Joint Bone Spine 80 (2013) 368373

Available online at

www.sciencedirect.com

Review

Estrogens, osteoarthritis and inflammation

b

Marta Martn-Milln a, , Santos Castaneda

a
b

Department of Internal Medicine, IFIMAV, Hospital Universitario Marqus de Valdecilla, Avenida de Valdecilla s/n, 39008 Santander, Cantabria, Spain
Department of Rheumatology, IIS-Princesa, Hospital Universitario de La Princesa, c/Diego de Len 62, 28006 Madrid, Spain

a r t i c l e

i n f o

Article history:
Accepted 30 November 2012
Available online 23 January 2013
Keywords:
Estrogens
Osteoarthritis
Bone
Inflammation
Atherosclerosis

a b s t r a c t
Estrogens participate in several biological processes through different molecular mechanisms. Their final
actions consist of a combination of both direct and indirect effects on different organ and tissues. Estrogen may have pro- and anti-inflammatory properties depending on the situation and the involved tissue.
In general, acute loss of estrogens increases the levels of reactive oxygen species and activates nuclear
factor-!B and pro-inflammatory cytokine production, indicating their predominant anti-inflammatory
properties. Furthermore, pro-inflammatory cytokine expression has been shown to be attenuated by
estrogen replacement. Osteoarthritis and cardiovascular disease are two of the more prevalent diseases
once menopause is established, which has suggested the link between estrogens and both processes.
In addition, deletion of estrogen receptors in female mice results in cartilage damage, osteophytosis
and changes in the subchondral bone of the joints suggesting that estrogens have a protective role on
the maintenance of joint homeostasis. Furthermore, in spite of the negative effect of estrogen replacement reported in 2002 by the Womens Health Initiative study, several works published afterwards
have explored the potential protective effect of estrogen supplementation in animal models and have
postulated that these actions may justify a beneficial role of estrogens in different diseases where inflammation is the major feature. In this review, we will analyze the effects of estrogens on certain pathological
situations such as osteoarthritis, some autoimmune diseases and coronary heart disease, especially in
postmenopausal women.
2013 Published by Elsevier Masson SAS on behalf of the Socit Franaise de Rhumatologie.

1. Introduction
Estrogens regulate many physiological processes, including normal cell growth, development, and tissue-specific gene regulation
in the reproductive tract, the brain, the immune system, and in the
cardiovascular and skeletal systems [1,2]. Estrogen was originally
thought to be exclusively a sexual hormone implicated mainly in
the development of the reproductive system. However, the understanding of its physiological functions has considerably improved
in last years.
Epidemiological evidences suggest that female sex hormones
play an important role in the etiology and pathophysiology
of chronic inflammatory and degenerative diseases. However,
whether estrogens are friends or not in inflammatory and immunemediated diseases is still a matter of debate [3,4]. Several significant
factors generate confusion in evaluating the role of estrogens in
inflammatory or immune diseases. However, as supported by the
higher prevalence of autoimmune diseases in women, estrogens are
generally considered as enhancers of cell proliferation and immune

Corresponding author. Tel.: +34 942 201990.

E-mail addresses: martinmma@unican.es, mmmillan1974@hotmail.com
(M. Martn-Milln).

response. As an example, in systemic lupus erythematosus (SLE),

female to male ratio ranges from 10:1 to 15:1 [5].
Osteoarthritis (OA) is another disease commonly seen in postmenopausal women. The prevalence of OA is higher among women
than men, and this prevalence is associated with menopause. In
fact, a nationwide population survey showed that radiographic OA
is three times more common among women aged 4564 years compared to their male peers [6,7]. In the EPISER study, the estimated
prevalence of symptomatic knee OA in subjects aged 20 years or
above was 10.2% (5.8% in men vs. 14% in women). The prevalence
of symptomatic hand OA in the same population was 2.3% in male
and 9.5% in female [8].
In this review, we update the relationship between estrogens, OA and inflammation and the main mechanisms by which
estrogens mediate their pathologic effects in inflammatory and
degenerative joint diseases.
2. Estrogen receptor structure and characteristics
The biological actions of estrogens are mediated by binding to
one of two specific estrogen receptors (ERs), ER" or ER#, which
belong to the superfamily of nuclear receptors, a family of ligandregulated transcription factors, located mainly in the cytoplasm

1297-319X/$ see front matter 2013 Published by Elsevier Masson SAS on behalf of the Socit Franaise de Rhumatologie.
doi:10.1016/j.jbspin.2012.11.008

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neda / Joint Bone Spine 80 (2013) 368373
Table 1
Tissues in which estrogen receptor subtypes (ERs) are expressed.
Type of ER

Tissues in which they are expressed

ER"

Uterus, placenta, pituitary and cardiovascular system

ER#

Ventral prostate, urogenital tract, ovarian follicles, lung

and immune system

ER" and #

Mammary gland, bone, brain and joint tissues: growth

plate chondrocytes, articular chondrocytes; subchondral
osteoclasts, osteoblasts and osteocytes; synoviocytes,
ligament fibroblasts and myoblasts

ER": estrogen receptor alpha; ER#: estrogen receptor beta.

