Estrogens, cartilage, and osteoarthritis

Joint Bone Spine 70 (2003) 257–262 www.elsevier.com/locate/bonsoi

Review

Estrogens, cartilage, and osteoarthritis Pascal Richette a,b,*, Maïté Corvol b, Thomas Bardin a b

a Rheumatology Federation, Lariboisière Teaching Hospital, 2, rue Ambroise Paré, 75010 Paris, France Inserm U 530, St Pères School of Medicine, Biomedical UFR 4th floor, sector P, 45, rue des St Pères, 75270 Paris cedex 6, France

Received 19 March 2002; accepted 26 August 2002

Abstract A role for estrogens in osteoarthritis is consistent with the larger increases in women than in men in the incidence and prevalence of hip, knee, and finger osteoarthritis after 50 years of age. Furthermore, hormone replacement therapy for the menopause seems to be associated with a decrease in the prevalence of symptoms and radiological alterations related to hip and knee osteoarthritis. The two estrogen receptors alpha and beta (ERa and Erb) have been identified in normal and osteoarthritic cartilage, indicating that cartilage can respond to estrogens. Finally, in vivo experiments in animals and in vitro studies have shed light on the mechanisms by which estrogens may influence chondrocyte metabolism. © 2003 Éditions scientifiques et médicales Elsevier SAS. All rights reserved. Keywords: Cartilage; Osteoarthritis; Estrogens; Estrogen receptors; Hormone replacement therapy

1. Introduction That estrogens may play a role in osteoarthritis was first suggested over three-quarters of a century ago, by Cecil and Archer [1], who described “arthritis of the menopause” as rapid development of hand and knee osteoarthritis coinciding with cessation of menses. Epidemiological observations provided support for a link between estrogen deprivation and osteoarthritis development by showing that the age-related increases in the incidence and prevalence of hip, knee, and finger osteoarthritis were larger in men than in women before 50 years of age but subsequently became larger in women. This gender difference widened with advancing age [2–5]. Furthermore, hip and knee osteoarthritis were more likely to be progressive in women than in men. Finally, hip and knee osteoarthritis were more often symptomatic in postmenopausal women than in same-age men [4,6]. Many studies are now available, although their results are often conflicting. However, studies of the prevalence and incidence of osteoarthritis in postmenopausal women with and without hormone replacement therapy (HRT) have provided strong support for a beneficial effect of estrogens in osteoarthritis. Subsequently, the identification of the two estrogen receptors alpha and beta (ERa and Erb) in chondro* Corresponding author. E-mail address: [email protected] (P. Richette). © 2003 Éditions scientifiques et médicales Elsevier SAS. All rights reserved. doi:10.1016/S1297-319X(03)00067-8

cytes provided further evidence that the cartilage is sensitive to estrogens [7]. Finally, several in vitro studies and in vivo animal experiments confirmed that chondrocytes respond to estrogens and also provided insight into the mechanisms by which estrogens may influence chondrocyte metabolism.

2. Estrogens and osteoarthritis: epidemiological data 2.1. Osteoarthritis, menopause, and hysterectomy No association has been found between the duration of estrogen exposure and osteoarthritis: age at menarche and age at menopause are not correlated with the prevalence of osteoarthritis [8–10]. In two studies of gynecological risk factors for osteoarthritis, Spector et al. [11] found a significant association with hysterectomy. The first study found that hysterectomy was significantly more prevalent among cases with osteoarthritis than among controls without the disease (odds ratio [OR], 2.8; 95% confidence interval [95%CI], 1.7–4.6). The second study was a retrospective investigation of a cohort of women, in which a history of hysterectomy was associated with higher prevalence of osteoarthritis at the trapeziometacarpal joint (relative risk [OR], 2.6; 95%CI, 1.29–5.23) and knee (OR, 4.5; 95%CI, 1.83–11.05) but not at the distal interphalangeal joints [12]. In a cross-sectional study of 57 patients with severe and 40 with moderate knee

