183 Is estrogen receptor  key to controlling ’ resistance to fracture?

Lance Lanyon, Victoria Armstrong, Delia Ong, Gul Zaman and Joanna Price Royal Veterinary College, London NW1 OTU, UK (Requests for offprints should be addressed to L Lanyon; Email: [email protected])

Abstract The ability of bones to withstand functional loading paper, we briefly review evidence of the mechanism(s) by without damage depends upon their cell populations which the mechanical strains engendered by loading establishing and subsequently maintaining a mass and influence cells to establish and maintain structurally architecture that are appropriately robust for the purpose. competent bone architecture. We highlight the finding In women, the rapid loss of bone associated with the that at least one strain-related cascade responsible for menopause represents a steplike decline in the effective- adaptive control of bone architecture is mediated through ness of this process with consequent increase in bone estrogen receptor (ER) , the number and activity of fragility. In men, loss of bone tissue and reduction in bone which are regulated by estrogen. We hypothesize that strength are more gradual and the increased incidence of a major contributor to the rapid loss of bone mass that fragility fractures occurs later. In both sexes, bone mass is occurs in females, and the slower age-related fall in males associated with levels of bioavailable estrogen. This poses and females, is reduced effectiveness of ER-mediated the major question as to how the presence or concentration processing of strain-related information by resident bone of the reproductive hormone estrogen influences the cells. relationship between bone mass and bone loading. In this Journal of Endocrinology (2004) 182, 183–191

Introduction 1991, Romanello et al. 2002). The hormones most closely associated with remodeling activity have been those con- In adults, the resorptive and formative activities of the cerned with regulation, such as parathyroid remodeling cycles by which bone cells replace and hormone (Wiske et al. 1979, Jilka et al. 1999, Neer et al. rearrange existing tissue are coupled, so that normally bone 2001, Kim et al. 2003), (Martin 1983) and mass and architecture are maintained more or less stable (Gallagher et al. 1979, Chapuy et al. 1992). between the ages of 20 and 50. In women at the time of However, ever since Albright (1941) first described the menopause, or in association with ovariectomy, there the phenomenon of postmenopausal bone loss, the is a rapid decline in bone mass sufficient to place a sub- influence of estrogen on bone has received considerable stantial proportion of the population at risk of fracture attention. during comparatively trivial loading activities. The life- The effects of ovarian sex hormones on the human time expectancy of a fragility fracture in a 50-year-old are consistent with those revealed in numerous Caucasian US woman is 45% (Rodan & Martin 2000) and animal models. The reduction in bone mass following loss that of a man 15%. of ovarian function, and the reversal of ovariectomy- induced bone loss by exogenous estrogen demonstrated in man (Lindsay et al. 1976) has also been demonstrated The endocrine influence on bone modeling and in the monkey (Jerome et al. 1994), dog (Snow & remodeling Anderson 1986), rat (Lane et al. 1999) and mouse (Daci et al. 2000). High-dose estrogen promotes osteogenesis It has long been evident that the local influences on in ovary-intact female mice (Samuels et al. 1999), an and activity are influenced by sys- effect that can be inhibited by blocking the estrogen temic endocrine factors (Centrella et al. 1988, Hofbauer receptor (ER) by selective estrogen-receptor modulators et al. 1999, Tsai et al. 2000) as well as being under local (SERMs) such as tamoxifen or ICI 182,780 (Samuels paracrine control (Gowen et al. 1990, Mohan & Baylink et al. 2000).

Journal of Endocrinology (2004) 182, 183–191 Online version via http://www.endocrinology.org 0022–0795/04/0182–183  2004 Society for Endocrinology Printed in Great Britain

Downloaded from Bioscientifica.com at 09/29/2021 08:25:44PM via free access 184 L LANYON and others · Estrogen receptor  and bone

Figure 1 Schematic representation of the feedback mechanism by which changes in bone mass and architecture are influenced to regulate the strains that functional loading engenders in bone tissue.

Functional strain as an objective and stimulus for Frost (1987a,b) provided the insight that the mechanical bone architecture variable to which bone cells respond was most probably the local deformation of the bone tissue that loading Hormones circulate systemically and are produced by engenders within the bone tissue. This deformation is glands with little or no association with the skeleton. It is commonly resolved into strains. Strain is a proportional difficult to envisage a mechanism by which the secretions change in dimension. A strain change in length of 1 from remote endocrine organs could directly regulate [L/L=1] represents a doubling of a structure’s linear mechanically appropriate bone modeling and remodeling dimension. Frost envisaged that bone cells ‘measured’ at each skeletal location. Thus, although systemic agents strains and adapted bone architecture to bring them to produce generalized effects on the cellular activity by some uniform optimum/minimum level. This homeo- which bone mass and architecture are adjusted, control of static mechanism he termed the ‘mechanostat’ (Fig. 1). In these processes requires local regulation directed towards this system, higher than optimal functional strains stimu- meeting local structural requirements. A striking example late an increase in bone mass that, if the loading remains of this process can be seen in professional athletes, such as constant, re-establishes optimal strains. The increase in the tennis players and baseball pitchers, the architecture of cortical cross-sectional area of the tennis player’s dominant whose bones reflects the one-sided nature of their humerus reflects the difference in mass necessary to activities (Jones et al. 1977, Haapasalo et al. 2000, Bass et al. produce similar strains in these two differently loaded 2002). bones. Conversely, where functional loading is reduced to This concept of local control of bone remodeling arising the extent that optimal strains are not achieved, bone loss from the local mechanical environment revisits the earliest occurs to restore them (Fig. 1). considerations of how bones achieve architectural suit- When it became possible to measure functional bone ability for their load-bearing role (Wolff 1892, Roux strains in vivo (Lanyon & Smith 1970, Lanyon et al. 1975, 1895). These studies started from the natural assumption 1979, Goodship et al. 1979, Lanyon & Bourn 1979, Rubin that load-bearing itself somehow stimulated the most & Lanyon 1982, Lee et al. 2002), it became clear that peak appropriate architecture to bear those loads without functional strains on bone surfaces were commonly at the damage. Mechanical suitability appeared most evident in level of 0·001–0·003 (sometimes referred to as 2000–3000 cancellous regions of the bone, the structure of which microstrain). However, since most long bones are subject lends itself to mathematical analysis (Fazzalari et al. 1989). to bending, the peak strains throughout them vary from

