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CRITICAL REVIEWS IN ORAL BIOLOGY & MEDICINE |
Bone Remodeling in Post-menopausal Osteoporosis
U.H. Lerner
Department of Oral Cell Biology, Umeå University, Umeå SE-901 87, Sweden; Ulf.Lerner{at}odont.umu.se
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ABSTRACT
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Bone mass in the skeleton is dependent on the coordinated activities of bone-forming osteoblasts and bone-resorbing osteoclasts in discrete bone multi-cellular units. Remodeling of bone in these units is important not only for maintaining bone mass, but also to repair microdamage, to prevent accumulation of too much old bone, and for mineral homeostasis. The activities of osteoblasts and osteoclasts are controlled by a variety of hormones and cytokines, as well as by mechanical loading. Most importantly, sex hormones are very crucial for keeping bone mass in balance, and the lack of either estrogen or testosterone leads to decreased bone mass and increased risk for osteoporosis. The prevalence of osteoporotic fractures is increasing dramatically in the Western part of the world and is a major health problem in many countries. In the present review, the cellular and molecular mechanisms controlling bone remodeling and the influence of sex hormones on these processes are summarized. In a separate paper in this issue, the pathogenesis of post-menopausal osteoporosis will be compared with that of inflammation-induced bone remodeling, including the evidence for and against the hypothesis that concomitant post-menopausal osteoporotic disease influences the progression of periodontal disease.
Key Words: osteoporosis • bone • estrogen • osteoclasts • osteoblasts
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(1) INTRODUCTION
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The skeleton serves several important functions, such as structural functions that provide mobility, support for, and protection of the body. It also has an important function as a reservoir for calcium and phosphorus. To fulfill the structural functions, it is not only the amount of bone tissue present in the skeleton that is important, but also the architecture and shapes of bones. One important structural function of the skeleton is the anchoring of the teeth to the jawbones, a function that involves bone tissue, periodontal ligament, and cementum on the roots of the teeth. The reservoir role played by the skeleton is important for regulation of blood levels of calcium and phosphorus, which, in turn, are influenced by mineral uptake in the intestine and mineral excretion in the urine. The mineral homeostatic mechanisms in the skeleton are controlled by the calcium-regulating hormones—parathyroid hormone (PTH), calcitonin (CT), and 1,25(OH)2-vitamin D3 (D3)—which regulate the activity of the bone-resorbing cells.
Bone tissue is not static, and healthy bones require continuous remodeling and modeling to adapt to their dual roles as a supporting frame and as a regulator of mineral homeostasis. Remodeling is a lifelong coordinated and dominant process in the adult skeleton, whereby cortical and trabecular bone is rebuilt, a process initiated by resorption and followed by new bone formation at the same site where the resorption process occurs. If the two processes are quantitatively equal, the remodeling process is balanced. Remodeling is important for the maintenance of bone mass, to repair microdamage of the skeleton, to prevent accumulation of too much old bone, and for mineral homeostasis. Unbalanced remodeling may lead either to loss of bone, as in osteoporosis, or, more rarely, to gain of bone, as in osteopetrosis. Modeling is a process where bone resorption takes place in one site and bone formation at another. Thus, modeling implies that new bone is formed independent of preceding bone resorption at the site of formation. Modeling can lead to a new shape of the skeleton, or to thickening of cortical bone due to periosteal new bone formation.
Unbalanced bone remodeling, leading to the loss of bone tissue, is observed in pathological conditions such as osteoporosis, rheumatoid arthritis, periodontitis, periapical osteitis, osteomyelitis, loosened joint prosthesis, metastatic cancers, and the syndrome, humoral hypercalcemia of malignancy. Pathological remodeling can also be a consequence of mutations in molecules regulating osteoclast and osteoblast differentiation and function (Tolar et al., 2004).
In osteoporosis, unbalanced remodeling leads to decreasing amounts of bone tissue in several sites of the skeleton (Figs. 1A, 1B ) and, eventually, to skeletal fractures, whereas, in periodontitis, the local unbalance in remodeling causes loss of alveolar bone surrounding the roots of the teeth (Fig. 1C), which in turn leads to increasing mobility and eventually to tooth loss.
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Figure 1. Unbalanced remodeling of the skeleton in post-menopausal osteoporosis because of excessive osteoclastic bone resorption and reduced capacity of osteoblasts to refill the resorption lacunae results in a decreased amount of bone tissue, loss of trabecular bone architecture, and, eventually, increased risk for fracture (compare normal bone in A and bone from an osteoporotic patient in B) [reproduced with permission of the American Society for Bone and Mineral Research from
Dempster et al., J Bone Miner Res 1:15–21, 1986[Medline]
[Order article via Infotrieve]
]. Unbalanced remodeling of the jawbones close to a chronic inflammatory process in the gingiva leads to loss of bone surrounding the roots of the teeth, and eventually to increased mobility and loss of teeth (C). (magnification not defined)
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Osteoporosis is defined as a disease characterized by low bone mass and deterioration of bone structure, causing bone fragility and increased risk of fracture (Figs. 1A, 1B ). Primary osteoporosis is mainly seen in elderly people. The mechanisms by which elderly people, both men and women, lose bone are not fully understood. Decreased quantities of sex hormones are one important factor causing bone loss. Although most patients suffering from osteoporosis are post-menopausal women exhibiting loss of estrogen, elderly men also develop primary osteoporosis. Women exhibit two phases of age-related bone loss: The first starts at menopause, predominantly in trabecular bone, is caused by estrogen deficiency, and results in a disproportionate increase in bone resorption as compared with formation. When this phase peaks after 4–8 years, the second phase starts, exhibiting a persistent, slower loss of both trabecular and cortical bone, and is mainly a result of decreased bone formation. Men exhibit only the slow phase of bone loss, which is believed to be due to decreased levels of bioavailable testosterone and estrogen, as a consequence of increased levels of sex-hormone-binding globulin (SHBG). Decreasing levels of estrogen are thought to be responsible for increased resorption, and decreasing testosterone for decreased bone formation (Riggs et al., 2002).
