An explanation for the skeletal phenotype of both these groups could be RNA Synthesis inhibitor that the osteoregulatory effects of mechanical strain influence Wnt signalling through the Lrp5 receptor. This explanation envisages the low bone mass in OPPG patients being due to inadequate strain-related stimulation of the Wnt pathway
resulting from failure of Wnt stimulation at the Lrp5 receptor ,  and . The high bone mass (HBM) in people with the Lrp5 mutation could be explained as being due to an exaggerated response to strain-related stimulation at the same receptor  and . A potential mechanism for this hypothetical link between the osteogenic effects of strain and the Wnt pathway became evident with reports that sclerostin was a ligand for the Lrp5 receptor  and . Sclerostin, the protein product of the SOST gene predominately expressed in Galunisertib in vitro osteocytes, is down-regulated by high local mechanical strain in vivo and SOST expression is up-regulated in the absence of loading  and . Thus in normal individuals high strains would act to
depress sclerostin production allowing increased activity of the Wnt/Lrp5 pathway and enhanced bone formation. Low strains would be associated with high levels of sclerostin which would down-regulate activity of the Wnt/Lrp5 pathway with subsequent reduced bone formation. This could be one of the ways in which functional strains influence bone mass. Experiments on mice have shown that animals with the Lrp5 G171V HBM mutation recapitulate the HBM phenotype found in humans . Those with the Lrp5 loss of function mutation also have a low bone mass phenotype similar to humans with OPPG . Sawakami et al. (2006) report that the osteogenic response to mechanical load is significantly lower in male and female mice with the Lrp5 loss of function
mutation (Lrp5−/−) compared with Wild Type (WT+/+) controls , while Akhter et al. (2004) report that load-induced cortical bone formation is higher in female mice heterozygous for the Lrp5 Gl71V HBM mutation (Lrp5HBM+) SPTBN5 than in their WT (WTHBM−) controls . Both of these reports are consistent with the hypothesis that Lrp5/Wnt signalling is involved in the osteoregulatory response of cortical bone to mechanical loading. Both Sawakami et al. and Akhter et al. performed their experiments using the axially loadable ulna technique originally developed in the rat by Torrance et al.  but now routinely applied to the mouse , , ,  and . One disadvantage of using the ulna is that it does not allow examination of loading-related effects on (re)modelling in trabecular bone. Another disadvantage is that it is not easy experimentally to induce disuse in the front limb and to assess the effects of removal of normal functional loading.