Curr Osteoporos Rep (2014) 12:181–188 DOI 10.1007/s11914-014-0202-7
BIOMECHANICS (M SILVA AND P ZYSSET, SECTION EDITORS)
Diabetes, Collagen, and Bone Quality Mitsuru Saito & Yoshikuni Kida & Soki Kato & Keishi Marumo
Published online: 13 March 2014 # Springer Science+Business Media New York 2014
Abstract Diabetes increases risk of fracture, although type 2 diabetes is characterized by normal or high bone mineral density (BMD) compared with the patients without diabetes. The fracture risk of type 1 diabetes as well as type 2 diabetes increases beyond an explained by a decrease of BMD. Thus, diabetes may reduce bone strength without change in BMD. Whole bone strength is determined by bone density, structure, and quality, which encompass the micro-structural and tissue material properties. Recent literature showed that diabetes reduces bone material properties rather than BMD. Collagen intermolecular cross-linking plays an important role in the expression of bone strength. Collagen cross-links can be divided into beneficial enzymatic immature divalent and mature trivalent cross-links and disadvantageous nonenzymatic cross-links (Advanced glycation end products: AGEs) induced by glycation and oxidation. The formation pathway and biological function are quite different. Not only hyperglycemia, but also oxidative stress induces the reduction in enzymatic cross-links and the formation of AGEs. In this review, we describe the mechanism of low bone quality in diabetes and the usefulness of the measurement of plasma or urinary level of AGEs for estimation of fracture risk.
Keywords Diabetes . Bone quality . Collagen . Cross-links . Advanced glycation end products . Pentosidine . Homocysteine . Fracture risk
Introduction Diabetes is associated with increased risk of fracture [1], although type 2 diabetes is often characterized by normal or high bone mineral density (BMD). Thus, diabetes may be associated with a reduction of bone strength that is not reflected in the measurement of BMD. The important determinants of bone strength are bone mineral density, structural properties, and tissue material quality. Bone is composed of a 2-phase composite material. Hence, the mineral composition contributes to stiffness. In contrast, collagen fibers provide the intrinsic material properties such as tensile strength, ductility and toughness. Material property of bone is regulated by not only tissue turnover rate, but also the cellular activity and the levels of oxidative stress and glycation [2]. Collagen enzymatic and nonenzymatic cross-linking affect primary mineralization process and bone mechanical properties. Impaired enzymatic cross-linking and/ or an excessive formation of nonenzymatic cross-links, pentosidine (Pen), which is a surrogate marker of advanced glycation end products (AGEs), may be a major cause of bone fragility in aging, osteoporosis, and diabetes mellitus [3, 4••, 5]. We summarize the roles of collagen enzymatic and nonenzymatic cross-linking and how bone quality in diabetes deteriorates.
Cross-Link Formation in Collagen Fibers
M. Saito (*) : Y. Kida : S. Kato : K. Marumo Department of Orthopaedic Surgery, Jikei University School of Medicine, 3-25-8, Nishi-Shinbashi, Minato-ku, Tokyo 105-8461, Japan e-mail: [email protected]
Type I collagen is the most major component of protein in bone. Type I collagen has 2 nonhelical telopeptides at the amino and carboxyl terminal and a central triple helical domain. Collagen fiber shows crucial roles in bone strength and this is attributed in part to the formation of intermolecular cross-linking formation between the adjacent collagen molecules.