Secondary osteoporosis can be observed in both young and old people as a consequence of other diseases, or due to medication. A common cause of secondary osteoporosis is hypercortisolism, most frequently due to medication but, in some cases, also due to Cushing’s disease. Other diseases that may cause osteoporosis are anorexia nervosa, athletic amenorrhea, hyperparathyroidism, thyrotoxicosis, cystic fibrosis, osteogenesis imperfecta, diabetes mellitus type I, gastrectomy, inflammatory bowel disease, rheumatoid arthritis, immobilization, stroke, depression, and post-transplant bone disease.
In clinical practice, osteoporosis is diagnosed by dual-energy x-ray absorptiometry scan (DEXA) measurements, and, according to the WHO, the diagnosis of osteoporosis is established when bone mineral density is 2.5 standard deviations below the mean for normal Caucasian women. It is often argued, however, that this definition focuses too much on bone mass, rather than on bone strength. Therefore, it has been proposed that a clinically defined fracture should be present before the diagnosis of osteoporosis can be made. It has been shown that loss of connectivity within the network of trabecular bone is a risk factor, independent of bone mineral density, for fractures (Legrand et al., 2000). Therefore, new diagnostic tools have recently been used in attempts to get a better insight into bone microarchitecture (Dempster, 2003). The most common sites for osteoporotic fractures are the wrist, the spine, and the hip, with wrist fractures occurring more frequently in women 50–60 years of age, spine fractures in 60- to 80-year-old women, and hip fractures in the most elderly women. Since patients suffering from hip fractures are usually old, the risk of death is high, not due to the fracture itself, but due to complications, especially during the first year.
The prevalence of osteoporosis varies globally, but in Bone Health and Osteoporosis. A Report of the Surgeon General (2004), it is estimated that 35% of post-menopausal Caucasian American women have osteoporosis in the hip, spine, or distal forearm. There are large variations, however, in the prevalence of osteoporosis in different parts of the world. As an example of the differences in geographic distribution, 21% of Swedish post-menopausal women suffer from hip osteoporosis, whereas only 8% of Canadian post-menopausal women exhibit hip osteoporosis. In the Surgeon General’s report, it is estimated that 40% of American women over the age of 50 will experience an osteoporotic fracture, with the risk for men over 50 being 13%. Incidence increases, however, not only as a result of the increasing number of older individuals, but also due to age-adjusted incidence of the disease, and it is calculated that, in 2020, 50% of Americans over 50 will be at risk for developing osteoporosis. Osteoporosis is by far the most common disease of the skeleton, and it imposes a tremendous burden on patients as well as on society. The costs for direct expenditures in the United States for the estimated 1.3 million fractures per year have been calculated to be $14 billion (Ray et al., 1997).
Although not a bone disease by definition, patients with periodontitis exhibit local loss of bone, and, therefore, while periodontitis is primarily an infectious disease, it should also be regarded as a bone disease. It is the loss of bone which causes loosening of the teeth and thereby the disability for the patients. Periodontitis is an infectious disease caused by bacteria in the biofilm present on tooth surfaces, which triggers an inflammatory-immune response in the gingival tissue. As with other inflammatory conditions in the vicinity of the skeleton, molecules present in the inflamed gingiva affect the remodeling of the skeleton in the jawbones such that tooth-supporting tissue is destroyed, and gingivitis will develop into periodontitis. The prevalence of periodontitis has been studied extensively in Sweden, and, in 1993, was found to be 13% for the severe form and 27% for mild periodontitis (Hugoson et al., 1998). In a cohort consisting of an older (60–75 years) ethnically diverse population in North America, the prevalence of periodontitis was as high as 48.5%, as assessed radiographically (Persson et al., 2002). The prevalence of mild periodontitis in Sweden decreased from 47% in 1973 to 27% in 1993, mainly due to increased awareness that it is an infectious disease and can be prevented by mechanical dental hygiene (Hugoson et al., 1998). However, the prevalence of the severe form of periodontitis has not decreased, despite intensive dental hygiene programs, indicating that it is not only the amount of bacteria in the dental biofilm which is important for the initiation and progression of the disease, but that also hitherto-unrecognized host defense mechanisms play crucial roles.
Although the etiologies of post-menopausal osteoporosis and periodontitis are different, the pathogenetic mechanisms causing loss of bone in the two diseases share several features. It is the aim of the present review to present the current views on the cellular and molecular mechanisms involved in the pathogenesis of post-menopausal osteoporosis. A short overview of physiological remodeling precedes the discussion of pathological remodeling. Readers interested in more details on physiological remodeling are referred to recent reviews (Takahashi et al., 2002; Boyle et al., 2003; Teitelbaum and Ross, 2003; Lerner, 2004). In a separate paper in this issue, the pathogenesis of inflammation-induced bone remodeling will be discussed and compared with that of post-menopausal osteoporosis (Lerner, 2006). In that same paper, the possibility that concomitant osteoporosis may contribute to the pathogenesis of periodontal disease will also be discussed.
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(2) PHYSIOLOGIC BONE REMODELING
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Remodeling of the skeleton is crucial for maintaining its quality, and it is estimated that approximately 10% of the skeleton is renewed each year by this process. Trabecular rather than cortical bone is more frequently remodeled, which explains why metabolic bone diseases such as osteoporosis are mainly, but not exclusively, observed in bones with comparatively large amounts of trabecular bone, e.g., the distal forearm, spine, and hip.