[1]. ER" is located at chromosomal locus 6q25.1 [9], whereas ER#

is found at position 14q22-24 [10]. Several ER" and ER# splicing variants have been described, but whether all transcripts are
expressed as functional proteins and have biological functions
remains unclear.
Both receptors are expressed in a variety of tissues throughout
the body, but in different proportions in each tissue. ER" is highly
expressed in classical estrogen target tissues such as the uterus,
placenta, pituitary and cardiovascular system, whereas ER# is more
abundant in the ventral prostate, urogenital tract, ovarian follicles,
lungs and immune system (Table 1). However, both ERs are coexpressed in the mammary gland, bone, and certain regions of the
brain [11] (Table 1). Although both ER subtypes can be expressed
in the same tissue, they may not be expressed in the same cell
type.
In joint tissues, both ER types are expressed by the chondrocytes [12], subchondral bone cells [13], synoviocytes [14], ligament
fibroblasts [15] and myoblasts [16] in humans and other species.
However, ER" is predominant in cortical bone and ER# predominates in cartilage, cancellous bone and synovium [17].
The two receptors have the typical structure of the nuclear
receptor family, which consists of six regions designated by letters
from A to F (Fig. 1). The central C domain is a highly conserved region also known as the DNA-binding domain (DBD). This
region contains two zinc fingers which recognize sequences of
13 bp (5" GGTCAnnnTGACC3" ), called the estrogen response element
(ERE). The ERE is located in the promoter of target genes, which is
where the ER interacts with the DNA [18]. After the DBD domain,
we can find the D domain, a less conserved region, whose flexibility
allows the protein to fold up easily. The C-terminal domain includes
the ligand-binding domain (LBD), which is where the ligand binds
to its receptor. The LBD contains a nuclear localization, a dimerization and a ligand-dependent transactivation region. This latter
domain is also called AF-2, and is responsible for recruiting coactivators or repressors depending on the ligand bonded [19]. The F

369

domain varies in length depending on the species. It is not directly

involved in ligand-binding or transcriptional activation, but modulates receptor activity [20].
The amino-terminal region is the most variable among family members, both in size and amino acid sequences. It contains
a transactivation region, called AF-1, which unlike the AF-2 it
is ligand-independent. Both AF-1 and AF-2 regions can activate
transcription independently or synergistically. In addition, the Nterminus contains 14 serine residues that can be phosphorylated
by a variety of protein kinases [2123].
The resulting conformation obtained once the ligand has bonded
to the ER will determine the type of regulator that will be recruited.
Binding of agonists promotes interaction with co-activators, while
binding of antagonists induces the interaction with co-repressors.
On the other hand, it is important to remember that not only do
different cell types have different proportions of ERs, but also different proportions of transcription factors, which will establish the
final transcriptional effect.
Estrogens are essentials in the development of the reproductive
system. However, estrogens have other important functions. Thus,
estrogens contribute also to promote both skeleton mineralization
and epiphyseal maduration. As a matter of fact, the description
of a 28-year-old man with estrogen resistance due to truncated
estrogen receptor unable to bind the DNA-binding and hormonebinding domains revealed the importance of estrogens in growth
plate closure eighteen years ago [24]. The most remarkable phenotypic finding of the human estrogen resistance was tall stature due
to a continued slow linear growth determined by unfused epiphyses. As well as this, this man had low bone mass with biochemical
evidence of increased bone resorption. These observations highlighted the importance of estrogen signals via its ER" to promote
not only skeletal maturation, but also, epiphysis maturation, since
without them the final adult length limbs are disproportionally
increased.
Estrogens, through direct and indirect mechanisms on different cell types, exert a broad spectrum of pleiotropic effect on
non-sexual tissues, and that loss of estrogen is involved in many
age-related conditions. Yet, its precise molecular mechanism is still
not fully understood.
It has been developed estrogen receptor analogues, such as
the Selective Estrogen Receptor Modulators, which as their name
says, SERMs are selective this means that a SERM that blocks
estrogens action in some tissues, such as breast cells, can activate
estrogens action in other cell types, such as bone, liver, and uterine cells. This tissue-specificity makes them very useful drugs in
clinic, since they allow us to dissect the positive effects of estrogens on non-sexual tissues from the deleterious effects on breast,
when they are used for long periods of time.

Fig. 1. Nuclear estrogen receptor structure. Estrogen receptors have four functional domains, which harbor a DNA-binding domain (DBD), a ligand-binding domain (LBD), an
N- terminal domain (NTD) and two transcriptional activation functions (AF-1 and AF-2). At the AF-1 there are several phosphorylation sites that can be activated by different
growth factors regardless of the ligand.

