Osteoarthritis associated with estrogen deficiency.

ERT has displayed mixed effects on joint tissues in various animal and human studies while SERMS conversely have demonstrated a homogeneous response in these tissues (a general description of the effects of SERMs on different tissues is presented in Table 1 ). Partial list of selective estrogen receptor modulators and selective estrogen receptor ligands in clinical development *Products currently on the market. Levormeloxifen, a discontinued selective estrogen receptor modulator, also showed beneficial effects on cartilage in an animal model. BMD, bone mineral density; ER, estrogen receptor; OP, osteoporosis. Estrogen administration in OVX animals has paradoxical effects on joint cartilage, in contrast to the clear benefits of SERM administration [ 24 ]. While intra-articular E 2 injections [ 103 ] and high supraphysiological estrogen concentrations [ 104 ] caused deleterious effects on joint cartilage in a dose-and time-dependent fashion, the beneficial effects of long-term estrogen treatment have been seen in different models [ 24 , 25 , 99 ]. Early estrogen administration maximizes its positive effects on cartilage [ 16 ] and, in turn, tamoxifen decreases cartilage damage in a rabbit model of OA, even in males [ 105 ]. Furthermore, tamoxifen antagonized the chondro-destructive effects of high dose intra-articular E 2 during early knee OA in rabbits [ 106 ]. Also, NNC 45-0781 and levormeloxifen both inhibited the OVX-induced acceleration of cartilage and bone turnover, and they significantly suppressed cartilage damage in female Sprague-Dawley rats [ 24 , 107 ]. In subchondral bone, the effects of long-term ERT have only recently begun to be studied. ERT limits bone formation in both subchondral bone and epiphyseal/metaphyseal cancellous bone of the proximal tibia in OVX cynomolgus monkeys [ 27 ]. ERT also reduces the prevalence of marginal osteophytes, particularly in the lateral tibial plateau, while the presence of axial osteophytes is not affected. However, neither the cross-sectional area in osteophytes nor its static and dynamic histomorphometric parameters are significantly influenced by ERT [ 28 , 108 ]. In addition, a significant effect of ERT has been described on several components of the IGF system in the synovial fluid of OVX female adult cynomolgus monkeys, suggesting a potential stimulatory effect of estrogen on joint tissues in vivo [ 109 ]. In turn, estrogen administration reversed OVX-induced contractile muscle and myosin dysfunction, as well as the OVX-induced increase of muscle wet mass in mature female mice caused by fluid accumulation [ 110 ]. The effect of ERT on the risk of developing OA and on its progression in postmenopausal women remains unclear. Unlike observational clinical studies, some radiographic studies have suggested a protective effect of ERT on the radiographic detection of OA or its progression [ 111 - 115 ]. In a cross-sectional study, ERT significantly reduced the risk of radiographic hip OA, particularly in long-term users [ 111 ]. Similarly, an initial cross-sectional analysis of two of the largest studies found an inverse association between ERT use and radiological knee OA, suggesting that ERT may have a chondroprotective effect. However, a subsequent follow-up analysis failed to show significant ERT protection against either the development or progression of radiographic knee OA [ 112 - 115 ]. Additionally, contradictory results were described regarding the association between ERT and the requirement for arthroplasty [ 116 ]. Nevertheless, in the largest study, females that received estrogen alone had significantly fewer arthroplasties, particularly in the hip. Thus, unopposed estrogen administration might have a protective effect against the risk of joint replacement, an effect that may be particularly relevant in hip compared to knee OA [ 117 ]. Magnetic resonance imaging-estimated subchondral bone attrition and bone-marrow abnormalities associated with cartilage degradation in knee OA was delayed or prevented by ERT or alendronate in postmenopausal women [ 118 ]. In turn, ERT may preserve muscle performance. A 12-month trial showed that ERT protects against the detrimental effects of estrogen deficiency on skeletal muscle in early postmenopausal women, thereby positively influencing muscle performance and structure. Moreover, high-impact physical training provided additional benefits [ 119 ]. Recently, novel ER ligands, both pathway-selective and ERβ-selective, have been developed due to the potent anti-inflammatory activity they have been attributed [ 120 , 121 ] (Table 1 ). Indeed, the pathway-selective ER ligands WAY-169916 and WAY-204688 inhibit NF-κB transcriptional activity in the absence of conventional estrogenic activity in different animal models of inflammatory diseases [ 122 , 123 ]. The suppressive effects of estrogen on inflammatory mediators, including NF-κB, inducible nitric oxide synthase, cyclooxygenase-2, and reactive oxygen species in articular chondrocytes [ 17 , 18 , 80 ], in association with other selective estrogenic benefits on joint tissues might reflect their potential utility in OA treatment.

