期刊
ENDOCRINOLOGY
卷 149, 期 1, 页码 146-153出版社
ENDOCRINE SOC
DOI: 10.1210/en.2007-0734
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资金
- NIAMS NIH HHS [R01 AR049794] Funding Source: Medline
- NIA NIH HHS [P01 AG013918, P01 AG13918] Funding Source: Medline
- NIDDK NIH HHS [R01 DK074993] Funding Source: Medline
- NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES [R01AR049794] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK074993] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [P01AG013918] Funding Source: NIH RePORTER
Receptor activator of nuclear factor-kappa B 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 D3 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 D3 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.
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