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3. Estrogen on inflammation and autoimmune diseases

Inflammation is a critical component in several inflammatory
and autoimmune diseases such as multiple sclerosis, inflammatory
bowel disease, rheumatoid arthritis (RA) or SLE. Almost all these
disorders mainly affect women. This aspect of estrogens was originally highlighted by the clinical observation that pregnancy tended
to reduce symptoms of some inflammatory diseases [25].
Sex hormones modulate the onset and progression of several connective tissue diseases, including RA, in both clinical and
in vivo studies [26]. The peak RA incidence in women occurs
around menopause, when ovary dysfunction leads to a fall in
estrogen and progesterone levels. Moreover, RA activity often
decreases during the postovulatory phase of the menstrual cycle
and pregnancy, when sex hormones are in high levels, whereas
the disease flares in the postpartum period, when sex hormone levels drop [27]. The matter, however, turned out to be
not that simple. Many players, such as B and T lymphocytes,
antigen-presenting cells, monocyte/macrophages, neoangiogenesis, adhesion molecules, pro-inflammatory cytokines and reactive
oxygen species (ROS) production can contribute to the development of an inflammatory environment. The global effect of
estrogens on inflammation depends on their influence not only on
the key players implicated in a particular inflammatory disorder,
but also on the cells of the target tissues involved.
Experiments performed in vitro and on animal models have indicated that estrogens stimulate autoantibody production by B cells,
in part, by inhibiting T cell suppression of B cells. In contrast, high
levels of estrogens induce a down-regulation of B-lymphocyte lineage in the bone marrow. Therefore, if B cells are the major players
in a given autoimmune disease, estrogens would promote the disorder when auto-aggressive B cells are already developed, while
chronically elevated estrogens would blunt the initiation of the disease. These data might explain why B cell-dependent diseases, such
as SLE, develop in women either during their reproductive years or
during late pregnancy or after pregnancy [4].
On the other hand, if tissue-destructive T cells play the most
important role, the onset of the disease will be delayed until the
late reproductive or postmenopausal period, when estrogen has
already declined and T cell autoimmunity is not attenuated [4].
Nave T cells differentiate into either Th1 or Th2, depending on
the cytokines secreted by dendritic cells in response to a specific
antigenic challenge [28]. Th1 lymphocytes are known to be a wellestablished component of the RA, meanwhile Th2 lymphocytes are
the ones typically involved in SLE disease. High levels of estrogens
suppress Th1-mediated responses and stimulate Th2-mediated
immunologic responses. Th2 cells, unlike Th1 cells, produce mostly
IL-4, -5, -10 and -13 to promote IgG, IgA, and IgE antibody isotype
responses, which is why Th1-mediated diseases, such as RA, tend
to improve during pregnancy while Th2-mediated diseases, such
as SLE, tend to worsen (Table 2) [29].
Finally, it has been observed that synovial fluid concentration of free estrogens tend to be higher in RA patients versus
controls. Synovial fluid levels of estrogens relative to androgens are significantly elevated, while those of androgens are
markedly reduced [30]. It is believed that this imbalance is
probably due to increased aromatase activity in patients with
RA compared to controls. The increased estrogen concentration
observed in RA synovial fluid of both sexes are characterized by
the hydroxylated forms, in particular 16alpha-hydroxyestrone, that
is a mitogenic and proliferative endogenous hormone [31]. In
contrast to 16alpha-hydroxylated estrogens, the 2-hydroxylated
forms inhibit growth promoting effects of estrogens. This latter form was found to be lower in RA synovial fluid. Therefore,
dose-related conversion to pro- or anti-inflammatory downstream metabolites of estrogens might support the dual role

Table 2
Effects of estrogen on immune and vascular systems.
System

Main effects

Immune

Increases autoantibody production

Blunts T cells inhibition of B cells
Suppresses Th1-mediated responses

Vascular

Decreases adhesion molecules (sICAM, VCAM, E and

P-selectins)
Decreases ROS production
Decreases NF-kB
Decreases human monocyte-derived macrophage cell
cytokine expression
Increases nitric oxide synthase
Increases neoangiogenesis

NF-kB: nuclear factor-kappa B; ROS: reactive oxygen species; sICAM: soluble intracellular adhesion molecule; VCAM: vascular cell adhesion molecule.