Journal of Endocrinology (2004) 182, 183–191 www.endocrinology.org

Downloaded from Bioscientifica.com at 09/29/2021 08:25:44PM via free access Estrogen receptor  and bone · L LANYON and others 185 compression (–) on one surface through zero at the neutral estrogen to stimulate deposition of more bone than is axis to tension (+) on the opposite side. Experiments in necessary to maintain functional strains at an appropriate which bone loading was manipulated showed that the level. They do not clarify whether this is a direct effect or strain waveform (rate of change of strain and frequency) a modification of the existing strain-related response. and strain distribution also have a critical influence on Unfortunately, since exercise was used in their studies as bone cell remodeling activity (Torrance et al. 1994, the load-bearing stimulus, it is not possible to relate either Mosley et al. 1997, Mosley & Lanyon 1998, Lee et al. bone mass or apparent responsiveness to loading to any 2002, Srinivasan et al. 2002). High strains, fast changing quantified strain or any reduction in strain-related stimulus strains, unusual strain distributions and perhaps certain under different estrogen regimens. strain frequencies (Rubin et al. 2002) are effective at stimulating increases in bone mass, whereas slowly chang- ing strains are less effective or have no effect at all. The mechanisms of strain-adaptive control of bone Nevertheless, although the objective of the modeling and cell behavior remodeling processes in bone is less simple than a uniform optimal strain, the principle of bone mass and architecture Most work on postmenopausal bone loss has concentrated representing the outcome of homeostatic regulation of on the biology of , since it is their activity that local functional strains is both valid and valuable. actually reduces bone mass. However, it is now clear that These studies clearly show that bone cells adjust bone osteoclast behavior is substantially influenced by the mass and architecture in response to changes in strain. This activity of (Takami et al. 1999, Udagawa et al. raises the question of how this mechanism relates to 1999, Chambers 2000, Udagawa et al. 2000). In this hormonal influences on the same (re)modeling process. It review, we assume that in coordinated remodeling the is evident that hormonal and mechanical demands for behavior of cells of the osteoclast lineage is normally under (re)modeling may conflict with one another. Situations the influence of cells of the osteoblast lineage resident occur where there is a structural requirement to retain within the bone tissue. Although this is a substantial calcium in the skeleton to maintain its strength and a simplification of an evidently complex situation in terms of hormonal requirement for it to be released to meet local control of bone remodeling, it makes sense. demands such as foetal growth, lactation or a deficiency in One of bone’s earliest responses to an increased loading intake. It is logical that a reproductive hormone such as challenge is to recruit the osteoblasts required to form the estrogen should have a role in pregnancy and lactation, and new bone necessary to increase the amount of tissue its action may explain some of the changes in bone mass available to restore acceptable levels of strain under the associated with these situations (Ritchie et al. 1998, new loads. This initial proliferative response of cells of the Holmberg-Marttila et al. 1999, Holmberg-Marttila & osteoblast lineage may be elicited in vivo (Pead et al. 1988, Sievanen 1999). Estrogen action is almost certainly Chambers et al. 1993) and ex vivo (Cheng et al. 1996) by responsible for the deposition of medullary bone in birds to exposure of the bone to a short single period of loading. A provide a readily accessible store of the calcium needed to similar response can be elicited in monolayer cultures of make eggshell (Miller 1992). osteoblast-like cells in vitro (Damien et al. 1998). In the At the level of bone remodeling, the effect of estrogen in vitro situation, both estrogen and strain stimulate an withdrawal (Wronski et al. 1989, Laib et al. 2001, Yang increase in cell number that can be blocked by neutraliz- et al. 2003) is similar to that associated with reduction in ing antibodies to insulin-like growth factors (IGFs) or mechanical use (Jaworski & Uhthoff 1986), namely, IGF-receptor blockers (Cheng et al. 1999). When estrogen increased activation frequency of resorptive units followed and strain act together, the maximum proliferative effect by incomplete restitution of the bone tissue removed. of each separate stimulus is additional to, rather than Animal models of disuse result in bone loss comparable to synergistic with, that of the other (Damien et al. 1998). If that seen in man (Bikle & Halloran 1999, Giangregorio & this effect of estrogen obtains in vivo, it could explain the Blimkie 2002). The loss of bone tissue associated with direct effects of estrogen in increasing bone mass, and by disuse is similar to that seen after ovariectomy or at the inference the bone loss following estrogen withdrawal. menopause, and, like this, it can be partially ameliorated However, it does not explain why the reduction in bone by administration of estrogen (Kawano et al. 1997, 2001). mass that would follow any direct effect of estrogen Studies in female rats have shown them to have higher withdrawal should not be successfully countered by density than male or ovariectomized female the anabolic consequences that should result from the counterparts, prompting Jarvinen et al. (2003) to suggest increased strain engendered by reduction in bone mass that estrogen stimulates more bone than is necessary accompanied by sustained bone loading. To follow the mechanically, and that this extra bone is associated with mechanostat analogy, if the door to a temperature- reduced responsiveness to load. This group also hypoth- controlled room is opened, engendering loss of heat, the esize that in man the relatively higher bone mass thermostat responds to the change in temperature by in females than males similarly represents the effect of turning on the boiler to increase the heat output and so www.endocrinology.org Journal of Endocrinology (2004) 182, 183–191