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osteoarthritis, Inoue et al. [13] showed a significant association between hysterectomy and severe osteoarthritis (OR, 4.28). The small sample sizes, absence of detailed information on the effects of ovariectomy probably performed in some patients, and the poor study designs limit the interpretation of these results. Hysterectomy was not associated with osteoarthritis in recent studies [8,14,15]. Finally, studies of hysterectomy without ovariectomy provide no information on a potential role for estrogens in osteoarthritis, since hysterectomy alone does not modify circulating estrogen levels. 2.2. Serum estrogen levels and osteoarthritis Two studies measured serum estradiol levels in women with osteoarthritis. One investigated perimenopausal women with generalized osteoarthritis and found no differences in serum 17b estradiol levels as compared to the controls, although the steroid binding protein level was significantly decreased (58 nmol/l vs. 67.9 nmol/l, P < 0.05) [16]. The other found no correlation between the radiological severity of finger osteoarthritis in postmenopausal women and serum estrogen levels [17]. Sowers et al. [18] assayed serum estradiol and the prevalence of radiological knee and finger osteoarthritis in premenopausal women and found a positive correlation only between severe knee osteoarthritis and 17b estradiol levels. Taken in aggregate, these results do not prove or disprove an association between the prevalence of osteoarthritis and serum estrogen levels. 2.3. Hormone replacement therapy and osteoarthritis The most informative studies on the role of estrogens in osteoarthritis evaluated the prevalence and incidence of the disease in women taking HRT. Nevitt et al. [19] conducted a cross-sectional study of the prevalence of radiological hip osteoarthritis in 4366 Caucasian women older than 65 years, comparing those who took HRT to those who did not. HRT was associated with a lower relative risk of hip osteoarthritis (OR, 0.62; 95%CI, 0.49–0.86), and the reduction was particularly marked for moderate to severe hip osteoarthritis (OR, 0.54; 95%CI, 0.33, 0.88). This protective effect was greater in the subgroup of women who had been on HRT for 10 years or longer (OR, 0.57; 95%CI, 0.40–0.82) than in those with shorter treatment durations (OR, 0.75; 95%CI, 0.47–1.24). Hannan et al. [20] evaluated the prevalence of radiological knee osteoarthritis in 831 women (mean age, 73 years) from the Framingham cohort. The relative risk of radiologically defined knee osteoarthritis was lower in the women who had been on HRT for longer than 4 years, although the difference was not statistically significant (OR, 0.71; 95%CI, 0.42–1.20). The protective effect was greater (OR, 0.39, 95%CI, 0.14–1.04) when only severe knee osteoarthritis was considered. Five other cross-sectional studies provided some support for a protective effect of estrogens by showing relative risks of osteoarthritis of less than 1 in the women on HRT, although the confidence intervals included

1, indicating that the difference with untreated women was not statistically significant. In a study of hip and knee osteoarthritis (n = 1329), a slight nonsignificant decrease in the prevalence of symptomatic osteoarthritis was found in the women on HRT (OR, 0.9; 95%CI, 0.7–1.2) [21]. Similarly, in another study [8], HRT was associated with trends toward lower prevalences of symptomatic hip and knee osteoarthritis (OR, 0.3; 95%CI, 0.1–1.4) and of finger osteoarthritis (OR, 0.6, 95%CI, 0.2– 1.9). A longitudinal study in the Chingford population found that HRT offered significant protection against radiological knee osteoarthritis (RR, 0.31; 95%CI, 0.11–0.93) as compared to a control group [23]. Among 413 women, those who took HRT for longer than 5 years were at lower risk for hip osteoarthritis, although the difference was not statistically significant (OR, 0.6; 95%CI, 0.2–1.8) [9]. Finally, a casecontrol study comparing 230 women with total hip replacement for primary hip osteoarthritis to 273 women with normal hips found that HRT reduced the relative risk of hip replacement (OR, 0.7; 95%CI, 0.5–1.0) [22]. The two available studies of radiological osteoarthritis found no evidence that HRT was significantly protective. Zhang et al. [24] followed 551 women from the Framingham cohort for 8 years, using the Kellgren and Laurence score to evaluate knee osteoarthritis. HRT tended to reduce the incidence (OR, 0.4; 95%CI, 0.1–3) and the progression (OR, 0.5; 95%CI, 0.1–2.9) of knee osteoarthritis. When the incidence and progression of the disease were cumulated, the relative risk of knee osteoarthritis in the women on HRT was 0.4 (95%CI, 0.1–1.5). The other longitudinal study also focused on radiological knee osteoarthritis. After 4 years, the incidence of knee osteoarthritis was lower in the women on HRT (OR, 0.41; 95%CI, 0.12–1.42) [25]. Conversely, an increased prevalence of osteoarthritis in patients on HRT was found in a few studies. HRT was associated with knee replacement surgery in one study (OR, 1.8; 95%CI, 1.2–2.6) [26] and with a higher prevalence of osteoarthritis in another [27]. The methodological shortcomings of this last study, particularly regarding the definition of osteoarthritis [28], limit the interpretation of the results. HRT had no effect in two cross-sectional studies that evaluated the effects of HRT on symptoms of finger osteoarthritis [29] and the relative risk of unilateral or bilateral osteoarthritis associated with HRT in women awaiting replacement surgery for hip or knee osteoarthritis [30], respectively. The only controlled study published to date compared an estrogen-progestin combination to a placebo taken for 4 years in the population of the Heart and Estrogen/progestin Replacement Study (HERS) [31], using a randomized double-blind design. At the end of the study, the prevalence of knee pain was similar with and without HRT (24.1% and 26.1%, respectively; 95%CI, –7.4 to +3.5%, P = 0.47). Among the women with knee pain, no differences were found between the HRT and control groups regarding pain severity assessed by the WOMAC index (5.9 vs. 6.1, 95%CI, –1.2 to +0.8; P = 0.65) or functional impairment (19.1 vs.