Bone resorption and bone formation do not occur randomly in the skeleton, but take place at so-called bone multi-cellular units. It is estimated that the human skeleton has 1–2 x 106 such units (Riggs and Parfitt, 2005). The remodeling process in bone multi-cellular units is initiated by osteoclastic resorption. However, since osteoclast formation and activation are controlled by osteoblasts (covering the bone surfaces), the most initial phase consists of the catabolic activation of osteoblasts. It is not likely that actively bone-forming osteoblasts are the cells that activate osteoclasts. Rather, inactive osteoblasts, either the so-called lining cells or the pre-osteoblast, are responsible, although this has not been definitively shown. It is completely unknown which molecules activate this change in the phenotype of osteoblasts/lining cells during the physiological remodeling process, with the exception of the remodeling that is part of the hormonal regulation of calcium homeostasis. It is well-known that loading plays an important role: A low amount of loading leads to bone loss, due to decreased anabolic activity of osteoblasts and increased osteoclastic resorption, and high loading causes increased bone mineral density, due to the anabolic activation of osteoblasts. Two commonly cited examples are the decreased bone mineral density that can be observed during space flights (up to 2% loss per month) and the increased bone mineral density (up to 35% more) in the racket arms of tennis players.
The surfaces of all bone tissues are covered by a single cell layer of osteoblasts, which means that these cells cover all trabecular bone and are present as the innermost cell layer in the endosteum and periosteum of cortical bone (Fig. 2A). Activation of a remodeling cycle initially leads to osteoblastic degradation of the unmineralized osteoid that exists between the osteoblastic cell layer and the mineralized bone (Fig. 2B). This is necessary, since the osteoclast cannot adhere to unmineralized bone and is capable of only resorbing mineralized bone. Next, the osteoblasts increase their expressions of receptor activator of nuclear factor  B ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) (Fig. 2C). In addition, the expression of osteoprotegerin (OPG; an inhibitor of RANK activation due to its function as a decoy receptor binding to RANKL) is decreased. This will allow more of the RANKL molecules to activate the receptor RANK. By a process that requires cell-to-cell contact, RANKL will activate its cognate receptors, RANK, on osteoclast progenitor cells (Fig. 2D). Together with the activation of the receptor c-Fms by M-CSF, this will lead to an expansion of the osteoclast progenitor pool, increased survival of these cells, and the initiation of a differentiation program that terminates in fusion of the mononucleated progenitor cells and the development of latent multi-nucleated osteoclasts (Fig. 2E). Finally, these latent osteoclasts become activated to bone-resorbing osteoclasts (Fig. 2F).
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Figure 2. Mineralized extracellular matrix in bone is covered by a non-mineralized extracellular matrix (osteoid) produced by osteoblasts, which form a one-cell layer covering all bone surfaces (A). Bone resorption is initiated by hormones, cytokines, or unknown molecules activating receptors present on osteoblasts, which leads to degradation of the osteoid (B) and increased expression of M-CSF and RANKL (C). M-CSF activates its cognate receptor c-fms on osteoclast progenitor cells, which results in proliferation and increased survival, and RANKL activates the receptor RANK, also on osteoclast progenitor cells, resulting in differentiation of these cells along the osteoclastic lineage (D). For osteoclast differentiation to occur, the immunoreceptor tyrosine-based activation motifs harboring molecules FcR and DAP12 need to be activated by hitherto-unknown ligands (D). The differentiation of the mononuclear osteoclast progenitor cells ends up with fusion to latent multi-nucleated osteoclasts (E), which finally become activated to bone-resorbing osteoclasts (F). The osteoclasts will attach to mineralized bone surface when the osteoblasts have retracted from the area to be resorbed (F).
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Very recently, it has been shown that activation of two adapter proteins, DNAX-activating protein 12 (DAP12) and Fc receptor common subunit (FcR), is also crucial for osteoclast differentiation (reviewed by Takayanagi, 2005). DAP12 associates with a variety of ligand-recognizing receptors—so-called DAP12-associated receptors (DARs), such as triggering receptor expressed in myeloid cells 2 (TREM2), TREM3, myeloid DAP12-associated lectin-1 (MDL-1), natural killer cells group 2D (NKG2D), and signal-regulatory protein β1 (SIRP1β)—whereas FcR associates with two receptors: osteoclast-associated receptor (OSCAR) and paired immunoglobulin-like receptor A (PIR-A). Activation of FcR and DAP12 leads to recruitment and activation of the tyrosine kinases Syk and Zap70, and to the activation of immunoreceptor tyrosine-based activation motifs (ITAM), which are present in the cytoplasmic tails of both FcR and DAP12, and it seems as if there is a redundancy between the two activation pathways. Very little is known about the ligands for the receptors associated with FcR and DAP12, but circumstantial evidence indicates that DARs are activated by an unknown ligand expressed by osteoclast progenitor cells, and that the ligand for OSCAR is expressed on osteoblasts.
The final step in the activation of the remodeling process is the retraction of the osteoblasts from the bone surface, so that the multi-nucleated osteoclasts can gain access to mineralized bone (Fig. 2F). The giant cells attach to bone by vitronection receptors ( vβ3), expressed preferentially in the sealing zone. Importantly, this integrin has binding sites for Arg-Gly-Asp (RGD) sequences in osteopontin and bone sialoprotein, present on the surface of the exposed mineralized bone. When bound to bone extracellular matrix, osteoclasts develop a ruffled border, and by means of a proton pump and a chloride channel (ClC-7) in the ruffled border membrane, an acidic milieu is created in Howship’s resorption lacunae, and the hydroxyapatite crystals will be dissolved. The demineralized organic matrix of bone will subsequently be degraded by proteolytic enzymes, including highly collagenolytic cathepsin K.
When remodeling has been initiated by osteoblast-dependent stimulation of osteoclast formation and activity, the osteoclasts create resorption lacunae (Figs. 3A, 3B). Then, the osteoclasts leave the lacunae (Fig. 3C), and a less-well-characterized mononuclear cell appears in the lacunae, "cleaning up" the organic matrix left behind by the osteoclasts, and possibly also forming the more intensively stained cementum line in the bottom of the lacunae (Fig. 3C; Everts et al., 2002). Subsequently, osteoblast precursor cells are recruited to the lacunae, where they differentiate into fully active osteoblasts that will fill the resorption lacunae with new bone (Figs. 3D, 3E). It has been suggested that insulin growth factor-I (IGF-I) and transforming growth factor-β (TGF-β), both of which are abundant in the extracellular matrix of bone and are released during the resorption process, play important roles in the recruitment and activation of the osteoblasts in the bone multicellular units. In this context, these growth factors are referred to as "coupling factors", linking bone formation to bone resorption.
