β-catenin through the differentiation of osteoblast precursors (Col1a1 + cells) to osteoblasts (Ocn + cells) to osteocytes (DMP1 + cells) in the regulation of OPG. Shortly after the discovery of the link between Lrp5 and bone mass, Johnson hypothesized that Lrp5 is crucial in the sensation and response of bone to load [101]. Mice carrying germline mutations in Lrp5 have been made that model the high [45] and [65] and low bone mass [42], [43] and [44] phenotypes. Johnson’s hypothesis was confirmed when mice with a deletion of Lrp5 did not respond to mechanical loading [102]. Furthermore, selleck products mice with missense mutations of Lrp5 (A214V and G171V) that cause high bone mass had an altered response to mechanical loading. Inositol monophosphatase 1 One of these mutations (A214V) increased periosteal bone formation compared with wild-type controls, while the other (G171V) improved endosteal bone formation compared with the wild-type [103]. The mechanosensitivity

of Lrp5 acts at least in part through the osteocytes, because mice with an osteocyte-specific deletion of Lrp5 were less responsive to mechanical loading [67]. Mechanical loading decreases Sost transcription and sclerostin protein expression while increasing bone formation [11] and [104]. Mechanical loading also decreases the transcription of Dkk1, while sFRP1 transcription is unchanged [11]. When mice underwent unloading through hindlimb tail suspension, Sost transcription significantly increased in the tibia, while increases in Dkk1 and sFPR1 transcription approached significance [11], though a recent study has suggested that sclerostin response may be site-specific [105]. Local down-regulation of sclerostin in osteocytes is required for mechanotransduction-based bone formation [106], and mice with a deletion of Sost that underwent unloading through hindlimb tail suspension were resistant to bone loss [72]. Taken together, these reports suggest that the response of bone to mechanical loading is crucially regulated by osteocytes secreting sclerostin, which binds to Lrp5.