of estrogens (pro or anti-inflammatory) for example during

estrogen replacement therapy (ERT), depending on local concentration of 16alpha-hydroxyestrone or 2-hydroxyestrogens.
4. Estrogen and atherosclerosis
It is well known that premenopausal women have lower risk
and incidence of cardiovascular events compare to age-matched
males, and that this gender advantage disappears after menopause,
suggesting that sexual hormones play a protective role against
cardiovascular diseases [32,33]. Although this issue has recently
come into question based on large scale, randomized clinical trials [34,35], the potentially favourable biological effects of estrogen
on the cardiovascular system is widely recognized. Estrogen has
numerous nuclear-initiated genomic effects on endothelial cells,
including the repression of athero-promoting and the induction of
atheroprotective genes [36].
On the other hand, inflammation also plays a critical role in the
development of coronary heart disease. Atherosclerosis involves
a process of monocyte migration into the intima-media layer
of the arteries. Adhesion molecules such as soluble intracellular
adhesion molecule-1 (sICAM), vascular cell adhesion molecule-1
(VCAM), E and P-selectins are important factors during inflammation, since they mediate leukocyte adhesion and migration into
the vascular wall. Circulation of these molecules is strongly associated with both atherosclerosis and a risk for cardiovascular events.
Monocytes recruited into the subendothelial wall differentiate into
macrophages and begin to take up oxidized lipoproteins, leading to
the formation of foam cells, which are the initial component of the
atheroma lesion and a source of pro-inflammatory cytokines such
as tumoral necrosis factor alpha (TNF-"), IL-6 and IL-1 [37].
Lack of estrogens, as well as age-dependent damage at the
cellular level, is associated with increased levels of ROS. Moreover, estrogen replacement in ovariectomyzed mice attenuates
ROS-induced by ovariectomy (OVX) in bone marrow [38]. One of
the consequences of increased ROS production is the activation of
redox-sensitive cytoplasmic kinases of the nuclear factor-kB (NFkB) pathway, which leads to up-regulation of genes involved in
inflammation. One of the mechanisms by which estrogen diminishes the generation of ROS and decreases the phosphorylation of
p66shc an adapter protein that amplifies mitochondrial ROS production and influences lifespan in mice in bone marrow, is via a
non-genomic mechanism, which attenuates the phosphorylation
of the redox-sensitive cytoplasmic kinase PKC# [39]. Apart from a
non-genomic mechanism, inhibition of NF-KB transcription factor
by estrogens can also happen through a protein-protein interaction
mechanism.
Nevertheless, the role of ERT in postmenopausal women
still remains controversial. Ex vivo experiments performed with

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primary cultures of human monocyte-derived macrophage

(HMDM) cells from premenopausal females have shown greater
pro-inflammatory cytokine expression after estrogen withdrawal
compared to HMDM continually exposed to the hormone [40].
Divergent results have been seen in older postmenopausal HMDM
cells where the beneficial anti-inflammatory effect of estrogens
depends on the levels of small-dense low density lipoprotein
cholesterol. This information correlates with clinical observations,
suggesting that estrogen therapy is beneficial in younger premenopausal women, but can be harmful in the older women, for
whom other interactions should be taken into account [41].
Furthermore, there is an inverse association between sICAM1 and estrogens among postmenopausal estradiol therapy users,
which indicates that estrogens have an evident anti-inflammatory
effect when pharmacologic levels are achieved [42]. Although there
is substantial evidence regarding the anti-inflammatory effect of
estrogens in the vascular system, there is still a lack of knowledge
about the role of the hormone once the atherosclerotic process has
already established. Parallel to the effects on both cytokines and
adhesion molecules, estrogen also increases endothelial vasodilator function via a non-genomic mechanism, which promotes the
activity of endothelial Nitric Oxide (NO) synthase and the availability of NO [43].
Neoangiogenesis is another important element in inflammation,
and it has been shown to be up regulated by estrogens. Moreover,
estrogen in the presence of TNF" enhances TNF induced-vascular
endothelial growth factor (VEGF). This data may explain why estrogen treatment may be protective in women without atherosclerotic
disease but, in the presence of chronic inflammation, may lead to
destabilization of atherosclerotic plaques [44].
Therefore, based on this evidence we can conclude that
estrogens have beneficial effects on some aspects of cardiovascular disease, but can also be deleterious to other mechanisms
involved in cardiovascular events (Table 2). It seems that, for
this particular system, the dose and timing of estrogen administration may determine the final outcome in relation to disease
development.

5. Estrogen and osteoarthritis

The prevalence of OA is higher among women than men, and
this prevalence increases considerably after menopause. Moreover,
and with the same degree of radiographic damage, OA is also more
symptomatic in women. The dramatic rise in OA prevalence among
postmenopausal women, which is associated with the presence of
estrogen receptors (ERs) in joint tissues [12,14,15], suggests a link
between OA and loss of ovarian function.
Different studies have provided compelling information on the
relevant effects of estrogen deficiency on joint components in
cell culture, animal models and humans. Although much of the
attention has focused on the effects of estrogen on articular cartilage, estrogen deficiency also affects other joint tissues during
the course of OA, such as subchondral bone, synovial lining, periarticular muscles, ligaments and the articular capsule [11] (Table 3).
This association indicates a potential protective role for estrogens
against the development of OA. Indeed, recent in vitro, in vivo,
genetic and clinical studies have shed further light on these issues.
Animal models have shown that OVX can induce joint damage,
and ER" knockout animals develop more and larger osteophytes,
as well as a thinner lateral subchondral plate [45,46]. Furthermore, a lack of estrogens increases subchondral bone remodeling,
and this bone remodeling has been suggested to ultimately induce
osteoarthritis changes [47]. However, results obtained from the
models described above can make the interpretation of some data
difficult, in terms of whether the effect of estrogen deprivation on