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Figure 3. Remodeling of bone in a bone multi-cellular unit starts with osteoblastic activation of osteoclast differentiation, fusion, and activation (A,B). When resorption lacunae are formed, the osteoclast leaves the area, and mononucleated cells of uncertain origin appear and "clean up" the organic matrix remnants left by the osteoclast, also possibly forming the cementum line (dotted line) at the bottom of the lacunae (C). During the resorption process, coupling factors, including IGF-I and TGF- β, are released from the bone extracellular matrix, and these growth factors contribute to the recruitment and activation of osteoblasts to the resorption lacunae (D). The osteoblasts will then fill the lacunae with new bone, and when the same amount of bone is formed as that being resorbed, the remodeling process is finished, and the mineralized extracellular matrix will be covered by osteoid and a one-cell layer of osteoblasts (E).
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A crucial event in the initiation of bone resorption is the activation of the receptors RANK and c-Fms on osteoclast progenitor cells. Although much is known about the regulation of RANKL, OPG, RANK, and M-CSF expression by hormones and cytokines, it is not known which molecules regulate the expression of these cytokines during physiological remodeling.
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(3) SKELETAL REMODELING IN POST-MENOPAUSAL OSTEOPOROSIS
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Post-menopausal osteoporosis is characterized by increased frequency of bone remodeling—i.e., in the skeletons of women suffering from this disease, an increased quantity of bone multi-cellular units is present. There are two components in bone multi-cellular units that are important for the remodeling of bone. One is the activation frequency, which is the statistical probability that bone remodeling will be initiated on any bone surface at any given time (Riggs and Parfitt, 2005). This is the most variable component in the bone multi-cellular units in the healthy and diseased skeleton. The other part is the algebraic difference between the formation and resorption phases. Decreased ability of osteoblasts to fill resorption lacunae will, of course, contribute to unbalanced remodeling and loss of bone, but this component varies much less than activation frequences in the healthy and diseased skeleton.
Increased frequency of bone multi-cellular unit activation in post-menopausal women leads to increased numbers of osteoclasts and resorption lacunae in the skeleton (Fig. 4A). Patients do not exhibit increased serum calcium, because of the tight control exercised by the calcium-regulating hormones. However, the excretion of calcium in the urine increases along with deoxypyridinoline crosslinks, as a consequence of increased degradation of the abundant type I collagen fibres in the bone extracellular matrix. Since the number of resorption sites is increased, the number of formation sites will also be increased (Fig. 4B). Osteocalcin, one of the very few bone-specific molecules made by osteoblasts and incorporated into the organic matrix of bone, is a widely used marker for bone formation. This is because the protein/peptide recognized by the antibodies in the ELISA used to assess serum osteocalcin represents "spillover" of osteocalcin produced by osteoblasts, rather than degradation products released during bone resorption. In post-menopausal osteoporosis, osteocalcin levels are increased, not because individual osteoblasts make more osteocalcin, but because of the increase in the number of bone-forming osteoblasts.
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Figure 4. In post-menopausal osteoporosis, the decrease of estrogen will lead to increased numbers of osteoclasts and, thus, enhanced numbers of bone multi-cellular units (A). As a consequence, the urinary excretion of calcium and collagen degradation products, such as deoxypyridinoline crosslinks, will be increased. Since more bone multi-cellular units are present in the skeleton of a post-menopausal woman, the number of active osteoblasts will be enhanced, and because of that, the serum level of osteocalcin will be increased (B). The more severe the osteoporosis, the more bone multi-cellular units will be present, and therefore the number of active osteoblasts and serum osteocalcin levels will be an indicator of "high turnover" osteoporosis. However, since the individual osteoblasts are less-well-functioning because of the lack of estrogen, the net effect of resorption and bone formation will be such that the amount of bone tissue will decrease.
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Thus, in post-menopausal osteoporosis, the number of osteoclasts as well as the number of actively bone-forming osteoblasts is increased. It is the increased frequency of activation sites, together with the decreased ability of individual osteoblasts to produce new bone, which is the reason bone mass decreases and bone strength is reduced. Most of the drugs used today target the osteoclasts, to inhibit their activity. Although this strategy focuses on inhibiting further loss of bone, treatments with osteoclast inhibitors such as the bisphosphonates alendronate and risedronate can reduce fracture rates by 50% (Cranney et al., 2002a,b). Of course, the ultimate therapeutic goal would be to restore lost bone in patients with existing osteoporosis. Recently, intermittent administration of a 34-amino-acid fragment of human PTH (teriparatide) has been found to be a useful stimulator of bone formation in both trabecular and cortical bone (Jiang et al., 2003). It causes increased bone mineral density and decreased incidence of vertebral and non-vertebral fractures (Hodsman et al., 2005). It is not understood, at a molecular level, how sustained increased levels of PTH, such as in hyperparathyroidism, lead to increased bone resorption and bone loss, whereas intermittently injected PTH results in increased bone formation and gain of bone mass.
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(4) ESTROGEN RECEPTORS
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The receptors for estrogen, as for all other steroid hormones, are protein molecules present in the cytosol. In contrast to peptide receptors present on cell surfaces, steroid hormone receptors are ligand-dependent transcription factors. Upon ligand binding, the receptors dimerize and translocate into the nucleus, where, together with a large variety of transcription activators and repressors, they either induce or inhibit the transcription of genes.
There are two different estrogen receptors (ER), the classic receptor, now called estrogen receptor (ER), and the recently discovered ERβ. Although genetically distinct, the two receptors have extensive homology within the ligand and DNA-binding domains (Kuiper et al., 1996). ER is widely distributed and is expressed in both osteoblasts and osteoclasts. ERβ is expressed mainly in epithelial and mesenchymal tissues, including osteoblasts, but its expression in osteoclasts is more controversial. The expression of estrogen receptors in bone cells is less than that in classic estrogen-responsive target cells in the reproductive tissues.