Downloaded from Bioscientifica.com at 09/29/2021 08:25:44PM via free access 186 L LANYON and others · Estrogen receptor  and bone

Figure 2 The smaller change in cross-sectional area induced by loading the ulna in ER/ mice than in their ER+/+ littermates (after Lee et al. 2003).

restore the temperature. The temperature will continue to times less new cortical bone in response to the same fall only if the boiler’s maximum heat output is insufficient mechanical stimulus as their ER+/+ littermates (Lee et al. to counter the heat loss through the open door. In the case 2003). Primary cultures of osteoblast-like cells derived of bone, the early responses to mechanical strain which from ER/ mice fail to increase in number in response inform the (re)modeling processes of what structural to mechanical stimulation, and rescue of this response changes are necessary to maintain optimum strains are requires transfection with fully functional (but not equivalent to the thermostat, and the remodeling processes mutated) human ER (Lee et al. 2003). Conversely, responsible for adjusting bone architecture are the boiler. osteoblast-like cells derived from ER/ mice show an The situation in postmenopausal is more enhanced proliferative response to strain compared with reminiscent of an unresponsive thermostat that allows the ER+/+ mice (Jessop et al. 2004), suggesting that ER boiler to remain inactive despite the temperature being modulates the effects of ER in the strain-related response. lower than the setting on the dial, rather than a boiler These data all indicate that at least one aspect of bone working at maximum capacity to compensate for an open cells’ early responses to mechanical strain involves ER, door. and that if ER is blocked, nonfunctional or absent, the strain-adaptive stimulus required to increase, and perhaps maintain, osteoblast number sufficient to adjust appropri- The role of the ER in bone cell adaptive response ately bone mass according to its mechanical demands is to mechanical strain diminished or eliminated. Involvement of ER in bone cells’ adaptive response to strain does not by itself explain In our attempts to identify the mechanisms of bone cells’ the reduced effectiveness of strain-related control of bone early response to mechanical strain, we made the remark- architecture with estrogen withdrawal at the menopause. able finding that in both males and females the increase in This could, however, be explained if ER number or osteoblast-like cell number caused by strain, as well as that activity were substantially regulated by estrogen. In mice, caused by estrogen, can be blocked by the SERMs ovariectomy leads to a reduced expression of ER in tamoxifen and ICI 182,780 (Damien et al. 2000). Stimula- trabecular bone (Lim et al. 1999). Data on whether ER tion by both strain and estrogen results in upregulation number is regulated in man by estrogen are surprisingly of the extracellular regulated kinase (ERK) pathway, scarce, but there appears to be a higher proportion of phosphorylation of the ER (Jessop et al. 2001), and ER-positive bone cells in women replete with ovarian upregulation of estrogen-response element (ERE) activity steroids than in those that are hormone deficient (Hoyland (Zaman et al. 2000). The responsiveness to estrogen or et al. 1999). Similar observations have been made in other strain in terms of increase in cell number is also influenced estrogen-responsive tissues, including brain (Rose’Meyer by the number of ERs (Zaman et al. 2000). As shown in et al. 2003) and kidney (Potier et al. 2002). These data are Fig. 2, this relationship between ER number and adaptive consistent with the generalization that steroid receptors are responsiveness of the osteoblast population is evident sensitive to changes in the levels of their hormone ligands in vivo, since mice lacking functional ER produce three (Tata et al. 1993).

Journal of Endocrinology (2004) 182, 183–191 www.endocrinology.org

Downloaded from Bioscientifica.com at 09/29/2021 08:25:44PM via free access Estrogen receptor  and bone · L LANYON and others 187

Figure 3 Possible pathways for estrogen and strain signal transduction in osteoblasts. In order for bone cells to adjust bone mass in response to changes in mechanical loading, resident bone cells respond to the local strains that such loading engenders. Integrins, in conjunction with the IGF-IR, play an important role in the initial transduction process, which initiates a cascade of events, including activation of the MAPK/ERK pathway and subsequently ER. As with estrogen (E2), strain causes ERK1/2 to phosphorylate ER, resulting in both classical activation of gene transcription within the nucleus and ER participation in extranuclear signaling events. IGF-I and -II genes regulated by E2 and strain interact in an autocrine or paracrine fashion at the IGF-IR, which in turn requires ER to be present for signaling to occur.