The authors declare that they have no competing interests.

Progressive structural and functional changes on articular structures commence at early menopause and persist post-menopause, leading to an increase in the prevalence of OA in the latter population and representing a big impact on health costs worldwide. Both experimental and observational evidence support a relevant role for estrogens in the homeostasis of joint tissues and, hence, in the health status of joints. Indeed, estrogens influence their metabolism at many crucial levels and through several complex molecular mechanisms. These effects of estrogens at joints are either significantly dampened or lost as a result of postmenopausal ovary insufficiency. A better understanding of the role that estrogen and its deficiency plays in the molecular mechanisms of menopause-induced osteoarthritic changes that affect the different joint structures will help further development of new and precise therapeutic strategies to prevent and/or restore damaged articular tissues in OA. These improved therapeutic approaches must be devoid of the widely known undesirable effects of estrogens in other target tissues. Thus, in OA, which represents a particularly challenging disease due to its effects upon different joint structures, these therapeutic options should target the joint as a whole organ rather than focusing only on cartilage damage.

Estrogen influences the biology of joint tissues by regulating the activity and expression of key signaling molecules in several distinct pathways (Figure 3 ). Intracellular signaling pathways used to regulate the activity of estrogens, estrogen receptors, and selective estrogen receptor modulators on articular tissues . Pathway 1: canonical estrogen signaling pathway (estrogen response element (ERE)-dependent) - ligand-activated estrogen receptors (ERs) bind specifically to EREs in the promoter of target genes. Pathway 2: non-ERE estrogen signaling pathway - ligand-bound ERs interact with other transcription factors, such as activator protein (AP)-1, NF-κB and Sp1, forming complexes that mediate the transcription of genes whose promoters do not harbor EREs. Co-regulator molecules regulate the activity of the transcriptional complexes. Pathway 3: non-genomic estrogen signaling pathways - ERs and GP30 localized at or near the cell membrane might elicit the rapid response by activating the phosphatidylinositol-3/Akt (PI3K/Akt) and/or protein kinase C/mitogen activated protein kinase (PKC/MAPK) signal transduction pathways. Pathway 4: ligand-independent pathways - ERs can be stimulated by growth factors such as insulin-like growth factor (IGF)-1, transforming growth factor-β/mothers against decapentaplegic (TGF-β/SMAD), epidermal growth factor (EGF) and the Wnt/β-catenin signaling pathway in the absence of ligands, either by direct interaction or by MAP and PI3/Akt kinase-mediated phosphorylation. Since members of these signaling pathways are transcription factors, some of them, such as SMADs 3/4, can elicit estrogen responses by interacting with ER in the non-ERE-dependent genomic pathway. ERK, extracellular signal regulated kinase; GF, growth factor; GFR, growth factor receptor; MNAR, Modulator of nongenomic action of estrogen receptors; TF, transcription factor. Estrogen primarily exerts its effects on target tissues by binding to and activating ERs. ERs act as ligand-activated transcription factors in the nucleus that specifically bind to estrogen response elements (EREs) in the promoters of target genes such as the human oxytocin, prolactin, cathepsin D, progesterone receptor, vascular endothelial growth factor, insulin-like growth factor (IGF)-1, or c-fos genes [ 61 ], as diagrammatically shown in Figure 3 (pathway 1). The ERE is a 13 base-pair inverted sequence that binds ERs as dimers. Because imperfect palindromic EREs, or even half EREs, are often seen in the regulatory region of estrogen target genes, transcriptional synergism might occur that could include the co-operative recruitment of co-activators, direct interaction between ER dimers, or allosteric modulation of the DNA-ER complexes [ 62 ]. ERs contain four functional domains. The variable amino-terminal A/B domain harbors the constitutive activation function (AF)-1, which modulates transcription in a gene- and cell-specific manner. The central and most conserved C domain contains the DNA binding domain, and it also mediates receptor dimerization. The D domain is a less well understood region. Finally, the