Mice deficient in either ER or ERβ, or both, show complex different phenotypes, which vary in males and females. The interpretation of data obtained with these knockout mice is complicated by the fact that it has been found that there are two distinct splice variants of ER, both of which can bind estrogen and are transcriptionally active (Sanyal et al., 2005), and not all ER knockout mice are deficient in both variants (for discussion, see Syed and Khosla, 2005). Although these experiments, using global knockout strategies, clearly demonstrate the importance of estrogen receptors in bone biology, they do not indicate if the phenotypes are due to direct effects by estrogen on bone cells, or if they are mediated indirectly by other ER-positive cells.
It is firmly established, however, that the estrogen receptors present in osteoblasts and osteoclasts are functional and can regulate several activities in these cells. Thus, stimulation of estrogen receptors in osteoblasts activates their anabolic activities and decreases the pathway by which osteoblasts can activate osteoclasts. Activation of estrogen receptors in osteoclast progenitor cells decreases osteoclast formation, and activation of estrogen receptors in terminally differentiated osteoclasts inhibits their bone-resorbing activity. As mentioned, estrogen receptors are present in many different cell types, and it is likely that not only are those present in bone cells important for the effects of estrogen on the skeleton, but also that effects mediated by other ER-positive cells play crucial roles. As will be discussed, most attention has been paid to effects on the skeleton mediated by immune cells.
The estrogen receptors can bind not only estrogen, but also the so-called selective estrogen-receptor modulators (SERMs). For reasons not fully understood, these compounds activate estrogen receptors in bone, but act as antagonists in other organs, such as the breast and uterus. One SERM, raloxifene, is currently used for the treatment of osteoporosis. Like estrogen, the compound mainly acts as an inhibitor of bone resorption.
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(5) REGULATION OF OSTEOCLAST FORMATION AND ACTIVITY BY THE EFFECTS OF ESTROGEN ON BONE CELLS
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Since both osteoblasts and osteoclasts express estrogen receptors, it is reasonable to assume that the effects of estrogen on skeletal remodeling could be caused, at least partly, by a direct effect on bone cells. It has in fact been shown that estrogen receptors in differentiated osteoclasts are functional and cause decreased bone-resorbing activity (Oursler et al., 1991a; Taranta et al., 2002) and enhanced apoptosis (Hughes et al., 1996; Chen et al., 2005). However, ER mRNA is substantially down-regulated during osteoclastic differentiation (Garcia Palacios et al., 2005); therefore, estrogen receptors present in osteoclast progenitor cells are probably more important than those in the terminally differentiated osteoclasts. Activation of these estrogen receptors leads to the inhibition of osteoclast formation, as shown with use of the monocytic RAW 264.7 cells stimulated by RANKL (Shevde et al., 2000; Srivastava et al., 2001; Garcia Palacios et al., 2005) and mouse bone marrow macrophages stimulated by both M-CSF and RANKL (Shevde et al., 2000; Srivastava et al., 2001). The mechanism has been attributed to effects by estrogen on signaling pathways downstream of RANK, including inhibition of c-Jun amino terminal kinases, resulting in decreased activation of AP-1 (Shevde et al., 2000; Srivastava et al., 2001), NF-B and ERK1,2 (Garcia Palacios et al., 2005) (Fig. 5). These mechanisms of action by estrogen make sense, since the crucial roles of AP-1 and NF-B pathways in osteoclasto-genesis have been demonstrated in mice deficient in c-Fos, or in both the NF-B subunits p50 and p52. Thus, c-Fos–/– and p50–/– /p52–/– mice exhibit osteopetrosis due to lack of osteoclasts (Grigoriadis et al., 1994; Iotsova et al., 1997). The inhibitory effects of estrogen are mediated by ER, since osteoclast progenitor cells are devoid of ERβ. The inhibitory effects on osteoclast formation and c-Jun amino terminal kinase are also obtained with the selective estrogen-receptor modulators raloxifene and tamoxifen (Shevde et al., 2000).
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Figure 5. Activation of the receptor RANK starts with trimerization of the receptor and subsequent binding of different tumor necrosis factor receptor-associated factors (TRAFs), including the most important, TRAF6, to the cytoplasmic tail of RANK. This leads to activation of the inhibitor-B kinase (IKK) complex and subsequent phosphorylation of the nuclear factor-B (NF-B) inhibitor IB, which then becomes ubiquitinated and degraded in proteasomes. Released NF-B dimers translocate to the nucleus and bind to responsive elements in different genes. The activation of NF-B can be inhibited by estrogen by mechanisms the details of which are unknown. Activation of RANK also leads to activation of the mitogen-activated protein kinases (MAP kinases) p38, extracellular signal-regulated kinases (ERK)  , and c-jun amino-terminal kinase (JNK), which then phosphorylate and activate the transcription factor AP-1. Activation of ERK and JNK has also been shown to be inhibited by estrogen. In addition to RANK activation, stimulation of either FcR or DAP12 is crucial for osteoclast differentiation. This pathway then leads to enhanced intracellular calcium and activation of calcineurin, which then dephosphorylates the transcription factor nuclear factor of activated T-cells 2 (NFAT2). It is not yet known if estrogen also affects this pathway. The importance of these pathways for osteoclastogenesis is shown by the findings that NF-B–/–, c-fos–/–, and NFAT2–/– mice all lack osteoclasts and are osteopetrotic.
