Circulating amounts of osteoprotegerin and RANK ligand: genetic influence and relationship with BMD assessed in female twins.
Osteoprotegerin (OPG) is a circulating receptor that inhibits osteoclastogenesis by binding to RANK ligand (RANKL). OPG knock-out animals develop severe osteoporosis. Treatment with OPG lowers bone resorption and increases BMD. OPG production is influenced by a wide range of hormones and cytokines. The influence of genetic factors on circulating amounts of OPG and RANKL is not known. BMD has been demonstrated to have a high heritability and there is evidence also that bone turnover and bone loss rates are controlled at least in part by genetic factors.


OBJECTIVE
Assessing the genetic impact on serum OPG and RANKL in women and estimation of the relative contribution of this inheritance to the total heritability of BMD.


METHODS
188 female twins (52 DZ and 42 MZ pairs) from the Danish Twin Registry were included in the study. Mean age was 35 years (range 19-64 years), average spine BMD was 1.04 +/- 0.11 g/cm2. Serum levels of OPG and RANKL were measured by ELISA (Biomedica, Vienna, Austria). This register covers twins born in Denmark since 1870. Heritability and environmental influence was assessed using a maximum-likelihood model for genetic pleiotropy.


RESULTS
RANKL levels showed a negative correlation with age and lower values in smokers. OPG levels were higher in postmenopausal women. Heritability (h(2)) was 85% for spine BMD and 52% for serum RANKL after adjustment for age, smoking and BMI. By contrast, there was no significant genetic influence on OPG levels (h(2) = 0, 95% CI: 0 to 0.31). Serum OPG was determined almost exclusively by individual environment (e(2) = 0.79), with a small, non-significant contribution from shared environment (c(2) = 0.21). Restricting analyses to the 158 premenopausal twins did not alter the findings.


CONCLUSIONS
Serum OPG and RANKL levels have only a weak relation to BMD in healthy women. Phenotype correlations indicate that the genes that contribute to twin similarity for BMD are not genes regulating serum levels of RANKL or OPG. The weak correlation with BMD appears to consist in shared environmental factors.
Abrahamsen
Bo
B
Department of Endocrinology, Odense University Hospital, Denmark. b.abrahamsen@dadlnet.dk
Hjelmborg
Jacob Vb
JV
Kostenuik
Paul
P
Stilgren
Lis S
LS
Kyvik
Kirsten
K
Adamu
Stephen
S
Brixen
Kim
K
Langdahl
Bente L
BL
D000328:Adult; D015519:Bone Density; D002352:Carrier Proteins / Q000097:blood*; D003276:Contraceptives, Oral / Q000008:administration & dosage; D003718:Denmark; D005260:Female; D006023:Glycoproteins / Q000097:blood*; D006801:Humans; D008562:Membrane Glycoproteins / Q000097:blood*; D008593:Menopause; D008875:Middle Aged; D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear / Q000097:blood*; D018124:Receptors, Tumor Necrosis Factor / Q000097:blood*; D012042:Registries; D012044:Regression Analysis; D012907:Smoking
D002352:Carrier Proteins; D003276:Contraceptives, Oral; D006023:Glycoproteins; D008562:Membrane Glycoproteins; D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C505686:TNFRSF11A protein, human; C506030:TNFRSF11B protein, human; C505688:TNFSF11 protein, human