carboxy-terminal multifunctional E/F domain holds the ligand-binding domain as well as sites for cofactors, transcriptional activation (AF-2) and nuclear localization (Figure 4 ) [ 63 ]. There are two receptor subtypes, ERα and ERβ, which are different proteins encoded by distinct genes located on chromosomes 6 (q24-q27) and 14 (q21-q22), respectively [ 64 ]. These two receptor subtypes have 96% amino acid homology in the DNA binding domain but only 53% identity in the ligand-binding domain. As a result, similar ERE binding properties have been associated with a partially distinct spectrum of ligands for each receptor, although with similar affinities for estrogen. Even weaker amino acid identity is found in the A/B domain of ERα and ERβ (Figure 4 ). Both receptors also show little conservation in AF-2 and, therefore, several proteins may direct ERα and ERβ to different targets as observed in their contrasting effects at the activator protein (AP)-1 site of the collagenase promoter. Thus, ERα and ERβ have different transcriptional activities that may contribute to their distinct tissue-specific actions [ 63 , 65 ]. Structural composition of estrogen receptor (ER)α and ERβ . Both receptors have four functional domains that harbor a DNA-binding domain (DBD), a ligand-binding domain (LBD) and two transcriptional activation functions (AF-1 and AF-2), as indicated for ERβ. The percent of homology in these domains between ERα and ERβ is indicated, as well as the location of several phosphorylation sites in ERα whereby this receptor is activated by important kinases that modulate a wide variety of cellular events. aa, amino acids; Akt, serine/threonine specific-protein kinase family encoded by the Akt genes; CDK2, cyclin-dependent kinase 2; MAPK, mitogen activated protein kinase; PKA, protein kinase A; Src: steroid receptor coactivator. Both ERs are distributed widely throughout the body, displaying distinct but overlapping expression in a variety of tissues. ERα is highly expressed in classical estrogen target tissues such as the uterus, placenta, pituitary and cardiovascular system, whereas ERβ is more abundant in the ventral prostate, urogenital tract, ovarian follicles, lung, and immune system. However, the two ERs are co-expressed in tissues such as the mammary gland, bone, and certain regions of the brain [ 66 ]. Although both ER subtypes can be expressed in the same tissue, they may not be expressed in the same cell type. Nonetheless, in cells where the two ER subtypes are co-expressed, ERβ can antagonize ERα-dependent transcription [ 64 ]. The generation of human ERα and ERβ mRNA transcripts is a complex process that is controlled by sophisticated regulatory mechanisms leading to the generation of several isoforms/variants for each receptor subtype. Most ERα variants only differ at the 5' untranslated region and they are involved in tissue-specific regulation of ERα gene expression. Several species-specific and common ERβ isoforms have been described, many of which are expressed as proteins in tissues [ 67 ]. In articular tissues, both ER types are expressed by the chondrocytes [ 10 ], subchondral bone cells [ 11 ], synoviocytes [ 12 ], ligament fibroblasts [ 13 ] and myoblasts [ 14 ] in humans and other species. However, ERα is predominant in cortical bone and ERβ predominates in cartilage, cancellous bone and synovium [ 10 , 12 , 68 ]. More mRNA transcripts for both subtypes of ERs were found in male than in female human cartilage, but there were no differences between different joints, or between cartilage from OA patients and the normal population [ 10 ]. In bone, ERα and ERβ are expressed by OBs and they are differentially expressed during rat OB maturation [ 69 ]. Pre-osteoclasts express ERα, while osteoclast maturation and bone resorption is associated with the loss of ERα expression [ 70 ]. ERβ mRNA and protein are predominantly found in the stroma and lining cells of normal human synovium, independent of sex or menopausal status of the tissue donor [ 12 ]. Fibroblasts from human ACL, medial cruciate ligament and patellar tendon express functional ER transcripts. Indeed, 4 to 10% of ACL cells express ERs in patients with acute ACL injuries, approximately twice the proportion found in control subjects [ 13 , 71 ]. In human skeletal muscle, ERα mRNA expression was 180-fold higher than that of ERβ [ 72 ]. Remarkably, individuals that undergo high endurance training have more ERα and ERβ mRNA transcripts in skeletal muscles than moderately active individuals [ 73 ]. Characterizing the phenotypes of knockout models has advanced our understanding of the role of ER in biological processes. Indeed, ERβ plays a significant role in bone remodeling in female ER knockout mice, whereas ERα does so in both sexes. Thus, male and female ERα -/- mice show decreased bone turnover and greater cancellous bone volume, even though the cortical thickness and BMD was reduced. Female ERβ -/- mice have slightly increased trabecular bone volume, while male animals do not show any change in their bones. Male and female double ER -/- mice showed significant defects in cortical bone and BMD, while female mice alone displayed a profound decrease in trabecular bone volume [ 74 ]. A recent study has shown that ERα -/- β -/- double knockout increased osteophytosis and thinning of the lateral subchondral plate, both osteoarthritic characteristics, in the knee of transgenic mice [ 75 ]. These results confirm the relevant changes described in subchondral bone of OVX animal models [ 27 - 29 ]. However, no difference in cartilage damage was observed between the ERα -/- , ERβ -/- and ERα -/- β -/- double knockout and wild-type mice at 6 months of age, although the cartilage damage was very mild in all mice [ 75 ]. Whether the absence of significant cartilage damage in all ER knockout mice groups reflects some important differences between ER knockout mice, which lack ER expression since birth, and OVX models that show significant OA cartilage changes associated with estrogen depletion at a later age [ 7 , 24 - 26 ] remains to be established. As regards muscle, ERα -/- mice have lower tetanic tension per calculated anatomical cross-sectional and fiber areas in tibialis anterior and gastrocnemius than in wild-type mice. In contrast, ERβ -/- and wild-type mice were comparable in all measures. These results suggest that the effects of estrogen on skeletal muscle are mainly mediated by ERα [ 76 ]. With respect to ligaments, no changes in medial cruciate ligament or ACL viscoelastic or tensile mechanical properties were observed in ERβ -/- mice [ 77 ]. The second genomic mechanism involves the interaction of ligand-bound ERs with other transcription factors like Fos/Jun (AP-1-responsive elements), c-Jun/NF-κB and specificity protein 1 (Sp1) recruiting co-regulators to form initiation complexes that regulate the transcription of genes whose promoters do not harbor EREs [ 64 , 78 ]. In this tethering mechanism, ERs do not bind directly to DNA (Figure 3 , mechanism 2) and, thus, ERs can up-regulate the expression of promoters containing AP-1 sites, such as the collagenase and IGF-1 genes. Interestingly, E 2 exerts distinct transcriptional activation on the AP-1 site of the collagenase promoter depending on whether ERα or ERβ is involved: it elicits transcriptional activation with ERα, while it represses transcription with ERβ [ 65 , 78 ]. The interaction of ERs with Sp1 activates uteroglobin, retinoic acid receptor alpha, IGF-binding protein 4 (IGFBP4), TGF-α, bcl2 and the low-density lipoprotein receptor genes [ 61 , 78 ]. Similarly, suppression of IL-6 expression by E 2 occurs through interactions of the ligand bound ER with the NF-κB complex [ 64 ]. Ligand-dependent activation of ERs, both ERE and non-ERE-mediated, attracts co-regulator molecules that modify the chromatin state, thereby recruiting or hindering the transcriptional complex and representing another level of control in ER gene regulation [ 61 , 63 , 79 ]. Co-activators stimulate transcription by interacting with helix 12 (H12) of the AF-2 region through their short 'nuclear receptor boxes', transducing ligand signals to the basal transcriptional machinery. The best characterized co-activators include the steroid receptor co-activator (SRC) family (SRC1, SRC2 and SRC3) and members of the mammalian mediator complex (thyroid receptor associated proteins, vitamin-D receptor interacting proteins, activator-recruited cofactor) [ 63 , 79 ]. Alternatively, co-repressors that impede transcription include the nuclear receptor co-repressor (NCoR) and the silencing mediator for the retinoic acid and thyroid hormone receptor (SMRT), which interact with ligand-free ER through an elongated amino acid sequence called the CoRNR-box. By contrast, if H12 assumes a 'charge clamp' configuration in response to agonist binding, then it could not hold the long NCoR/SMRT helices. Thus, agonist binding reduces the affinity of ERs for co-repressors and increases their affinity for co-activators [ 63 , 79 ]. In addition, both