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Conditional Activation of NF-kB Inducing Kinase (NIK) in the Osteolineage Enhances both Basal and Loading-Induced Bone Formation

ABSTRACT: Studies from global loss-of-function mutants suggest that alternative NF-kB downstream of NF-kB inducing kinase (NIK) is a cell-intrinsic negative regulator of osteogenesis. However, the interpretation of the osteoblast and/or osteocyte contribution to the bone phenotype is complicated by simultaneous osteoclast defects in these models. Therefore, we turned to a transgenic mouse model to investigate the direct role of NIK in the osteolineage. Osx-Cre;NT3 animals (NT3-Cre+), which bear a constitutively active NIK allele (NT3) driven by Osx-Cre, were compared to their Cre-negative, Control (Ctrl) littermates. NT3-Cre+ mice had elevated serum P1NP and CTX levels. Despite this high turnover state, microCT showed that constitutive activation of NIK resulted in a net increase in basal bone mass in both cortical and cancellous compartments. Furthermore, NT3-Cre+ mice exhibited a greater anabolic response following mechanical loading compared to controls. We next performed RNA-Seq on non-loaded and loaded tibiae to elucidate possible mechanisms underlying the increased bone anabolism seen in NT3-Cre+ mice. Hierarchical clustering revealed two main transcriptional programs: one loading-responsive and the other NT3 transgene-driven. Gene ontology (GO) analysis indicated a distinct upregulation of receptor, kinase and growth factor activities including Wnts, as well as a calcium-response signature in NT3-Cre+ limbs. The promoters of these GO-term associated genes, including many known to be bone-anabolic, were highly enriched for multiple kB recognition elements (kB-RE) relative to the background frequency in the genome. The loading response in NT3-Cre+ mice substantially overlapped (>90%) with Ctrl. Surprisingly, control animals had 10-fold more differentially expressed genes (DEGs) in response to loading. However, most top DEGs shared between genotypes had a high incidence of multiple kB-RE in their promoters. Therefore, both transcriptional programs (loading-responsive and NT3 transgene-driven) are modulated by NF-kB. Our studies uncover a previously unrecognized role for NF-kB in the promotion of both basal and mechanically-stimulated bone formation.

ORGANISM(S): Mus musculus

PROVIDER: GSE133212 | GEO | 2019/06/25

REPOSITORIES: GEO

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