Figure 6. MVNP-induced increase in TBK1 protein and activity contributes to the generation of pagetic osteoclasts.

MVNP stabilization of TBK1 protein and stimulation of TBK1 activation in BMM results in increased total and phospho-Ser⁵³⁶-p65 NF-κB, ATF7 and TAF12. These changes induce elevation of IL-6 expression, which acts to increase the number of osteoclasts formed in response to RANKL and TNF-α. ATF7 and TAF12 increases also result in hypersensitivity to 1,25(OH)₂D (34). While TBK1 directly phosphorylates Ser⁵³⁶-p65 NF-κB, MVNP decreases Sirt1 via activation of phosphorylation-induced proteolysis of the Sirt1 regulator FoxO3, which also leads to increased NF-κB activity by decreasing its deacetylation, further contributing to increased IL6 expression. The identity of the FoxO3 kinase activated by MVNP is not known. These two pathways stimulated by MVNP act in concert to increase IL-6 production, a key feature and requirement for developing pagetic osteoclasts.