SMRT and NCoR recruit the protein SIN3 and histone deacetylases to form a large co-repressor complex, implicating histone deacetylation in transcriptional repression [ 79 ]. In rabbit articular chondrocytes, ERα activation inhibits NF-κB p65 activity and, subsequently, decreases IL-1β-stimulated inducible nitric oxide synthase expression and nitric oxide production [ 80 ]. Moreover, ERα and, particularly, ERβ transfection significantly enhances MMP-13 promoter activity through an AP-1 site, which may be modulated through the sites of the Runt-related (Runx) and PEA-3 Ets transcription factors in a rabbit synovial cell line lacking endogenous ER [ 81 ]. A normal balance between classic ERE-mediated and non-ERE-mediated ERα, genomic and non-genomic, pathways in cortical bone have also been described in ERα -/NERKI mice and its disruption can lead to an aberrant response to estrogen [ 82 ]. Estrogens may also exert their ligand-dependent effects through non-genomic mechanisms that are responsible for more rapid effects, occurring within seconds or minutes of stimulating cell signal transduction pathways, such as the mitogen activated protein (MAP) kinases, in particular the extracellular signal regulated kinase 1/2 (ERK 1/2), p38 and phosphatidylinositol-3 (PI3) kinase/Akt pathways [ 64 ]. A small ER population and/or a G-protein-coupled receptor termed GP30, localized at or close to the cell membrane, may elicit these responses [ 83 , 84 ]. ER translocation to the cell membrane is nourished by its interaction with membrane proteins such as caveolin 1/2, striatin and the adaptor proteins Shc and p130 Cas [ 64 ]. S-palmitoylation and myristoylation of ERα also promote ERα association with the plasma membrane and its interaction with caveolin-1 [ 64 ]. Furthermore, interaction between ER, the tyrosine kinase cSrc and an adaptor protein called modulator of nongenomic action of estrogen receptors (MNAR) generates a signaling complex that may be crucial for the important cSrc activation and further kinase phosphorylation [ 85 ]. Thus, several molecular processes have been shown to mediate the non-genomic effects of ER (Figure 3 , pathway 3). However, the precise mechanisms involved in ER localization in the cell membrane, as well as the interaction between ERs and signaling pathways, are yet to be fully established. There appears to be sexual dimorphism in the non-genomic pathways described in human articular and rat growth plate chondrocytes. Thus, only female cells respond to estrogens by promoting a rapid protein kinase C (PKC)-α-mediated increase in proteoglycan production and alkaline phospha-tase activity (PKC increase occurred within 9 minutes and was maximal at 90 minutes). Treatment with the PKC inhibitor chelerythrine blocked these effects [ 86 , 87 ]. PKC activation initiated a signaling cascade involving the ERK1/2 and p38 MAP kinase pathways, which in turn mediate the downstream biological effects of estrogen on alkaline phosphatase activity and [(35)S]-sulfate incorporation in rat growth plate chondrocytes. A membrane receptor has been proposed to elicit this response, although its precise nature remains to be established [ 88 ]. Estrogen also regulates intracellular calcium concentrations ([Ca 2+ ] i ) in a sex-specific and cell maturation state-dependent manner in rat growth plate chondrocytes. Indeed, E 2 more rapidly increased [Ca 2+ ] i in resting zone chondrocytes than in growth-zone chondrocytes from female rats, while no effect was observed in chondrocytes from male rats. This effect is mediated by membrane-associated events, phospholipase C-dependent inositol triphosphate-3 production and Ca 2+ release from the endoplasmic reticulum [ 89 ]. In the light of the higher prevalence of OA in postmenopausal females, it has been proposed that these intrinsic sex-specific differences may contribute to OA development [ 86 ]. In addition, inclusion of the gender variable when interpreting experimental data and the functional adaptation of donor cells in transplants between organisms of different sexes should be considered [ 86 ]. Both ERK phosphorylation kinetics and the duration of phospho-ERK nuclear retention determine the pro- or anti-apoptotic effects of estrogen in bone cells. In fact, E 2 -induced transient ERK phosphorylation (lasting 30 minutes) leads to anti-apoptotic effects in OBs and osteocytes, whereas it produces pro-apoptotic signals in osteoclasts through sustained ERK phosphorylation (for at least 24 hours) [ 90 ]. Also, the ERK 1/2 