Deletion of the Distal Tnfsf11 RL-D2 Enhancer That Contributes to PTH-Mediated RANKL Expression in Osteoblast Lineage Cells Results in a High Bone Mass Phenotype in Mice

Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research
Melda OnalJ Wesley Pike

Abstract

Receptor activator of nuclear factor-κB ligand (RANKL) is a tumor necrosis factor (TNF)-like cytokine that is necessary for osteoclast formation and survival. Elevated RANKL synthesis is associated with both increased osteoclast number and bone resorption. Earlier studies identified an enhancer 76 kb upstream of the Tnfsf11 transcriptional start site (TSS) termed RL-D5 or the distal control region (DCR) that modulates RANKL expression in response to PTH, 1,25(OH)2D3,, and an array of cytokines. Mice lacking RL-D5 exhibit high bone mass associated with decreased RANKL expression in bone, spleen, and thymus. In addition to RL-D5, genome-wide studies have identified 9 additional Tnfsf11 enhancers residing upstream of the gene's TSS, which provide RANKL cell type-specificity and responsiveness to local and systemic factors. ChIP-chip analyses has revealed inducible vitamin D receptor (VDR) and cAMP response element-binding protein (CREB) binding at an enhancer termed RL-D2 23 kb upstream of the Tnfsf11 TSS in osteoblastic ST2 cells. Herein, we use ChIP-seq analyses to confirm this finding and then delete this enhancer from the mouse genome to determine its physiological role in vivo. RL-D2(-/-) primary stromal cells showed decrease...Continue Reading

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Citations

Oct 21, 2016·Nature Communications·Marc N WeinHenry M Kronenberg
Aug 21, 2019·The Journal of Clinical Investigation·Shigeki NishimoriMarc N Wein
Feb 28, 2017·The Journal of Clinical Investigation·J Wesley PikeNancy A Benkusky
Oct 5, 2018·JBMR Plus·Marc N Wein
Jul 6, 2021·Biochemical Pharmacology·Tianhong ChenJingfeng Li

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