Targeted deletion of a distant transcriptional enhancer of the receptor activator of nuclear factor-kappaB ligand gene reduces bone remodeling and increases bone mass.
Receptor activator of nuclear factor-kappaB ligand (RANKL) is essential for osteoclast differentiation, and hormones and cytokines that stimulate bone resorption increase RANKL expression in stromal/osteoblastic cells. We have previously shown that PTH and 1,25-dihydroxyvitamin D(3) control murine RANKL gene expression in vitro, in part, via an evolutionarily conserved transcriptional enhancer, designated the distal control region (DCR), located 76 kb upstream from the transcription start site. Herein we describe the phenotype of mice lacking this enhancer. Deletion of the DCR reduced PTH and 1,25-dihydroxyvitamin D(3) stimulation of RANKL mRNA and osteoclast formation in primary bone marrow cultures as well as stimulation of RANKL mRNA in bone. DCR deletion also reduced basal RANKL mRNA levels in bone, thymus, and spleen. Moreover, mice lacking the DCR exhibited increased bone mass and strength. The increase in bone mass was due to reduced osteoclast and osteoblast formation leading to a low rate of bone remodeling similar to that observed in humans and mice with hypoparathyroidism. These findings demonstrate that hormonal control of RANKL expression via the DCR is a critical determinant of the rate of bone remodeling.
Galli
Carlo
C
Center for Osteoporosis and Metabolic Bone Disease, University of Arkansas for Medical Sciences, 4301 West Markham Street, MS 587, Little Rock, Arkansas 72205, USA.
Zella
Lee A
LA
Fretz
Jackie A
JA
Fu
Qiang
Q
Pike
J Wesley
JW
Weinstein
Robert S
RS
Manolagas
Stavros C
SC
O'Brien
Charles A
CA
D000818:Animals; D015519:Bone Density / Q000235:genetics*; D016723:Bone Remodeling / Q000235:genetics*; D001842:Bone and Bones / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D005260:Female; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000187:drug effects; D008221:Lymphoid Tissue / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016297:Mutagenesis, Site-Directed; D010281:Parathyroid Hormone / Q000494:pharmacology; D053245:RANK Ligand / Q000235:genetics* / Q000378:metabolism
D010281:Parathyroid Hormone; D053245:RANK Ligand; C505689:Tnfsf11 protein, mouse