and PI3K/Akt/Bad pathways mediate the anti-apoptotic effect of estrogens in C2C12 muscle cells following activation of ERα and ERβ located in diverse cellular compartments such as the mitochondria and perinucleus [ 91 ]. Divergent ER-induced gene expression has been found depending on whether the genomic or non-genomic signaling pathways are activated in different cell types. In osteoblastic OB-6 cells, E 2 stimulated complement 3 (C3) and IGF-1 expression after 24 hours, which did not occur following estren administration. This discrepancy is explained by the ERE present in the promoter of the C3 gene and by ER regulating IGF-1 through a protein-protein interaction that influences the AP-1 enhancer. Since estren is a non-genotropic ER activator, it did not activate these ERE-or AP-1-containing genes [ 92 ]. The stimulation of growth factors such as those of the IGF-1, epidermal growth factor, TGF-β/SMAD and Wnt/β-catenin signaling pathways can activate ERs or associated co-regulators via kinase phosphorylation in the absence of ER ligands [ 64 , 93 - 95 ]. In turn, ERα may also regulate growth factor signaling [ 64 , 93 - 95 ]. Crosstalk between growth factors and ERs occurs in both the nuclear and cytoplasmic compartments, promoting highly active interactions [ 64 , 93 - 95 ] (Figure 3 , pathway 4). In OBs, estrogen and TGF-β/SMAD signaling pathways may interact at several levels: activation of the TGF-β pathway by estrogens via TGF-β mRNA induction; increase of estrogen and TGF-β/SMAD signaling due to cytoplasmic MAP kinase activity; direct interaction between ERs and the SMAD proteins in the cytoplasm or nucleus; and interaction between ERs and the TGF-β-inducible early-response gene ( TIEG ) and Runx-2 transcription factors in the nucleus. Both TIEG and Runx-2 expression are induced by E 2 and TGF-β and, furthermore, TIEG appears to be required for the E 2 and TGF-β-induced regulation of Runx2 expression [ 95 ]. Thus, a relevant inhibition of osteoclastic bone resorption by osteocytes occurs as a result of TGF-β enhancement by estrogen [ 96 ]. ERs can interact with members of the Wnt/β-catenin signaling system in both the presence and absence of the ligand [ 97 ]. Bone response to mechanical forces can be influenced by interactions between the β-catenin and T-cell factor nuclear complex, and ERα in OBs. Indeed, ER modulators suppressed the accumulation of active β-catenin in the nucleus of OBs in vitro within 3 hours following a single period of dynamic strain of magnitude similar to the estimated strain that OBs regularly experience in vivo . Accordingly, microarray analysis performed with RNA extracted from the tibia of ERα -/- mice demonstrated the abrogation of dynamic axial loading-induced expression of Wnt-responsive genes (compared with RNA from the tibia of wild-type mice) [ 98 ]. These results suggest that ERα is required for early Wnt/β-catenin-induced bone cell responses to mechanical strain. Indeed, the reduced effectiveness of the bone cell responses to mechanical load associated with estrogen deficiency may alter the bone mass in postmenopausal OP women. In cynomolgus monkey joint cartilage, IGFBP2-mediated activation of the IGF system induces IGF-1 production, which in turn leads to increased sulfate incorporation into proteoglycans following estrogen administration [ 99 ]. In addition, ERs might interact with the TGF-β and Wnt/β-catenin signaling cascades in articular chondrocytes. Both the Wnt/β-catenin and TGF-β/SMAD signaling pathways play a prominent role in bone and cartilage biology. The TGF-β/SMAD pathway fulfils a beneficial role in bone and cartilage maintenance/repair, although it is also an important protagonist of osteophyte formation [ 95 , 100 ]. In turn, the Wnt/β-catenin system is essential in many biological aspects of bone, from differentiation, proliferation and cellular apoptosis to bone mass regulation and its ability to respond to mechanical load [ 101 ]. Activation of the Wnt/β-catenin pathway has also been implicated in OA cartilage damage, and Wnt inhibitors such as the secreted frizzled related protein 3 and Dickkopf-1 might modulate the susceptibility to, and the progress of, hip OA [ 102 ]. Although our understanding of the different molecular mechanisms by which estrogen deficits could act on articular tissues and their contribution to OA development has advanced significantly in recent years, it is still limited and more research will be necessary to identify therapeutic targets for this very prevalent disease.