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Since osteoblasts/stromal cells are crucial for osteoclast formation, due to the expression of M-CSF, RANKL, and OPG, activation of the estrogen receptors in these cells may also play a role in the regulation of osteoclastogenesis. Consistent with this view, it has been demonstrated that estrogen increases OPG mRNA and protein expression in human osteoblasts (Hofbauer et al., 1999) and murine stromal cells (Saika et al., 2001), an effect most likely mediated by ER. Similarly, the SERM compound raloxifene stimulates OPG formation at both protein and mRNA levels in human osteoblasts that predominantly express ER (Viereck et al., 2003). Furthermore, OPG levels in blood are higher in post-menopausal women on hormone replacement therapy, compared with those in women without treatment (Browner et al., 2001). Although serum analyses of OPG are complicated by the fact that OPG is ubiquitously expressed, another study showed that OPG serum levels were positively correlated with 17β-estradiol and bone mineral density (Rogers et al., 2002). No convincing evidence for a direct effect of estrogen on RANKL expression in osteoblasts, or stromal cells, has been reported so far, although the RANKL levels are likely to be influenced secondarily to effects by estrogen on RANKL-stimulating cytokines (see below). The fact that no estrogen-responsive elements seem to exist in the RANKL promoter (Kitazawa et al., 1999) also argues for the notion that estrogen does not directly regulate RANKL transcription. The studies by Eghbali-Fatourechi et al.(2003)—showing that surface-expressed RANKL protein on human bone marrow stromal cells, isolated by flow cytometry, was substantially increased in cells from post-menopausal women, as compared with pre-menopausal women, as well as with estrogen-treated post-menopausal women—demonstrate that estrogen can regulate RANKL expression on bone marrow stromal cells, although the studies do not demonstrate if this is a direct or indirect effect.
Estrogen may also influence osteoclast formation by decreasing the expression of M-CSF (Sarma et al., 1998; Lea et al., 1999).
Thus, it is possible that estrogen may control bone resorption by several mechanisms crucial for osteoclast differentiation, via receptors in both osteoblasts/stromal cells and osteoclast progenitor cells.
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(6) REGULATION OF PROSTAGLANDIN PRODUCTION BY ESTROGEN
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Prostaglandins are arachidonic acid metabolites, of which prostaglandin E2 (PGE2) is a potent stimulator of bone resorption in organ culture and osteoclast formation in bone marrow and spleen cell cultures (Pilbeam et al., 2002). There are four receptor subtypes for PGE2—EP1, EP2, EP3, and EP4—of which EP2 and EP4 are important for the effects of PGE2 on osteoclast formation and bone resorption (Li et al., 2000; Suzawa et al., 2000). PGE2 may enhance bone resorption by two mechanisms: one as a result of increasing RANKL expression caused by activation of prostaglandin receptors in osteoblasts/stromal cells (Yasuda et al., 1998), and the other due to potentiation of RANK signaling caused by activation of prostaglandin receptors in osteoclast progenitor cells (Ono et al., 2005).
In ex vivo cultures of mouse calvariae from estrogen-deficient animals, the amount of PGE2 formed is enhanced, an increase which can be inhibited by estrogen (Feyen and Raisz, 1987). It has also been shown that estrogen inhibits PGE2 production in mouse calvarial bones and human monocytes (Pilbeam et al., 1989; Miyagi et al., 1993). In addition, the urinary excretion of PGE2 is greater in post-menopausal than in pre-menopausal women (Akgul et al., 1998). Although all of these observations indicate an important role of estrogen in prostaglandin metabolism, it is not unlikely that the observation may be due to an indirect effect by estrogen caused primarily by inhibition of the cytokines that stimulate the enzyme cyclo-oxygenase-2, which is the rate-limiting enzyme in the conversion of arachidonic acid to prostaglandins.
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(7) REGULATION OF OSTEOCLAST-STIMULATING CYTOKINES BY ESTROGEN
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The decreasing levels of estrogen during menopause have implications for the functions of many organs in the body, both reproductive and non-reproductive. Although it is likely that different pathogenetic mechanisms are involved, at least partly, in the effects of estrogen on bone, cardiovascular system, and adipose tissues, there is much interest in the role that cytokines may play in the effects of estrogen deficiency in all these organs. For a comprehensive overview, readers are referred to a recent review by Pfeilschifter et al.(2002). In the present review, the effects of estrogen on osteotropic cytokines are summarized.
Although the RANKL-RANK-OPG system is crucial for osteoclast differentiation, the expression of these members of the tumor necrosis factor (TNF) ligand and receptor superfamilies is regulated by cytokines long known to stimulate bone resorption. Thus, interleukin-1 (IL-1) and TNF-, as well as cytokines in the interleukin-6 (IL-6) family of cytokines, enhance RANKL expression (Ahlen et al., 2002; Palmqvist et al., 2002; Kwan Tat et al., 2004). In contrast to PTH and D3 (which also enhance RANKL), IL-1, TNF-, and cytokines in the IL-6 family increase OPG expression (Vidal et al., 1998; Brändström et al., 2001; Palmqvist et al., 2002), instead of decreasing this decoy receptor in a manner similar to that observed with the calcium-regulating hormones. This may be the reason why PTH and D3 are usually more effective stimulators of bone resorption (Palmqvist et al., 2002). It is possible that the effect of estrogen on bone resorption could be due to the inhibition of RANKL-stimulating cytokines. In fact, estrogen is a potent inhibitor of IL-1β and TNF- production in bone marrow cells and monocytes (Pacifici, 1999). Estrogen also inhibits the production of IL-6 in stromal cells and osteoblasts (Girasole et al., 1992). In contrast, the expression of TGF-β in extracts from bone is decreased in ovariectomized rats and enhanced in estrogen-treated mouse calvarial osteoblasts (Finkelmann et al., 1992), human osteoblast-like cells (Oursler et al., 1991b), and bone marrow macrophages (Gao et al., 2004). These studies were prompted by a series of findings by Pacifici and collaborators, showing that the ex vivo production of IL-1 and TNF- was enhanced in circulating monocytes from post-menopausal women and from ovariectomized women (Pacifici et al., 1987, 1989, 1991). Later, it was shown that the production of IL-6 (Passeri et al., 1993), IL-1 (Kitazawa et al., 1994), TNF- (Kitazawa et al., 1994), and M-CSF (Kimble et al., 1996) is enhanced in bone marrow stromal cells and osteoblasts from ovariectomized mice, whereas the production of TGF-β in bone marrow macrophages is decreased (Gao et al., 2004). Ovariectomy also leads to enhanced expression of IL-1 and TNF-β in bone marrow macrophages (Kimble et al., 1996). The fact that estrogen did not affect M-CSF expression in isolated bone marrow cells, but that IL-1 and TNF- enhanced M-CSF expression in these cells, indicates that the increased production of M-CSF in stromal cells from ovariectomized mice may be an indirect effect caused by increased IL-1 and TNF-. These findings show that estrogen deficiency leads to enhanced expression of bone-resorbing cytokines in both women and female mice. However, attempts to assess circulating levels of these cytokines in post-menopausal women and to correlate them to osteoporosis have resulted in conflicting results. This is most likely due to the possibility that it is cytokine production in the local microenvironment of bone which is important, whereas the circulating levels reflect the production in many tissues and is also largely dependent on the rate of degradation. Analysis of the recent data from Eghbali-Fatourechi et al.(2003), showing enhanced expression of RANKL in bone marrow stromal cells isolated from post-menopausal women, demonstrates the importance of evaluating cytokine expression in cells present in bone.