The classically recognized role of ERs is to regulate apoptosis pathway individually. The nongenotropic gene transcription in the nucleus (Cano & Hermenegildo activity this group report is associated with ER localized 2000, Hall et al. 2001). However, there is increasing within caveolae and interestingly involves the Ras/Src/ evidence to suggest that ER function outside the nucleus ERK pathway (Kousteni et al. 2001, 2003). This is the may be equally important. In Fig. 3, we present a model of same pathway that we have previously reported to be interactions between the bimodal nuclear and extranuclear involved in estrogen- and strain-stimulated increases in functions of ER in osteoblasts. Manolagas and colleagues osteoblast cell number associated with concomitant phos- have demonstrated that membrane-bound ER can phorylation of the ER and ERK1/2 (Jessop et al. 2001). inhibit osteoblast apoptosis (Kousteni et al. 2001), and that The antiapoptotic effect of mechanical strain on osteo- this anti-apoptotic effect is distinct from the classical cytes (Noble et al. 2003) is similarly abolished by ERK transcriptional role of ER. These workers have shown inhibitors (Plotkin et al. 2003). That ER should be that synthetic compounds can activate either ERE- necessary at more than one stage of the bone cells’ strain- mediated transcription or the ‘nongenotropic’ anti- related response increases the likelihood that reduction www.endocrinology.org Journal of Endocrinology (2004) 182, 183–191

Downloaded from Bioscientifica.com at 09/29/2021 08:25:44PM via free access 188 L LANYON and others · Estrogen receptor  and bone

in ER function would reduce the effectiveness of the cells’ anabolic response to strain due to reduced ER response. number/activity associated with decline in bioavailable Much if not all the anabolic effect of strain on osteoblast estrogen. cell number is mediated by IGF’s action through the IGF-I 6 Bone cells interpret the reduced mechanical stimulus receptor (IGF-IR) (Cheng et al. 2002). This receptor is downstream of reduced ER function as lack of use, bound within the cell membrane (Cheng et al. 1999, initiating the usual consequences of bone loss leading to 2002), where its responsiveness to a ligand is regulated by lower bone mass. In this situation of continued loading, the integrins. Integrins in turn appear to be regulated by increased fragility resulting from reduced bone mass recent load history (Calvalho et al. 1996, Meazzini et al. results in the high incidence of fracture characteristic of 1998, Wozniak et al. 2000, Li et al. 2003, Sakata et al. postmenopausal osteoporosis. 2004). In addition, it seems that IGF-IR’s responsiveness to IGF also requires association with ligand-bound ER Acknowledgements (Kahlert et al. 2000). This association results in IGF-IR autophosphorylation and activation of the downstream Most of the authors’ work cited in this paper has been MAPK/ERK signaling cascade (Kahlert et al. 2000) and funded by the Wellcome Trust. VA is a BBSRC research the PI3K/Akt pathway. These pathways are crucial for cell student. survival and proliferation (Dudek et al. 1997, Franke et al. 1997). Even if ER number itself is not substantially References regulated by estrogen, the pathway of strain-related stimu- lation may require ER binding with estrogen to achieve its Albright F, Smith PH & Richardson AM 1941 Postmenopausal maximum strain-related effect. osteoporosis. Journal of the American Medical Association 116 ER appears therefore to be involved at more than one 2465–2474. Bass SL, Saxon L, Daly RM, Turner CH, Robling AG, Seeman E & stage in bone cells’ early adaptive responses to strain. It is Stuckey S 2002 The effect of mechanical loading on the size and these early stages that play a crucial role in the functional shape of bone in pre-, peri-, and postpubertal girls: a study in regulation of bone mass and architecture. By modulating tennis players. Journal of Bone and Mineral Research 17 2274–2280. the osteoregulatory effect of mechanical strain, ER may Bikle DD & Halloran BP 1999 The response of bone to unloading. play a vital role in the mechanisms by which strain Journal of Bone and Mineral Metabolism 17 233–244. Calvalho RS, Bumann A, Schwarzer C, ScottE&YenEH1996A regulates bones’ ability to withstand loading without molecular mechanism of integrin regulation from bone cells damage. Thus, the role of estrogen in this pathway may be stimulated by orthodontic forces. European Journal of Orthodontics 18 to regulate the regulator. 227–235. CanoA&Hermenegildo C 2000 Modulation of the oestrogen receptor: a process with distinct susceptible steps. Human Reproduction Update 6 207–211. Conclusions Centrella M, McCarthy TL & Canalis E 1988 modulates transforming beta activity and binding in The inferences we draw from the data reviewed here are osteoblast-enriched cell cultures from fetal rat parietal bone. PNAS as follows: 85 5889–5893. Chambers TJ 2000 Regulation of the differentiation and function of 1 The regulatory stimulus that influences bone cell osteoclasts. Journal of Pathology 192 4–13. populations to elevate and maintain bone mass above the Chambers TJ, Evans M, Gardner TN, Turner-SmithA&ChowJW genetically determined level associated with disuse is 1993 Induction of bone formation in rat tail vertebrae by derived from the strains that functional loading engenders mechanical loading. Bone and Mineral 20 167–178. within the bone tissue. Chapuy MC, Arlot ME, Duboeuf F, Brun J, Crouzet B, Arnaud S, Delmas PD & Meunier PJ 1992 Vitamin D3 and calcium to 2 Full expression of bone cells’ early adaptive responses prevent hip fractures in elderly women. New England Journal of to mechanical strain-related stimulation in both males and Medicine 327 1637–1642. females requires involvement of ER, possibly modified Cheng M, Zaman G, Rawlinson SC, Mohan S, Baylink DJ & Lanyon by ER. LE 1999 Mechanical strain stimulates ROS cell proliferation through IGF-II and estrogen through IGF-I. Journal of Bone and 3 The anabolic influence of mechanical stimulation in Mineral Research 14 1742–1750. osteoblasts is effected substantially through the IGF axis Cheng MZ, Zaman G, Rawlinson SC, Suswillo RF & Lanyon LE and mediated by the action of the ER, which acts both 1996 Mechanical loading and sex hormone interactions in organ within the nucleus to influence regulation of IGF gene cultures of rat ulna. Journal of Bone and Mineral Research 11 502–511. Cheng MZ, Rawlinson SC, Pitsillides AA, Zaman G, Mohan S, transcription activity and at the cell membrane, where it Baylink DJ & Lanyon LE 2002 Human osteoblasts’ proliferative affects the activity of the IGF-IR. responses to strain and 17 beta-estradiol are mediated by the 4ER number and activity in bone cells are regulated estrogen receptor and the receptor for insulin-like growth factor I. by estrogen. Journal of Bone and Mineral Research 17 593–602. 5 The rapid loss of bone that accompanies the meno- Daci E, Verstuyf A, Moermans K, BouillonR&Carmeliet G 2000 Mice lacking the plasminogen activator inhibitor 1 are protected pause in women, and the slower fall in males and females, from trabecular bone loss induced by estrogen deficiency. Journal of results, at least in part, from reduced effectiveness of bone Bone and Mineral Research 15 1510–1516.

