DO WE USE METHYLATION OF NFATC1 AND FOS GENES AS
A BIOMARKER FOR POSTMENOPAUSAL OSTEOPOROSIS?
Kalkan R, Tosun O
*Corresponding Author: Associate Professor Rasime Kalkan, Department of Medical Genetics, Faculty
of Medicine, Near East University, Near East Boulevard, Nicosia, Cyprus, 99138. Tel: +903-92-
223-6464. Fax: +903-92-223-6461. E-mail: rasime.kalkan@neu.edu.tr, kalkanr@yahoo.com
page: 35
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DISCUSSION
The RAS signaling pathway is important for the osteoclast
survival and triggers activation of downstream
genes [20]. NFATC1 and FOS are the downtargets of the
RAS pathway, which have an important role during osteoclastogenesis
[20]. NFATC1 regulates osteoclast-specific
genes during the regulation of osteoclast differentiation
and FOS is one of the genes which NFATC1 triggers their
expression [5-8]. Raggatt and Partridge [21], demonstrated
that NFATC1 is one of the important transcription factors
during the differentiation of osteoclast precursors.
Decreased level of estrogen triggers several physiological
and hormonal problems. Postmenopausal osteoporosis
is one of the consequences of decreased level of
estrogen [22,23]. Gavali et al. [24] demonstrated the effect
of estrogen on osteoclast differentiation and they showed
that lack of estrogen causes failure of apoptosis and inhibits
activation of NFATC1 and c-Src. Kim et al. [25]
tested the extract of Lycii Radicis Cortex (LRC) on an
ovariectomized (OVX) rat model and they showed suppression
of RANKL-induced osteoclast differentiation and
also demonstrated inhibitory effect of LRC on NFATC1
expression. On the other hand, Kim et al. [26] showed
that overexpression of NFATC1 induced differentiation
of osteoclasts. Also, Zhao et al. [27] also showed that
NFATC1 is an important transcription factor for RANKLmediated
osteoclast differentiation, and Winslow et al. [28]
demonstrated that lack of osteoclast differentiation and
osteoporosis was observed on NFATC1 knock-out mice.
Researchers also showed that inhibition of NFATC1 had
an important role during the RANKL-induced osteoclast
differentiation [29].
Many studies have shown the effects of inhibition
of NFATC1 and FOS on osteoclasts and postmenopausal
osteoporosis [8,20,29]. As we mentioned previously, FOS
is another member of RANK/RANKL pathway and stimulation
of FOS causes the activation of NFATC1 [11,27].
The FOS gene deletion was related to defective osteoclast
differentiation and osteopetrosis in mice [25].
For many years, the interaction between NFATC1 and
FOS has been studied in vitro animal models conditions.
Here, we studied NFATC1 and FOS methylation status
in blood samples of post- and premenopausal women. In
this study, we showed statistically significant association
between postmenopause and unmethylation of the NFATC1
promotor (p = 0.010) and methylation of NFATC1 with
premenopause. NFATC1 is important for osteoclast dif- ferentiation, which means important for bone resorption.
According to our results, osteoporosis is not an expected
condition in premenopausal women, and methylation data
also confirms this hypothesis; in postmenopausal women,
unmethylation of the NFATC1 promotor (p = 0.010) means
differentiation of osteoclasts were triggered. These results
could be used for epigenetic explanation of postmenopausal
osteoporosis. Future studies should also be designed
to inactivate the NFATC1 pathway as a possible targeted
therapy strategy in postmenopausal osteoporosis. On the
other hand, we did not find any significant associations
between menopause and FOS methylation (p >0.05). As
far we know, epigenetic alterations are tissue-specific but
we hope our results will shed light on further studies in
this field, and encourage researchers to use bone and other
related tissues for methylation analysis of this pathway.
Up to now, there have been no epigenetic studies in this
field, and we concluded that the NFATC1 gene was hypermethylated
during the premenopausal period and it could
be unmethylated during the postmenopausal period. We
hope our results will lead epigenetic studies in this field.
Conclusions. In conclusion, we found significant
association of unmethylation of NFATC1 and postmenopausal
status. NFATC1 and osteoclast formation interaction
has been shown by the in vitro studies. In this study, we
concluded that epigenetic silencing of the NFATC1 gene
can raise osteoclast activity and it is directly related to
post-menopausal osteoporosis. These results will further
epigenetic studies in postmenopausal women and could
be used as a potential epigenetic marker during the evaluation
of postmenopausal osteoporosis in clinical practice.
This study is the first epigenetic study that investigated
the NFATC1 and FOS methylation in postmenopausal
women and shows interaction between epigenetics and
postmenopausal osteoporosis. Although the limited sample
size in our study and lack of epigenetic studies in this field
proves our results crucial and therefore, our results showed
the magnitude of epigenetic profile of Turkish Cypriot
postmenopausal women. Future studies in larger samples
of postmenopausal women focused on the study of the
different gene methylations will help to clarify potential
effects of gene methylation in the menopause.
Acknowledgments. We thank all of the patients for
their voluntary support. The authors also thank Dr. Pinar
Tulay (Near East University, Nicosia, Turkish Republic
of Northern Cyprus) and Mohammed Altarda for technical
support and for help with DNA extraction. Authors’
contribution: RK supervised the project, RK conceived
and planned the experiments. OT carried out the statistical
analysis. RK carried out the experiment. RK and OT
wrote the manuscript. Both RK and OT contributed to the
final version of the manuscript. Both authors provided
critical feedback and helped shape the research, analysis
and manuscript.
Declaration of Interest. The authors report no conflicts
of interest. The authors alone are responsible for the
content and writing of this article.
Funding. This study was supported by the Near East
University Scientific Research Project Unit [Grant No.
SAG-2016-2-012], Nicosia, Cyprus.
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