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19.8; 95%CI, –3.8 to +2.4; P = 0.6). Thus, in this controlled longitudinal study, HRT had no statistically significant effects. However, there were several methodological shortcomings, including patient selection (women with coronary heart disease), absence of a baseline evaluation, and use of a questionnaire to collect the study data. Finally, in a recent study of women without osteoarthritis, HRT taken for longer than 5 years was associated with a larger volume of cartilage opposite the tibial plateaus as compared to women who were not taking HRT (0.3 vs. 0.23 ml, 95%CI, 0.08–0.52; P = 0.008) [32].

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been reported in a man with incomplete growth plate closure [55]. No cases of ERb gene mutation have been reported to date. Evidence that genetic factors influence cartilage sensitivity to estrogens was provided by a study of ERa gene polymorphism in 65 women with generalized osteoarthritis and 318 female controls. The PpXx genotype was significantly correlated with generalized osteoarthritis (OR, 1.86; 95%CI, 1.03–3.24, P = 0.039) [56]. These interesting results require confirmation by additional studies. 4. Effects of estrogens in vivo in animals and in vitro

3. Estrogen receptors and cartilage There is general agreement that estrogens cannot act on their target tissues unless they bind to a specific protein, the estrogen receptor [33], of which two isoforms have been cloned, alpha (ERa) and beta (ERb). ERa was isolated in 1986 [34,35] and ERb 10 years later from a rat prostate cDNA library [36–39]. The identification of this second receptor led to a radical change in concepts about the mechanism of action of estrogens. Estrogen receptors are nuclear proteins belonging to the steroid receptor family. After activation by their ligands, they act as transcription factors. Estradiol binds in the cytosol to a dimerized receptor, and the ligand-receptor complex then binds to a palindromic estrogen response element (ERE) present in target gene promoters, thereby ultimately activating or inhibiting gene transactivation [40]. Other binding sites have been identified, such as AP-1 [41]. The presence of functional variants of ERa and ERb produced by alternate gene splicing, the involvement of transcription coactivators (CBP, SRC-1, and SMRT), and the ability of estrogen receptors to form ERa-ERb heterodimers [42,43] add further levels of regulation [44]. Finally, a possible nonnuclear effect of estrogens [45] further increases the complexity of the mechanism of action. Moreover, many ligands, including physiological estrogens (17b estradiol) and antiestrogens, have closely similar affinities for the two receptors [46]. The identification of these two receptors in joint and growth plate cartilage in various species, including humans, provides strong evidence that the cartilage can respond to estrogens. Several studies showed that ERa is expressed in joint and growth plate cartilage in humans and other species [47–50]. An immunohistochemical study detected ERb in hypertrophic growth plate chondrocytes in humans [51]. Finally, the transcripts of both receptors have been identified in chondrocytes from osteoarthritic hips and knees [7], supporting the hypothesis that osteoarthritic cartilage is responsive to estrogens. The phenotypes of mice with disruption of the gene for ERa or ERb showed that these two receptors differ in their effects on genital tract maturation [52–54]. However, no data on possible effects of these gene disruptions on the joint cartilage are available. A gene mutation in the ERa gene has