Journal of Endocrinology (2004) 182, 183–191 www.endocrinology.org

Downloaded from Bioscientifica.com at 09/29/2021 08:25:44PM via free access Estrogen receptor  and bone · L LANYON and others 189

Damien E, Price JS & Lanyon LE 1998 The estrogen receptor’s cynomolgus monkeys (Macaca fascicularis) evaluated by serum involvement in osteoblasts’ adaptive response to mechanical strain. markers and dynamic histomorphometry. Journal of Bone and Mineral Journal of Bone and Mineral Research 13 1275–1282. Research 9 527–540. Damien E, Price JS & Lanyon LE 2000 Mechanical strain stimulates Jessop HL, Sjoberg M, Cheng MZ, Zaman G, Wheeler-Jones CP & osteoblast proliferation through the estrogen receptor in males as Lanyon LE 2001 Mechanical strain and estrogen activate estrogen well as females. Journal of Bone and Mineral Research 15 2169–2177. receptor alpha in bone cells. Journal of Bone and Mineral Research 16 Dudek H, Datta SR, Franke TF, Birnbaum MJ, Yao R, Cooper GM, 1045–1055. Segal RA, Kaplan DR & Greenberg ME 1997 Regulation of Jessop HL, Suswillo R, Rawlinson S, Zaman G, Lee K, Das-Gupta V, neuronal survival by the serine-threonine protein kinase Akt. Science Pitsillides AA & Lanyon LE 2004 Osteoblast-like cells from 275 661–665. knockout mice have deficient responses to Fazzalari NL, Crisp DJ & Vernon-Roberts B 1989 Mathematical mechanical strain. Journal of Bone and Mineral Research 19 938–946. modelling of trabecular bone structure: the evaluation of analytical Jilka RL, Weinstein RS, Bellido T, Roberson P, Parfitt AM & and quantified surface to volume relationships in the femoral head Manolagas SC 1999 Increased bone formation by prevention of and iliac crest. Journal of Biomechanics 22 901–910. osteoblast apoptosis with parathyroid hormone. Journal of Clinical Franke TF, Kaplan DR & Cantley LC 1997 PI3K: downstream Investigation 104 439–446. AKTion blocks apoptosis. Cell 88 435–437. Jones HH, Priest JD, Hayes WC, Tichenor CC & Nagel DA 1977 Frost HM 1987a Bone ‘mass’ and the ‘mechanostat’: a proposal. Humeral hypertrophy in response to exercise. Journal of Bone and Anatomical Record 219 1–9. Joint Surgery. American Volume 59 204–208. Frost HM 1987b The mechanostat: a proposed pathogenic mechanism Kahlert S, Nuedling S, van Eickels M, Vetter H, MeyerR&Grohe ff of osteoporoses and the bone mass e ects of mechanical and C 2000 Estrogen receptor alpha rapidly activates the IGF-1 receptor nonmechanical agents. Bone and Mineral 2 73–85. pathway. Journal of Biological Chemistry 275 18447–18453. Gallagher JC, Riggs BL, Eisman J, Hamstra A, Arnaud SB & DeLuca Kawano S, Kanda K, Ohmori S, Izumi R, Yasukawa K, Murata Y & HF 1979 Intestinal calcium absorption and serum vitamin D SeoH1997Effect of estrogen on the development of disuse ff metabolites in normal subjects and osteoporotic patients: e ect of atrophy of bone and muscle induced by tail suspension in rats. age and dietary calcium. Journal of Clinical Investigation 64 729–736. Environmental Medicine 41 89–92. GiangregorioL&BlimkieCJ2002Skeletal adaptations to alterations Kawano S, Kambe F, Ohmori S, Kanda K, NagayaT&SeoH2001 in weight-bearing activity: a comparison of models of disuse Changes in mRNA levels of alkaline phosphatase and osteoporosis. Sports Medicine 32 459–476. tartrate-resistant acid phosphatase in femur of ovariectomized rats: Goodship AE, Lanyon LE & McFie H 1979 Functional adaptation of effects of estrogen and unloading. Environmental Medicine 45 55–57. bone to increased stress. An experimental study. Journal of Bone and Kim CH, Takai E, Zhou H, von Stechow D, Muller R, Dempster Joint Surgery. American Volume 61 539–546. DW & Guo XE 2003 Trabecular bone response to mechanical and Gowen M, Chapman K, Littlewood A, Hughes D, Evans D & Russell parathyroid hormone stimulation: the role of mechanical G 1990 Production of tumor necrosis factor by human osteoblasts is microenvironment. Journal of Bone and Mineral Research 18 modulated by other , but not by osteotropic hormones. 