Osteoarthritis (OA) is a very common chronic disease that affects all joint tissues, causing progressive irreversible damage and, finally, the failure of the joint as an organ [ 1 ]. Characteristic pathological changes in OA not only include joint cartilage degeneration but also subchondral bone thickening, osteophyte formation and synovial inflammation, all of which are associated with capsule laxitude and decreased muscle strength [ 1 , 2 ]. The pathological changes that occur in OA are the result of the action of biomechanical forces coupled with multiple autocrine, paracrine and endocrine cellular events that lead to a breakdown of the normal balance in tissue turnover within the joint [ 3 , 4 ]. Among the multiple physiopathological mechanisms involved in OA, those related to sex hormone control have been attracting much attention, in particular those involving estrogens [ 5 ]. In contrast to other tissues such as the endometrium, breast, brain and non-joint bone, it was traditionally thought that joint tissues were non-responsive to estrogens and estrogen deficit. However, interest in estrogens was stimulated by the large proportion of postmenopausal women with OA and the complexity of their role in this disease. Indeed, considerable efforts have been made to understand the potential role of estrogens in the biology of joint tissues, as well as in the development and progression of OA, which has led to a better understanding of the effects of estrogen on joint tissues and on cartilage in particular [ 5 - 7 ]. There is increasing evidence that estrogens fulfill a relevant role in maintaining the homeostasis of articular tissues and, hence, of the joint itself. The dramatic rise in OA prevalence among postmenopausal women [ 8 , 9 ], which is associated with the presence of estrogen receptors (ERs) in joint tissues [ 10 - 14 ], suggests a link between OA and loss of ovarian function. 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. This review is based on a literature search of peer-reviewed articles written in English in the Medline and PubMed databases from 1952 to April 2009 carried out using the keywords estrogen, menopause, estrogen replacement therapy (ERT) and selective estrogen receptor modulators (SERMs) alone or in various combinations with joint, cartilage, subchondral bone, synovium, ligaments, muscle, tendons, OA and osteoporosis (OP). Accordingly, it addresses the effect of estrogen deficit on all joint tissues and the dual action of estrogen deficit on the association of OP and cartilage damage. In addition, we emphasize the relevance of these effects in the onset and/or progression of OA as well as summarizing our current knowledge on how estrogen regulates the metabolism of joint tissues. Finally, we examine the effects of ERT and current SERMs in OA, as well as the development of new specific estrogen ligands as potential therapeutic strategies to treat this disease.

ACL: anterior cruciate ligament; AF: activation function; AP: activator protein; BMD: bone mineral density; E 2 : 17β-estradiol; ER: estrogen receptor; ERE: estrogen response element; ERK: extracellular signal regulated kinase; ERT: estrogen replacement therapy; IGF: insulin-like growth factor; IGFBP: IGF-binding protein; IL: interleukin; MAP: mitogen activated protein; MMP: matrix metalloproteinase; NCoR: nuclear receptor co-repressor; NF: nuclear factor; OA: osteoarthritis; OB: osteoblast; OP: osteoporosis; OVX: ovariectomized; PI3: phosphatidylinositol-3; PKC: protein kinase C; SERM: selective estrogen receptor modulators; SMAD: mothers against decapentaplegic; SMRT: silencing mediator for the retinoic acid and thyroid hormone receptor; Sp: specificity protein; TGF: transforming growth factor; TNF: tumor necrosis factor.