Table 3
Effects of estrogen on joint and periarticular structures.
Tissue

Main effects

Cartilage

Increases PG/glycosaminoglycan synthesis

Decreases NF-kB, iNOS, COX-2, ROS
Regulates intracellular calcium concentration
Decreases cartilage damage
Decreases cyclooxigenase-2 mRNA expression
High doses increases PG degradation and
metalloproteinase production

Subchondral bone (SB)

Regulates bone growth and SB remodeling

Controls OB development and function
Regulates matrix production and
mineralization
Reduces bone formation and prevalence of
marginal osteophytes in OVX monkeys
Decreases MRI likelihood of bone attrition in
women

Synovium

Increases synovial levels of components of the

IGF pathway in animals
Reverses autoimmune arthritis development
in mice
Decreases RF, anti-ds-DNA and anti-type II
collagen serum levels in mice

Muscles

Promotes myoblasts proliferation and

differentiation
Decreases muscle cell apoptosis
Reverses muscle contractile dysfunction in rats
Decreases muscle atrophy and calpain levels in
rats
Enhances muscle performance and structure in
women

Ligaments

Contrasting effects on ACL mechanical

properties in animal models
High estrogen levels during menstrual cycle
have been associated with ACL ruptures in
young women

Modified from [11].

ACL: anterior cruciate ligament; COX-2: cyclooxygenase-2; IGF: insulin-like growth
factor; iNOS: inducible nitric oxide synthase; MRI: magnetic resonance imaging;
OB: osteoblasts; OVX: ovariectomized; PG: proteoglycan; RF: rheumatoid factor;
anti-ds-DNA: anti-double-stranded DNA.

joint impairment is due to the absence of the hormone itself, or if

it is due to an indirect effect derived from subchondral bone loss
[48].
For this purpose, the rabbit has been proposed as an appropriate model to perform this kind of study [48]. In this line, some
authors have shown that OVX rabbits did not suffer as much of
a bone mass decline, and have proposed this animal as a model to
study the direct effect of estrogen on cartilage [48,49]. Interestingly,
these authors found mild abnormalities in joint structure, as well
as higher Mankin scores, in a 22-week-old mature OVX rabbits.
These rabbits did not develop significant changes in subchondral
bone mineral density with respect to their controls, indicating that
estrogens have a protective effect on joint cartilage through both
direct and indirect actions [48].
In vitro studies have demonstrated that the direct chondroprotective role of estrogen might be due in part to glycosaminoglycan synthesis, which is an important component of connective
tissue [50]. Estrogen also inhibits cyclooxigenase-2 mRNA expression in bovine articular chondrocytes as well as in other tissues, and
this fact has been related to protection against ROS-induced chondrocyte damage [51,52]. Recent in vitro experiments performed in
chondrocytes suggested that not only estrogens, but also raloxifene
may have a potential chondro-protective role in osteoarthritis [53].
Human chondrocytes cultivated in the presence of interleukin-1
beta (IL-1#) have shown that IL-1# led to a significant decrease
in proteoglycan levels and increased metalloproteinase-3 (MMP3) and NO. On the other hand, when cells were co-incubated

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with raloxifene, a significant and dose-dependent increase in

proteoglycans and a reduction of MMP-3 and NO induced by IL-1#
were detected. Inducible Nitric Oxide Synthase (iNOS) was noticeably expressed in IL-1# stimulated chondrocytes, while raloxifene
decreased in a very significant manner the gene expression of iNOS,
which indicated the protective effect of SERMs on cartilage [53].
In contrast, some authors postulate that estrogen may also have
a deleterious effect on chondrocyte metabolism [54,55]. This statement is based on data found in young OVX rabbits that received
either systemic estrogen replacement [54] or intra-articular estrogen administration [55]. Unexpectedly, those animals exhibited
impairment of the joints. At the cellular level, it has been shown
that high doses of estrogens have an effect on IL1#-stimulated
proteoglycan degradation and metalloproteinase production [56].
Therefore, we can conclude that both high and low levels of estrogen can be deleterious for the normal balance of the joints, and the
final effect depends on the estradiol concentration in the cartilage
microenvironment.
Regarding humans, the available data are also contradictory.
Polymorphisms in the human ER" gene and radiographic knee OA
have been studied in different populations with paradoxical results
[57]. Observational studies, however, have shown the beneficial
effect of estrogen replacement in some kinds of OA, and that estrogen supplementation decreases the severity of the OA, especially at
the hip [58]. In line with these observations, a previous study [59]
reported the prevalence and risk of OA at each site according to
their hormone replacement status. The authors found that for current users there was a threefold significant protective effect of knee
OA as defined by osteophytes, and a twofold non-significant protective effect for the distal interphalangeal joints. No clear effect,
however, was distinguished at the carpometacarpal joint. In contrast, a recent study indicated that, in a dose-dependent manner,
estrogen induces temporo-mandibular joint inflammation via NFkB pathway [60].
While telopeptide of type I collagen accounts about 90% of the
organic matrix of bone, the type II collagen is the major organic
constituent of cartilage. Disruption of the structural integrity of
cartilage is the major histological finding in OA and RA. Following
the degradation of cartilage, fragments of C-terminal crosslinked
telopeptide type II collagen (CTX-II) are being released into circulation and subsequently secreted into urine. Some authors evaluated
urine CTX-II concentrations in healthy men and women between
20 and 87 years old, and the influence of menopause and hormone
replacement therapy (HRT) on their levels. What these authors
found was that CTX-II concentration in postmenopausal women
was higher than in an age-matched group of premenopausal
women, but significantly lower in women using HRT [61]. This data
suggests that this product of collagen degradation can be used as a
biomarker for OA progression in postmenopausal women, and that
HRT protects from collagen damage induced by estrogen deprivation.
All these observations indicate that both the concentration of
estrogen and the cartilage location should be taken into account
in order to understand the dual effect of estrogen on chondrocyte
homeostasis. Moreover, the addition of progestagens to estrogens
in HRT may counteract the beneficial effects on cartilage of estrogens alone [62].

