The receptor activator of nuclear factor-κB ligand (RANKL) is recognized as one of the important regulators of osteoclastogenesis. The expression of the tumour necrosis factor superfamily, member 11 (TNFSF11) gene, which encodes for RANKL protein, is increased relative to the expression of osteoprotegrin in cases of senile osteoporosis with hip bone fracture. Our aim was to find polymorphisms in the TNFSF11 gene promoter and to investigate their possible association with bone mineral density (BMD).
The TNFSF11 gene promoter region was screened for the presence of new sequence variations by direct sequencing. DNA sequencing revealed the presence of four sequence variations: −290C > T, −643C > T, −693G > C and −1594G > A. Association of the discovered polymorphisms with BMD was investigated in 115 Slovenian postmenopausal women, using restriction fragment length polymorphism analysis. After a year, bone loss in the association with the identified sequence variations was evaluated in 43 postmenopausal women.
Three of the discovered sequence variations (−290C > T, −643C > T, −693G > C) proved to be polymorphic, whereas variation −1594G > A was only found in one patient. The frequencies of genotypes were as follows: CC (27.8%), CT (43.5%), TT (28.7%) for −290C > T polymorphism; CC (23.5%), CT (47.8%), TT (28.7%) for −643C > T polymorphism; and GG (22.6%), GC (51.3%), CC (26.1%) for −693G > C polymorphism. A statistically significant association of genotype with BMD at the femoral neck was observed only in the −290C > T polymorphism. Genotype CC was associated with lower BMD than the TT genotype (P = 0.022). In polymorphism −693G > C, a significant difference in bone loss rate was observed in total hip (P = 0.011) and femoral neck BMD (P = 0.037).
Four sequence variations were identified in the studied region of TNFSF11 gene promoter. Our results of preliminary clinical evaluation suggest that the −290C > T polymorphism in the TNFSF11 gene promoter could contribute to the genetic regulation of BMD.
To read this article in full you will need to make a payment
Purchase one-time access:Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
One-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:Subscribe to Maturitas
Already a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
- Role of receptor activator of nuclear factor-B ligand and osteoprotegrin in bone cell biology.J Mol Med. 2001; 79: 243-253
- Differentiation and function of osteoclasts.Keio J Med. 2003; 52: 1-7
- Osteoprotegrin ligand is a cytokine that regulates osteoclast differentiation and activation.Cell. 1998; 93: 165-176
- A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function.Nature. 1997; 390: 175-179
- Osteoprotegrin: a novel secreted protein involved in the regulation of bone density.Cell. 1997; 89: 309-319
- The ligand for osteoprotegrin (OPGL) directly activates mature osteoclasts.J Cell Biol. 1999; 145: 527-538
- TRANCE is necessary and sufficient for osteoblast-mediated activation of bone resorption in osteoclasts.J Exp Med. 1998; 188: 997-1001
- Osteoclast differentiation factor is a ligand for osteoprotegrin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL.Proc Natl Acad Sci USA. 1998; 95: 3597-3602
- OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis.Nature. 1999; 397: 315-323
HUGO Gene Nomenclature Committee, Homepage, http://www.gene.ucl.ac.uk/nomenclature/ (accessed April 11, 2005).
- Localization of RANKL (receptor activator of NKκB ligand) mRNA and protein in skeletal and extraskeletal tissues.Bone. 1999; 25: 525-534
- Biology of TRANCE axis.Cytokine Growth Factor Rev. 2003; 14: 251-263
- Promoter structure of mouse RANKL/TRANCE/OPGL/ODF gene.Biochem Biophys Acta. 1999; 1445: 134-141
- Cbfa1 does not regulate RANKL gene activity in stromal/osteoblastic cells.Bone. 2002; 30: 453-462
- Functional role for heat shock factors in the transcriptional regulation of human RANK ligand gene expression in stromal/osteoblast cells.J Biol Chem. 2004; 12: 10500-10507
- The ratio of messenger RNA levels of receptor activator of nuclear factor κB ligand to osteoprotegrin correlates with bone remodeling indices in normal human cancellous bone but not in osteoarthritis.J Bone Miner Res. 2001; 16: 1015-1027
- Increased expression of IL-6 and RANK mRNA in human trabecular bone from fragility fracture of femoral neck.Bone. 2004; 35: 334-342
- In postmenopausal women, femoral neck BMD is positively correlated to circulating levels of soluble RANKL and negatively correlated to levels of IL-7.J Bone Miner Res. 2004; 19: M397
- A simple salting out procedure for extracting DNA from human nucleated cells.Nucleic Acid Res. 1988; 16: 1215
- Variation in genes involved in the RANKL/RANK/OPG bone remodelling pathway are associated with bone mineral density at different skeletal sites in men.Hum Genet. 2006; 118: 568-577
- Epigenetic control of mouse receptor activator of NF-κB ligand gene expression.Biochem Biophys Res Commun. 2002; 290: 650-655
Accepted: March 7, 2006
Received in revised form: March 3, 2006
Received: August 31, 2005
© 2006 Elsevier Ireland Ltd. Published by Elsevier Inc. All rights reserved.