2116–2125. Endocrinology 126 1250–1255. Kousteni S, Bellido T, Plotkin LI, O’Brien CA, Bodenner DL, Han Haapasalo H, Kontulainen S, Sievanen H, Kannus P, Jarvinen M & L, Han K, DiGregorio GB, Katzenellenbogen JA, Katzenellenbogen Vuori I 2000 Exercise-induced bone gain is due to enlargement in BS et al. 2001 Nongenotropic, sex-nonspecific signaling through the bone size without a change in volumetric : a peripheral estrogen or androgen receptors: dissociation from transcriptional quantitative computed tomography study of the upper arms of male activity. Cell 104 719–730. tennis players. Bone 27 351–357. Hall JM, Couse JF & Korach KS 2001 The multifaceted mechanisms Kousteni S, Han L, Chen JR, Almeida M, Plotkin LI, Bellido T & Manolagas SC 2003 Kinase-mediated regulation of common of estradiol and estrogen receptor signaling. Journal of Biological ff Chemistry 276 36869–36872. transcription factors accounts for the bone-protective e ects of sex 111 Hofbauer LC, Gori F, Riggs BL, Lacey DL, Dunstan CR, Spelsberg steroids. Journal of Clinical Investigation 16511664. TC & Khosla S 1999 Stimulation of osteoprotegerin ligand and Laib A, Kumer JL, MajumdarS&LaneNE2001Thetemporal inhibition of osteoprotegerin production by glucocorticoids in changes of trabecular architecture in ovariectomized rats assessed by human osteoblastic lineage cells: potential paracrine mechanisms of MicroCT. Osteoporosis International 12 936–941. glucocorticoid-induced osteoporosis. Endocrinology 140 4382–4389. LaneNE,HauptD,KimmelDB,ModinG&KinneyJH1999Early Holmberg-Marttila D & Sievanen H 1999 Prevalence of bone mineral estrogen replacement therapy reverses the rapid loss of trabecular changes during postpartum amenorrhea and after resumption of bone volume and prevents further deterioration of connectivity in menstruation. American Journal of Obstetrics and Gynecology 180 the rat. Journal of Bone and Mineral Research 14 206–214. 537–538. Lanyon LE & Smith RN 1970 Bone strain in the tibia during Holmberg-Marttila D, SievanenH&TuimalaR1999 Changes in normal quadrupedal locomotion. Acta Orthopaedica Scandinavica 41 bone mineral density during pregnancy and postpartum: prospective 238–248. data on five women. Osteoporosis International 10 41–46. Lanyon LE & Bourn S 1979 The influence of mechanical function on Hoyland JA, Baris C, Wood L, Baird P, Selby PL, Freemont AJ & the development and remodeling of the tibia. An experimental Braidman IP 1999 Effect of ovarian steroid deficiency on oestrogen study in sheep. Journal of Bone and Joint Surgery. American Volume 61 receptor alpha expression in bone. Journal of Pathology 188 294–303. 263–273. Jarvinen TL, Kannus P, Pajamaki I, Vuohelainen T, Tuukkanen J, Lanyon LE, Hampson WG, Goodship AE & Shah JS 1975 Bone Jarvinen M & Sievanen H 2003 Estrogen deposits extra mineral deformation recorded in vivo from strain gauges attached to the into bones of female rats in puberty, but simultaneously seems to human tibial shaft. Acta Orthopaedica Scandinavica 46 256–268. suppress the responsiveness of female skeleton to mechanical Lanyon LE, Magee PT & Baggott DG 1979 The relationship of loading. Bone 32 642–651. functional stress and strain to the processes of bone remodelling. An Jaworski ZF & Uhthoff HK 1986 Reversibility of nontraumatic disuse experimental study on the sheep radius. Journal of Biomechanics 12 osteoporosis during its active phase. Bone 7 431–439. 593–600. Jerome CP, Carlson CS, Register TC, Bain FT, Jayo MJ, Weaver DS Lee K, Jessop H, Suswillo R, ZamanG&LanyonL2003 & Adams MR 1994 Bone functional changes in intact, Endocrinology: bone adaptation requires oestrogen receptor-alpha. ovariectomized, and ovariectomized, hormone-supplemented adult Nature 424 389. www.endocrinology.org Journal of Endocrinology (2004) 182, 183–191

