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Figure 5: Mechanical stimulation activates intracellular signaling pathways that converge with growth factors to activate transcription factors, which promotes bone formation. Perception of load (strain, “1”) triggers a number of intracellular responses including the release of PGE2, “2,” through a poorly understood mechanism into the lacunar-canalicular fluid where it can act in an autocrine and/or paracrine fashion. Connexin-43 hemichannels (CX43 HC) in this PGE2 and integrin proteins appear to be involved. Binding of PGE2 to its EP2 and/or EP4 receptor, “3,” leads to a downstream inhibition of GSK-3β, “5” (likely mediated by Akt, “4”) and the intracellular accumulation of free β-catenin, “6.” (Integrin activation can also lead to Akt activation and GSK-3β inhibition.) New evidence suggests that ER may participate in the nuclear translocation of β-catenin, “7,” which leads to changes in the expression of a number of key target genes “8.” One of the apparent consequences is the reduction in sclerostin and Dkk1, “9,” with increased expression of Wnt, “10”. The net result of these changes is to create a permissive environment for the binding of Wnt to LRP5-Fz and an amplification of the load signal, “11.”