The observations that the neutralization of IL-1, TNF-, or IL-6 by the administration of neutralizing specific antibodies, binding proteins, or receptor antagonists inhibits ovariectomized-induced bone loss in mice and rats have provided more direct evidence for the importance of these cytokines in the loss of bone associated with estrogen deficiency (Jilka et al., 1992; Kitazawa et al., 1994; Kimble et al., 1994, 1997). Similarly, mice deficient in the functional type I IL-1 receptor (Lorenzo et al., 1998), mice deficient in p55 TNF receptors (Roggia et al., 2001), mice overexpressing the soluble TNF- receptor (Ammann et al., 1997), or mice lacking IL-6 (Poli et al., 1994) do not exhibit bone loss after ovariectomy. The importance of M-CSF for bone loss caused by estrogen deficiency is also demonstrated by the observation that M-CSF-deficient mice are resistant to bone loss caused by ovariectomy (Cenci et al., 2000a). Analysis of these data demonstrates that IL-1, TNF-, and IL-6 are crucial, at least in mice, for the pathogenetic mechanisms by which estrogen deficiency leads to increased expression of functional RANKL and M-CSF and to enhanced bone resorption and bone loss (Fig. 6). In addition to these cytokines, it has also been shown that treatment with antibodies neutralizing IL-11 decreased osteoclast formation and bone loss in ovariectomized mice (Shaughnessy et al., 2002).
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Figure 6. Osteoclast progenitor cell proliferation, differentiation, and fusion to bone-resorbing osteoclasts are enhanced during estrogen deficiency because of an increased RANKL/OPG ratio and the increased expression of M-CSF in periosteal osteoblasts and bone marrow stromal cells. Although it has been shown that estrogen can directly regulate M-CSF, it is not clear if the effect on RANKL and OPG expression is caused by a direct effect of estrogen, or if the increase is indirectly due to increased cytokines caused by a lack of estrogen.
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The view that estrogen does not regulate RANKL expression directly, but is more likely to do so via regulation of cytokines, is also compatible with the findings that estrogen receptors are able to interfere with the transcription of the genes of several cytokines. Although most of the action of the two estrogen receptors are due to their function as ligand-dependent transcription factors, the promoters of IL-1, TNF-, and IL-6 lack classic estrogen receptor response elements. However, it has been shown that the estrogen receptors interact with several other transcription factors, and it has been proposed that this is the mechanism by which the steroid hormone inhibits cytokine receptors. Thus, it has been shown that ligand-activated estrogen receptors can block the ability of NF-B to bind to response elements in the IL-6 gene (Stein and Yang, 1995). It is likely that this repression by estrogen receptors is also important for the control of the IL-1 gene, which contains several NF-B sites in the promoter. It has also been reported that estrogen receptors interact with the transcription factor CCAAT/enhancer-binding protein (C/EBP), which is crucial for the regulation of promoters in several cytokine genes (Stein and Yang, 1995). It seems as if both ER and ERβ are able to interact with NF-B-dependent activation of the IL-6 gene (Pelzer et al., 2001). Similarly, it has been shown that activation of estrogen receptors represses the stimulatory effect of the transcription factor AP-1 on the TNF- gene (Schmitt et al., 1995).
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(8) INVOLVEMENT OF T-CELLS IN POST-MENOPAUSAL OSTEOPOROSIS-INDUCED BONE RESORPTION
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There is evidence to support the view that the bone loss ‘sparing’ effect by estrogen might be explained by its effects on bone cells. It is also well-documented, however, that immune cells can regulate bone cell activities (Takayanagi, 2005), and since immune cells not only produce cytokines affecting osteoclast formation but also express estrogen receptors, it might very well be that the effects of estrogen on immune cells are more important for the bone loss ‘sparing’ effect. The studies by Pacifici and collaborators during the 1980s, showing that estrogen deficiency increases IL-1 and TNF- production in circulating monocytes, are clearly compatible with this view (Pacifici et al., 1987, 1989, 1991). As will be discussed below, this group of investigators has also published a series of papers to document this pathway further in experimentally induced osteoporosis in mice.