Downloaded from Bioscientifica.com at 09/29/2021 08:25:44PM via free access 190 L LANYON and others · Estrogen receptor  and bone

LeeKC,MaxwellA&LanyonLE2002Validation of a technique for Roux W 1895 Gesammel Abhandlungen über die Entwicklungsmechanik studying functional adaptation of the mouse ulna in response to der Organismen. Leipzig: Engelmann. mechanical loading. Bone 31 407–412. Rubin C, Turner AS, Mallinckrodt C, Jerome C, McLeodK&Bain Li L, Chen M, Deng L, Mao Y, Wu W, Chang M & Chen H 2003 S 2002 Mechanical strain, induced noninvasively in the [The effect of mechanical stimulation on the expression of alpha 2, high-frequency domain, is anabolic to cancellous bone, but not beta 1, beta 3 integrins and the proliferative, synthetic function in cortical bone. Bone 30 445–452. rat osteoblasts]. Shengwu Yixue Gongchengxue Zazhi 20 187–192. Rubin CT & Lanyon LE 1982 Limb mechanics as a function of speed Lim SK, Won YJ, Lee HC, Huh KB & Park YS 1999 A PCR and gait: a study of functional strains in the radius and tibia of horse analysis of ERalpha and ERbeta mRNA abundance in rats and the and dog. Journal of Experimental Biology 101 187–211. effect of ovariectomy. Journal of Bone and Mineral Research 14 Sakata T, Wang Y, Halloran BP, Elalieh HZ, CaoJ&Bikle DD 1189–1196. 2004 Skeletal unloading induces resistance to insulin-like Lindsay R, Hart DM, Aitken JM, MacDonald EB, Anderson JB & growth factor-I (IGF-I) by inhibiting activation of the IGF-I Clarke AC 1976 Long-term prevention of postmenopausal signaling pathways. Journal of Bone and Mineral Research 19 osteoporosis by oestrogen. Evidence for an increased bone mass after 436–446. delayed onset of oestrogen treatment. Lancet 1 1038–1041. Samuels A, Perry MJ & Tobias JH 1999 High-dose estrogen induces Martin TJ 1983 Drug and hormone effects on calcium release from de novo medullary bone formation in female mice. Journal of Bone bone. Pharmacology and Therapeutics 21 209–228. and Mineral Research 14 178–186. ff Meazzini MC, Toma CD, Scha er JL, Gray ML & Gerstenfeld LC Samuels A, Perry MJ, Goodship AE, Fraser WD & Tobias JH 2000 Is 1998 Osteoblast cytoskeletal modulation in response to mechanical high-dose estrogen-induced osteogenesis in the mouse mediated by strain in vitro. Journal of Orthopaedic Research 16 170–180. an estrogen receptor? Bone 27 41–46. Miller SC 1992 Bone Biology and Skeletal Disorders in Poultry. Snow GR & Anderson C 1986 The effects of 17 beta-estradiol and Abingdon, UK: Carfax progestagen on trabecular bone remodeling in oophorectomized MohanS&Baylink DJ 1991 Bone growth factors. Clinical Orthopaedics dogs. Calcified Tissue International 39 198–205. and Related Research 263 30–48. Srinivasan S, Weimer DA, Agans SC, Bain SD & Gross TS 2002 Mosley JR & Lanyon LE 1998 Strain rate as a controlling influence on Low-magnitude mechanical loading becomes osteogenic when rest adaptive modeling in response to dynamic loading of the ulna in is inserted between each load cycle. Journal of Bone and Mineral growing male rats. Bone 23 313–318. Research 17 1613–1620. Mosley JR, March BM, LynchJ&Lanyon LE 1997 Strain magnitude Takami M, Woo JT & Nagai K 1999 Osteoblastic cells induce fusion related changes in whole bone architecture in growing rats. Bone 20 and activation of osteoclasts through a mechanism independent of 191–198. macrophage-colony-stimulating factor production. Cell and Tissue Neer RM, Arnaud CD, Zanchetta JR, Prince R, Gaich GA, Research 298 327–334. Reginster JY, Hodsman AB, Eriksen EF, Ish-Shalom S, Genant Tata JR, Baker BS, Machuca I, Rabelo EM & Yamauchi K 1993 HK et al. 2001 Effect of parathyroid hormone (1–34) on fractures Autoinduction of nuclear receptor genes and its significance. Journal and bone mineral density in postmenopausal women with of Steroid Biochemistry and Molecular Biology 46 105–119. osteoporosis. New England Journal of Medicine 344 1434–1441. Noble BS, Peet N, Stevens HY, Brabbs A, Mosley JR, Reilly GC, Torrance AG, Mosley JR, Suswillo RF & Lanyon LE 1994 Reeve J, Skerry TM & Lanyon LE 2003 Mechanical loading: Noninvasive loading of