Sclerostin inhibits Wnt/β-catenin signaling by binding to Lrp5 and preventing the binding of Wnt in osteoblasts [79]. Taken together, it is suggested that osteocytes might coordinate the osteogenic response to mechanical forces by locally unleashing Wnt signaling [78]. As the function of this pathway in the osteocyte is not well known, further investigation of the Wnt pathway is necessary, VE821 particularly in terms of its relationship with bone responses to mechanical loading. Receptor activator of nuclear factor-kB ligand (RANKL) is a multifunctional cytokine expressed by several cell types in the bone and bone marrow, including osteoblasts,

osteocytes, BMSCs and lymphocytes [84], [85] and [86]. RANKL has been identified as the membrane-bound factor representing the osteoclast differentiation factor or the stromal osteoclast-forming activity expressed by osteoclastogenesis-supporting BGB324 research buy cells [84] and [87]. Recently, it has been

reported that osteocytes express a much higher amount of RANKL [41] and have a greater capacity to support osteoclastogenesis in vitro than do osteoblasts and bone marrow stromal cells [88]. Furthermore, the osteocytic cell line, MLO-Y4, expresses RANKL on their surface and their dendritic processes [87]. The ratio of RANKL/OPG mRNA is greatest in the MLO-Y4 cells compared with other cell types. OPG acts as a soluble factor whereas RANKL is a surface molecule that is functional in osteocyte bodies or along their exposed dendritic processes [88]. These results suggest that osteocytes are the most important in vivo source of RANKL required for osteoclastogenesis. In a recent study using mice with a conditional RANKL allele, hindlimb unloading caused Dimethyl sulfoxide an increase in RANKL mRNA levels in cortical bone [88]. Furthermore, the deletion of RANKL from DMP1-Cre expressing cells prohibited this cortical bone loss associated with hindlimb unloading [88]. However,

it is unknown how the elevated levels of RANKL are produced in osteocytes associated with hind limb unloading. Interleukin (IL)-33 is a newly identified factor produced by the osteoblast linage that influences osteoclast formation [89]. This widely expressed proinflammatory cytokine was detected in murine osteoblasts and sporadically in osteocytes [90]. It is suggested that the anti-osteoclastic effect of IL-33 is not compensated for by other factors in its absence [89] and [90]. GLAST was identified as a mechanical stress-responsive gene in bone by differential RNA display [91]. High levels of GLAST protein expression were observed localized to osteoblasts and osteocytes.