Athymic mice (nu/nu), lacking T-cells, do not exhibit bone loss after ovariectomy, in contrast to their control littermates (nu/+) (Cenci et al., 2000b). In bone marrow cultures from ovariectomized and sham-operated nu/nu and nu/+ mice, stimulated by D3 to induce osteoclast formation, the number of osteoclasts formed is substantially enhanced in cultures from ovariectomized nu/+ mice compared with cultures from sham-operated mice, whereas no difference between ovariectomy and sham operation was observed in cultures from nu/nu mice. Identical data were obtained in cultures without bone marrow stromal cells stimulated by M-CSF and RANKL. Analysis of these data suggests that T-cells in bone marrow are important for the enhanced osteoclast formation and bone loss caused by estrogen deficiency. The fact that the enhanced osteoclast formation seen in ex vivo bone marrow cultures from ovariectomized mice can be inhibited by blocking the function of TNF-, and that no enhancement of osteoclast formation in ex vivo cultures from ovariectomized mice could be seen in mice deficient in the p55 TNF- receptor, indicates that it is T-cell-derived TNF- that is the crucial factor for the enhancement of osteoclast formation (Cenci et al., 2000b). This view is further supported by the observations that TNF–/– mice and p55–/–, but not p75–/–, mice are resistant to bone loss caused by ovariectomy (Roggia et al., 2001). The authors also showed that it is the pool of TNF--producing T-cells which is up-regulated after ovariectomy, not the production of TNF- per cell.
But what is driving the expansion of the T-cells in estrogen-deficient mice? In a subsequent paper, the Pacifici group showed that ovariectomy in mice enhances the expression of class II transactivator (CIITA) in bone marrow macrophages, a transcriptional co-activator involved in antigen presentation to T-cells (Cenci et al., 2003). It is not known, however, which antigen could be triggering this response. Interferon- (IFN-) is a potent activator of antigen-presenting cells, and it was also shown that ovariectomy in IFN- receptor knockout mice does not lead to bone loss. The concept that IFN- should be driving osteoclast formation is controversial, since it is not compatible with the observations that INF- inhibits bone resorption (Gowen and Mundy, 1986) and osteoclast formation (Takayanagi et al., 2000) in vitro and, more importantly, with the in vivo observation that the numbers of osteoclasts are substantially enhanced in mice deficient in one of the IFN- receptor components (IFNGR1) after stimulation with lipopolysaccharide (Takayanagi et al., 2000). In a more recent paper, reporting on findings with mice deficient in TGF-β signaling in T-cells, because they overexpress a dominant-negative TGF-β type II receptor under the control of the CD4 promoter, it was reported that TGF-β is an upstream regulator of IFN- (Gao et al., 2004). In the transgene mice at least 8 wks old, with intact ovarium, the decreased TGF-β signaling in T-cells was associated with decreased bone mineral density. The low bone mass was due to enhanced bone resorption, since serum levels of a biochemical marker of bone resorption (CTX) were increased. No further loss was observed in ovariectomized transgenic mice. Since the authors also presented evidence that lack of TGF-β signaling results in increased INF- and increased expression of Class II transactivator, it is assumed that TGF-β is an upstream regulator of INF-. The view that T-cells are important for bone loss caused by estrogen deficiency is summarized in Fig. 7.
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(9) REGULATION OF BONE FORMATION BY ESTROGEN
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Although most of the loss in bone mass caused by estrogen deficiency is primarily due to enhanced bone resorption, decreased bone formation is also a contributing factor (Chow et al., 1992; Qu et al., 1998). It is less-well-understood, however, how estrogen controls the anabolic activities of osteoblasts. It has been suggested that decreased expression of TGF-β (Oursler et al., 1991b) and IGF-I (Ernst et al., 1989) in osteoblasts leads to a decreased stimulation of osteoblast proliferation and differentiation during estrogen deficiency. Estrogen also stimulates the expression of type I collagen (Ernst et al., 1989), and decreased levels of estrogen would then result in osteoblasts less active in producing an extracellular matrix. The observation that estrogen can decrease osteoblast apoptosis and thereby increase the lifespan of these cells has been put forward as a mechanism by which estrogen could control bone formation (Manolagas, 2000). The opposite effects of estrogen on osteoblast and osteoclast apoptosis have recently been attributed to different kinetics of Erk phosphorylation, since estrogen causes a transient phosphorylation of Erk in osteoblasts/osteocytes and a sustained phosphorylation in osteoclasts (Chen et al., 2005). There is also direct in vivo evidence that estrogen is important for osteoblastic function (Tobias and Compston, 1999).
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(10) SUMMARY
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Throughout adult life, the skeleton is continuously remodeled via the coordinated activities of bone-resorbing osteoclasts and bone-forming osteoblasts. Lack of estrogen leads to enhanced numbers of remodeling sites, due to enhanced formation of osteoclasts and to decreased formation of new bone in the resorption lacunae, eventually causing decreased bone mass and increased risk for osteoporosis. The enhancement of bone resorption is due to a decreased inhibition of estrogen on both osteoclastogenesis and osteoclast activity. This may be due to the presence of estrogen receptors in osteoclast progenitor cells and multi-nucleated osteoclasts. It might also be due to enhanced expression, in T-cells, of cytokines known to stimulate osteoclastogenesis, such as IL-1, IL-6, and TNF-, or to enhanced expression of M-CSF and RANKL in osteoblasts/stromal cells. The stimulatory effect of estrogen on bone formation is less-well-understood, but may be mediated by estrogen-receptor-responsive elements on promoters in genes involved in bone matrix biosynthesis, including type I collagen, or in genes for cytokines believed to be important for coupling of bone resorption and bone formation.
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ACKNOWLEDGMENTS
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Studies performed in the author’s laboratory have been supported by The Swedish Research Council, The Swedish Rheumatism Association, The Royal 80 Year Fund of King Gustav V, The Knut and Alice Wallenberg Foundation, the Swedish Foundation for Strategic Research, SalusAnsvar, Astra-Zenecca, Pharmacia-Upjohn, The Swedish Dental Association, Patentmedelsfonden, Anna-Greta Craaford Foundation, The County Council of Västerbotten, Umeå University and Centre for Musculoskeletal Research, and the National Institute for Working Life, Umeå, Sweden.
Received for publication June 15, 2005.
Accepted for publication November 23, 2005.
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Journal of Dental Research, Vol. 85, No. 7,
584-595 (2006)
DOI: 10.1177/154405910608500703
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ABSTRACT
(1) INTRODUCTION