English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Global: Zendy Tools annual

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Insights

Presents the pdf analysis as premium feature

PDF Analysis

Presents the zaia usage as premium feature

ZAIA

Global: Zendy Tools monthly

Global: Zendy Plus monthly

Presents the access of premium content as premium feature

Premium Content

Global: Zendy Plus annual

Global: Zendy Free Plan

Receptor activator of nuclear factor κB ligand (RANKL) is expressed by a number of cell types to participate in diverse physiological functions. We have previously identified 10 distal RANKL enhancers. Earlier studies have shown that RL-D5 is a multifunctional RANKL enhancer. Deletion of RL-D5 from the mouse genome leads to lower skeletal and lymphoid tissue RANKL, causing a high bone mass phenotype. Herein, we determine the physiological role and lineage specificity of 2 additional RANKL enhancers, RL-D6 and RL-T1, which are located 83 and 123 kb upstream of the gene's transcriptional start site, respectively. Lack of RL-D6 or RL-T1 did not alter skeletal RANKL or bone mineral density up to 48 weeks of age. Although both RL-D5 and RL-T1 contributed to activation induction of T-cell RANKL, RL-T1 knockout mice had drastically low lymphocyte and lymphoid tissue RANKL levels, indicating that RL-T1 is the major regulator of lymphocyte RANKL. Moreover, RL-T1 knockout mice had lower circulating soluble RANKL, suggesting that lymphocytes are important sources of circulating soluble RANKL. Under physiological conditions, lack of RL-D6 did not alter RANKL expression. However, lack of RL-D5 or RL-D6, but not of RL-T1, blunted the oncostatin M and lipopolysaccharide induction of RANKL ex vivo and in vivo, suggesting that RL-D5 and RL-D6 coregulate the inflammation-mediated induction of RANKL in osteocytes and osteoblasts while lack of RL-D6 did not alter secondary hyperparathyroidism or lactation induction of RANKL or bone loss. These results suggest that although RL-D5 mediates RANKL expression in multiple lineages, other cell type- or factor-specific enhancers are required for its appropriate control, demonstrating the cell type-specific and complex regulation of RANKL expression.

Unique Distal Enhancers Linked to the Mouse Tnfsf11 Gene Direct Tissue-Specific and Inflammation-Induced Expression of RANKL