6. Concluding remarks
Since WHI study, the interest for estrogens and HRT in postmenopausal women has dramatically decreased. Nevertheless, and
in spite of the severe side effects of HRT on the endometrium,
breast and cardiovascular system in late posmenopause, there are
no doubts regarding the beneficial effect of estrogens in various

organs, especially in early postmenopausal women. However, several questions regarding the optimal concentration for promoting
positive effects on joint tissues and the appropriate doses and timing of estrogen administration in relation to the course of certain
disorders, should be previously clarified.
At a cellular level, the expression of ERs based on the environment and intracellular metabolism of estrogens are aspects to be
taken into account when assessing the global effect of this hormone. A site-specific estrogen analogue able to trigger the precise
molecular pathway involved in a particular positive effect would be
useful, but until that is available, further clinical and basic studies
are needed.
7. Research agenda
1. To evaluate the optimal dose and timing of estrogen administration to promote a positive effect on joint tissues in particular in
patients with early postmenopausal OA.
2. To determine the efficacy of estrogens in patients with postmenopausal OA, especially in those patients with osteoporosis
associated.
3. To conduct clinical trials aimed to analyze the efficacy of SERMS
in patients with early postmenopausal OA and osteoporosis or
low bone mass phenotype.
4. To evaluate the effects of estrogens or long-term ERT on replacement joint surgery in patients with established postmenopausal
OA.
Disclosure of interest
The authors declare that they have no conflicts of interest concerning this article.
Acknowledgements
We thank Dr. G Herrero-Beaumont and Dr. JA Romn-Blas, from
the Bone and Joint Research Unit, Fundacin Jimnez Daz, Madrid,
Spain, for his critical reading and comments.
References
[1] Pettersson K, Gustafsson JA. Role of estrogen receptor beta in estrogen action.
Annu Rev Physiol 2001;63:16592.
[2] Couse JF, Korach KS. Estrogen receptor null mice: what have we learned and
where will they lead us? Endocr Rev 1999;20:358417.
[3] Cutolo M, Wilder RL. Different roles for androgens and estrogens in the susceptibility to autoimmune rheumatic diseases. Rheum Dis Clin North Am
2000;26:82539.
[4] Straub RH. The complex role of estrogens in inflammation. Endocr Rev
2007;28:52174.
[5] Michet Jr CJ, McKenna CH, Elveback LR, et al. Epidemiology of systemic lupus
erythematosus and other connective tissue diseases in Rochester, Minnesota,
1950 through 1979. Mayo Clin Proc 1985;60:10513.
[6] Srikanth VK, Fryer JL, Zhai G, et al. A meta-analysis of sex differences
prevalence, incidence and severity of osteoarthritis. Osteoarthritis Cartilage
2005;13:76981.
[7] Lawrence RC, Helmick CG, Arnett FC, et al. Estimates of the prevalence of arthritis and selected musculoskeletal disorders in the United States. Arthritis Rheum
1998;41:77899.
[8] Carmona L, Ballina J, Gabriel R, et al. The burden of musculoskeletal diseases
in the general population of Spain: results from a national survey. Ann Rheum
Dis 2001;60:10405.
[9] Menasce LP, White GR, Harrison CJ, et al. Localization of the estrogen receptor
locus (ESR) to chromosome 6q25.1 by FISH and a simple post-FISH banding
technique. Genomics 1993;17:2635.
[10] Enmark E, Pelto-Huikko M, Grandien K, et al. Human estrogen receptor
beta-gene structure, chromosomal localization, and expression pattern. J Clin
Endocrinol Metab 1997;82:425865.
[11] Roman-Blas JA, Castaneda S, Largo R, et al. Osteoarthritis associated with estrogen deficiency. Arthritis Res Ther 2009;11:241.
[12] Ushiyama T, Ueyama H, Inoue K, et al. Expression of genes for estrogen receptors alpha and beta in human articular chondrocytes. Osteoarthritis Cartilage
1999;7:5606.