No genes directly transactivated by 17b estradiol in chondrocytes have been identified to date. However, several studies have found incontrovertible evidence that estrogens have effects on chondrocytes both in vivo and in vitro. In vivo in animals, intraarticular estrogen injections had dose-dependent effects: supraphysiological dosages of 17b estradiol induced histological osteoarthritis, whereas lower dosages had no effect [57]. A study of joint cartilage from ewes showed decreased resistance to compression after ovariectomy, except when replacement estrogen therapy was given [58]. Administration of estrogens to ovariectomized sheep increased joint fluid levels of insulin growth factor (IGF) 1, IGF2, and IGF binding proteins 1 et 3, as compared to untreated animals [59]. Finally, in vivo in ovariectomized rats, estrogen replacement prevented the cartilage breakdown caused by interleukin-1b [60]. In vitro studies showed a dose-dependent change in matrix protein turnover when cultured chondrocytes were exposed to estradiol. Turnover was increased with doses within the normal range and decreased with higher doses [48,61–63]. A dose-dependent effect of 17b estradiol on proteoglycan biosynthesis by cultured cartilage explants has been reported [64,65]. Furthermore, 17b estradiol seems to potentiate the mitotic effect of IGF1 in rabbits [66] and to decrease basal cyclooxygenase type 2 expression in bovine chondrocytes [67]. These last results, however, require confirmation by further studies. Thus, the opposite effects of estradiol on the cartilage seem to depend on two main factors: estrogen dose and patient age. Estradiol has beneficial effects in physiological dosages [48,58,59,61,62,64,65] and deleterious effects in higher dosages [57,61,63–65,68]. In chondrocyte cultures, estrogens stimulate matrix protein turnover of articular chondrocytes from prepubertal children but not from infants younger than 1 year of age [62]. 5. Conclusions Epidemiological studies of a potential role for estrogens in osteoarthritis showed two very different findings. First, estrogen deprivation at the menopause seems to be associated with increases in the frequency of knee, hip, and finger

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osteoarthritis and in the severity of hip osteoarthritis. Second, HRT for the menopause may decrease the incidence and progression of hip and knee osteoarthritis. Differences across studies in evaluation criteria (symptomatic vs. structural osteoarthritis, radiological vs. functional scores), patient populations, and HRT duration contribute to the discrepancies in some of the results. The identification of the a and b estrogen receptors in normal and osteoarthritic cartilage and the effects of 17b estradiol on cartilage in vivo in animals and in vitro confirm that the cartilage responds to estrogens. Finally, this response is dose-dependent: physiological doses (as with HRT) are protective and higher dosages are deleterious. Importantly, the effects of estrogens in osteoarthritis may not be ascribable only to modulation of the biosynthesis or breakdown of chondrocyte matrix proteins. In postmenopausal women, estrogens may decrease the acceleration in subchondral bone remodeling that is undoubtedly a key factor in the pathophysiology of osteoarthritis [69–71]. Furthermore, expression of an estrogen receptor has been shown in synoviocytes, which are, therefore, another possible target for estrogen effects on joints [72]. Much work is needed to conclusively prove or disprove a role for estrogens in osteoarthritis. In the clinical field, only prospective controlled studies comparing HRT to a placebo in homogeneous populations will show whether HRT is useful in osteoarthritis. Experience with studies of HRT in osteoporosis indicates that a major obstacle to such studies will be the need for prolonged follow-up. The choice of the joint to be studied (hip or knee) and of the primary evaluation criterion (radiological or clinical) may prove difficult. A study of structural modulation, although technically difficult, would be extremely informative. Basic science studies have established that estrogens act on chondrocytes in vitro. However, the specific target gene for estradiol remains unknown. Identification of this gene would be a breakthrough in our understanding of cartilage physiology and would perhaps open up new treatment possibilities.

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