the rat ulna in vivo induces a strain-related biphasic survival and targeting of osteoclasts for bone modeling response uncomplicated by trauma or periostal pressure. destruction in rat cortical bone. American Journal of Physiology. Cell Calcified Tissue International 54 241–247. Physiology 284 C934–943. Tsai JA, Rong H, Torring O, Matsushita H & Bucht E 2000 Pead MJ, Skerry TM & Lanyon LE 1988 Direct transformation from Interleukin-1 beta upregulates PTHrP-mRNA expression and quiescence to bone formation in the adult periosteum following a protein production and decreases TGF-beta in normal human single brief period of bone loading. Journal of Bone and Mineral osteoblast-like cells. Calcified Tissue International 66 363–369. Research 3 647–656. Udagawa N, Takahashi N, Jimi E, Matsuzaki K, Tsurukai T, Itoh K, Plotkin LI, Aguirre JI, Strotman B, Manolagas SC & Bellido T 2003 Nakagawa N, Yasuda H, Goto M, Tsuda E et al. 1999 Mechanical stimulation promotes osteocyte survival: requirement of Osteoblasts/stromal cells stimulate osteoclast activation through ff nuclear targets of the Src/ERK pathway. Journal of Bone and Mineral expression of osteoclast di erentiation factor/RANKL but not Research 18 S44. macrophage colony-stimulating factor: receptor activator of Potier M, Karl M, Zheng F, Elliot SJ, Striker GE & Striker LJ NF-kappa B ligand. Bone 25 517–523. 2002 Estrogen-related abnormalities in glomerulosclerosis-prone Udagawa N, Takahashi N, Yasuda H, Mizuno A, Itoh K, Ueno Y, mice: reduced mesangial cell estrogen receptor expression and Shinki T, Gillespie MT, Martin TJ, HigashioK&SudaT2000 prosclerotic response to estrogens. American Journal of Pathology 160 Osteoprotegerin produced by osteoblasts is an important regulator 1877–1885. in osteoclast development and function. Endocrinology 141 Ritchie L, Fung E, Halloran B, Turnlund J, Van Loan M, Cann C & 3478–3484. King J 1998 A longitudinal study of calcium during Wiske PS, Epstein S, Bell NH, Queener SF, EdmondsonJ&Johnston human pregnancy and lactation and after resumption of menses. CC Jr 1979 Increases in immunoreactive parathyroid hormone with American Journal of Clinical Nutrition 67 693–701. age. New England Journal of Medicine 300 1419–1421. Rodan GA & Martin TJ 2000 Therapeutic approaches to bone Wolff J 1892 Das Gesetz der Transformation der Knochen. Berlin: A diseases. Science 289 1508–1514. Hirschwald [trans. P Maquet&RFurlongasThe Law of Bone Romanello M, Bicego M, Pirulli D, Crovella S, MoroL&D’Andrea Remodelling. Berlin: Springer, 1986]. P 2002 Extracellular NAD+: a novel autocrine/paracrine signal in Wozniak M, Fausto A, Carron CP, Meyer DM & Hruska KA 2000 osteoblast physiology. Biochemical and Biophysical Research Mechanically strained cells of the osteoblast lineage organize their Communications 299 424–431. extracellular matrix through unique sites of alphavbeta3-integrin Rose’Meyer RB, Mellick AS, Garnham BG, Harrison GJ, Massa HM expression. Journal of Bone and Mineral Research 15 17311745. &Griffiths LR 2003 The measurement of adenosine and estrogen Wronski TJ, Dann LM, Scott KS & Cintron M 1989 Long-term receptor expression in rat brains following ovariectomy using effects of ovariectomy and aging on the rat skeleton. Calcified Tissue quantitative PCR analysis. Brain Research 11 9–18. International 45 360–366.

Journal of Endocrinology (2004) 182, 183–191 www.endocrinology.org

Downloaded from Bioscientifica.com at 09/29/2021 08:25:44PM via free access Estrogen receptor  and bone · L LANYON and others 191

Yang J, Pham SM & Crabbe DL 2003 High-resolution micro-CT Received 16 May 2004 ff evaluation of mid- to long-term e ects of estrogen deficiency on rat Accepted 15 June 2004 trabecular bone. Academic Radiology 101153–1158. Zaman G, Cheng MZ, Jessop HL, WhiteR&Lanyon LE 2000 Made available online as an Mechanical strain activates estrogen response elements in bone cells. Accepted Preprint 17 June 2004 Bone 27 233–239.

www.endocrinology.org Journal of Endocrinology (2004) 182, 183–191

Downloaded from Bioscientifica.com at 09/29/2021 08:25:44PM via free access