M. Martn-Milln, S. Casta
neda / Joint Bone Spine 80 (2013) 368373
[13] Braidman IP, Hainey L, Batra G, et al. Localization of estrogen receptor beta
protein expression in adult human bone. J Bone Miner Res 2001;16:21420.
[14] Dietrich W, Haitel A, Holzer G, et al. Estrogen receptor beta is the predominant
estrogen receptor subtype in normal human synovia. J Soc Gynecol Investig
2006;13:5127.
[15] Sciore P, Frank CB, Hart DA. Identification of sex hormone receptors in human
and rabbit ligaments of the knee by reverse transcription-polymerase chain
reaction: evidence that receptors are present in tissue from both male and
female subjects. J Orthop Res 1998;16:60410.
[16] Kahlert S, Grohe C, Karas RH, et al. Effects of estrogen on skeletal myoblast
growth. Biochem Biophys Res Commun 1997;232:3738.
[17] Bord S, Horner A, Beavan S, et al. Estrogen receptors alpha and beta are
differentially expressed in developing human bone. J Clin Endocrinol Metab
2001;86:230914.
[18] Driscoll MD, Sathya G, Muyan M, et al. Sequence requirements for
estrogen receptor binding to estrogen response elements. J Biol Chem
1998;273:2932130.
[19] Pike AC. Lessons learnt from structural studies of the oestrogen receptor. Best
Pract Res Clin Endocrinol Metab 2006;20:114.
[20] Koide A, Zhao C, Naganuma M, et al. Identification of regions within the
F domain of the human estrogen receptor alpha that are important for
modulating transactivation and protein-protein interactions. Mol Endocrinol
2007;21:82942.
[21] Weigel NL, Zhang Y. Ligand-independent activation of steroid hormone receptors. J Mol Med 1998;76:46979.
[22] Britton DJ, Scott GK, Schilling B, et al. A novel serine phosphorylation site
detected in the N-terminal domain of estrogen receptor isolated from human
breast cancer cells. J Am Soc Mass Spectrom 2008;19:72940.
[23] Smith CL. Cross-talk between peptide growth factor and estrogen receptor
signaling pathways. Biol Reprod 1998;58:62732.
[24] Smith EP, Boyd J, Frank GR, et al. Estrogen resistance caused by a mutation in
the estrogen receptor gene in a man. N Engl J Med 1994;331:105661.
[25] Ostensen M. Sex hormones and pregnancy in rheumatoid arthritis and systemic
lupus erythematosus. Ann N Y Acad Sci 1999;876:13143.
[26] Cutolo M, Straub RH, Bijlsma JW. Neuroendocrine-immune interactions in synovitis. Nat Clin Pract Rheumatol 2007;3:62734.
[27] Silman A, Kay A, Brennan P. Timing of pregnancy in relation to the onset of
rheumatoid arthritis. Arthritis Rheum 1992;35:1525.
[28] Romagnani S. Regulation of the T cell response. Clin Exp Allergy
2006;36:135766.
[29] Doria A, Iaccarino L, Arienti S, et al. Th2 immune deviation induced by pregnancy: the two faces of autoimmune rheumatic diseases. Reprod Toxicol
2006;22:23441.
[30] Castagnetta LA, Carruba G, Granata OM, et al. Increased estrogen formation and
estrogen to androgen ratio in the synovial fluid of patients with rheumatoid
arthritis. J Rheumatol 2003;30:2597605.
[31] Cutolo M, Villaggio B, Seriolo B, et al. Synovial fluid estrogens in rheumatoid
arthritis. Autoimmun Rev 2004;3:1938.
[32] Stampfer MJ, Colditz GA. Estrogen replacement therapy and coronary heart
disease: a quantitative assessment of the epidemiologic evidence. Prev Med
1991;20:4763.
[33] Grady D, Rubin SM, Petitti DB, et al. Hormone therapy to prevent disease and
prolong life in postmenopausal women. Ann Intern Med 1992;117:101637.
[34] Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results
from the Womens Health Initiative randomized controlled trial. JAMA
2002;288:32133.
[35] Grady D, Applegate W, Bush T, et al. Heart and Estrogen/progestin Replacement
Study (HERS): design, methods, and baseline characteristics. Control Clin Trials
1998;19:31435.
[36] Mendelsohn ME, Karas RH. The protective effects of estrogen on the cardiovascular system. N Engl J Med 1999;340:180111.
[37] Blankenberg S, Barbaux S, Tiret L. Adhesion molecules and atherosclerosis.
Atherosclerosis 2003;170:191203.
[38] Almeida M, Han L, Martin-Millan M, et al. Skeletal involution by age-associated
oxidative stress and its acceleration by loss of sex steroids. J Biol Chem
2007;282:2728597.
[39] Almeida M, Han L, Ambrogini E, et al. Oxidative stress stimulates apoptosis and activates NF- kappaB in osteoblastic cells via a PKCbeta/p66shc

[40]

[41]

[42]

[43]
[44]

[45]
[46]

[47]

[48]

[49]
[50]

[51]

[52]
[53]

[54]
[55]
[56]

[57]

[58]

[59]

[60]

[61]

[62]

373

signaling cascade: counter regulation by estrogens or androgens. Mol

Endocrinol 2010;24:20307.
Kramer PR, Kramer SF, Guan G. 17 beta-estradiol regulates cytokine release
through modulation of CD16 expression in monocytes and monocyte-derived
macrophages. Arthritis Rheum 2004;50:196775.
Corcoran MP, Meydani M, Lichtenstein AH, et al. Sex hormone modulation of
pro-inflammatory cytokine and C-reactive protein expression in macrophages
from older men and postmenopausal women. J Endocrinol 2010;206:21724.
Karim R, Stanczyk FZ, Hodis HN, et al. Associations between markers of
inflammation and physiological and pharmacological levels of circulating sex
hormones in postmenopausal women. Menopause 2010;17:78590.
Kim KH, Bender JR. Membrane-initiated actions of estrogen on the endothelium. Mol Cell Endocrinol 2009;308:38.
Florian M, Florianova L, Hussain S, et al. Interaction of estrogen and tumor
necrosis factor alpha in endothelial cell migration and early stage of angiogenesis. Endothelium 2008;15:26575.
Ma HL, Blanchet TJ, Peluso D, et al. Osteoarthritis severity is sex dependent in
a surgical mouse model. Osteoarthritis Cartilage 2007;15:695700.
Sniekers YH, van Osch GJ, Ederveen AG, et al. Development of osteoarthritic
features in estrogen receptor knockout mice. Osteoarthritis Cartilage
2009;17:135661.
Bellido M, Lugo L, Roman-Blas JA, et al. Subchondral bone microstructural damage by increased remodelling aggravates experimental osteoarthritis preceded
by osteoporosis. Arthritis Res Ther 2010;12:R152.
Castaneda S, Largo R, Calvo E, et al. Effects of estrogen deficiency and low
bone mineral density on healthy knee cartilage in rabbits. J Orthop Res
2010;28:8128.
Castaneda S, Calvo E, Largo R, et al. Characterization of a new experimental
model of osteoporosis in rabbits. J Bone Miner Metab 2008;26:539.
Oestergaard S, Sondergaard BC, Hoegh-Andersen P, et al. Effects of ovariectomy
and estrogen therapy on type II collagen degradation and structural integrity of
articular cartilage in rats: implications of the time of initiation. Arthritis Rheum
2006;54:244151.
Morisset S, Patry C, Lora M, et al. Regulation of cyclooxygenase-2 expression in bovine chondrocytes in culture by interleukin 1alpha, tumor necrosis
factor alpha, glucocorticoids, and 17beta-estradiol. J Rheumatol 1998;25:
114653.
Claassen H, Schunke M, Kurz B. Estradiol protects cultured articular chondrocytes from oxygen-radical-induced damage. Cell Tissue Res 2005;319:43945.
Tinti L, Niccolini S, Lamboglia A, et al. Raloxifene protects cultured human chondrocytes from IL-1beta-induced damage: a biochemical and morphological
study. Eur J Pharmacol 2011;670:6773.
Rosner IA, Goldberg VM, Getzy L, et al. Effects of estrogen on cartilage and
experimentally induced osteoarthritis. Arthritis Rheum 1979;22:528.
Tsai CL, Liu TK. Estradiol-induced knee osteoarthrosis in ovariectomized
rabbits. Clin Orthop Relat Res 1993:295302.
Richette P, Dumontier MF, Francois M, et al. Dual effects of 17beta-oestradiol
on interleukin 1beta-induced proteoglycan degradation in chondrocytes. Ann
Rheum Dis 2004;63:1919.
Riancho JA, Garcia-Ibarbia C, Gravani A, et al. Common variations in
estrogen-related genes are associated with severe large-joint osteoarthritis: a multicenter genetic and functional study. Osteoarthritis Cartilage
2010;18:92733.
Cirillo DJ, Wallace RB, Wu L, et al. Effect of hormone therapy on risk of hip
and knee joint replacement in the Womens Health Initiative. Arthritis Rheum
2006;54:3194204.
Spector TD, Nandra D, Hart DJ, et al. Is hormone replacement therapy protective
for hand and knee osteoarthritis in women?: the Chingford Study. Ann Rheum
Dis 1997;56:4324.
Kou XX, Wu YW, Ding Y, et al. 17beta-estradiol aggravates temporo-mandibular
joint inflammation through the NF-kappaB pathway in ovariectomized rats.
Arthritis Rheum 2011;63:188897.
Garnero P, Conrozier T, Christgau S, et al. Urinary type II collagen C-telopeptide
levels are increased in patients with rapidly destructive hip osteoarthritis. Ann
Rheum Dis 2003;62:93943.
Nevitt MC, Felson DT, Williams EN, et al. The effect of estrogen plus progestin
on knee symptoms and related disability in postmenopausal women: The
Heart and Estrogen/Progestin Replacement Study, a randomized, double-blind,
placebo-controlled trial. Arthritis Rheum 2001;44:8118.