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Stabilization of newly secreted collagen fibers is initially formed by the formation of covalent cross-links between neighboring collagen molecules as post-translational modification. As a result, collagen cross-link formation affects the mechanical properties of bone at a material level. Collagen cross-links can be divided into lysyl oxidase regulated crosslinking and glycation or oxidation induced AGEs crosslinking. These 2 types vary in the mechanism of formation and display functional differences. The Beneficial Enzymatic Cross-Links of Bone Collagen Enzymatic cross-link formation is controlled by 2 enzymes such as the lysine hydroxylases (Procollagen-lysine, 2oxyglutarate, 5-dioxigenase, PLOD, LH) and lysyl oxidase (LOX, LOXL1-5a,5b). Tissue specific enzymatic cross-link pattern is regulated by PLOD intracellularly [6–9]. After hydroxylation, collagen molecules are secreted into the extracellular space. LOX binds to specific Lys or hydroxylysine (Hyl) residues in the telopeptides to determine total amount of enzymatic cross-link formation. Collagen molecules are aligned as quarter-stagger model. The initial step of cross-link formation extracellularly is conversion of ε-amino groups of specific for cross-linking site such as Lys and Hyl in the telopeptide domains. This reaction occurs via the action of LOX following aggregation of collagen molecules into fibers [10]. No excessive formation of enzymatic cross-linking occurs in the physiological mineralization process in vivo [11–13] and in vitro [7, 8, 14, 15] because the enzymatic cross-link formation is regulated by the expression of LOX [16•, 17]. Four isoforms of LOX likeproteins (LOXL1-4) were identified although a specific function of each isoform remains unclear [18]. Various regulatory factors of LOX expression are reported. Pyridoxal phosphate (vitamin B6) acts as an essential co-factor of LOX [19, 20]. Vitamin B6 deficiency in rats induced 25 % reduction in enzymatic cross-linking in bone compared with regularly fed rats [21]. It is well known that vitamin B6 deficiency commonly occurs in diabetes [22]. Vitamin B6 deficiency shows the adverse effects on cross-link formation in diabetes described the later section [22]. Various growth factors acting in bone formation such as transforming growth factor beta (TGF-β) [23], connective tissue growth factor (CTGF) [24], and insulin-like growth factor I (IGF-I) [25] are positive regulatory factors of LOX expression. Estrogen is a crucial regulatory factor of LOX expression. Estrogen deficiency induced by ovariectomy in rodent led to decrease the activity of LOX down to 25 %, but this reduced activity was rescued by estradiol injection [26]. Furthermore, ageing-related reduction in estrogen correlates to the activity of LOX in bone [27]. Ovariectomized rabbits exhibited a significant reduction in content of both immature, and mature enzymatic cross-links compared with the sham group [28]. This reduction of the
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enzymatic cross-link formation was improved by the administration of selective estrogen receptor modulator raloxifene [28]. This result indicates that estrogen like action via the receptor of estrogen may play a crucial role of LOX mediated enzymatic cross-link formation. Active vitamin D3 (alfacalcidol) also acts as a positive regulator of LOX expression from osteoblastic MC3T3-E1 cells in vitro [29]. In contrast, native vitamin D did not show any action for LOX expression. Thus, the pharmacological action of alfacalcidol may increase the expression of LOX. Similarly, in vivo, the administration of alfacalcidol induced enzymatic cross-link formation in bone from ovariectomized rat [30]. In contrast, the negative regulatory factors of LOX are reported. Glucocorticoid [31], fibroblast growth factor (FGF) [32], prostaglandin E2 [33], and tumor necrosis factor-alpha (TNF-alpha) [34] suppresses LOX gene expression and enzymatic activity. Deficient enzymatic cross-link formation by beta-aminopropionitrile treatment hampers osteoblastic differentiation [35]. These results indicate that proper enzymatic cross-link formation is essential for osteoblastic differentiation. Homocysteine (Hcys) inhibits enzymatic cross-link formation via a reduction in gene expression and enzymatic activity of LOX [36•, 37]. Hcys binds competitively to the aldehydic groups of precursor of cross-linking sites and results in a marked decrease in cross-linking [38]. Recently, mildly elevated plasma homocysteine in the general population was reported to be an independent fracture risk [39••]. This plausible mechanism is thought to low bone quality induced by abnormal collagen cross-link formation [36•, 37, 40, 41]. Hyperhomocysteinemia is a risk factor of arteriosclerosis as well as fracture risk in general population [42]. Type 2 diabetes also increases plasma level of homocysteine, resulting in arteriosclerosis [43•]. Hyperhomocysteinemia induced by methionine fed rabbit model exhibit a marked decrease of enzymatic cross-link formation in bone [28]. Thus, hyperhomocysteinemia in diabetes may show an additive adverse effect of bone quality (Fig. 1). The precursor of enzymatic cross-linking amino-acids such as the telopeptide Lys aldehydes (allysine) and Hyl aldehydes (hydroxyallysine) in the N-terminal telopeptide and in the Cterminal telopeptide then react and condensate with Lys or Hyl residues in the triple helical region of an adjacent collagen molecule to form divalent immature cross-links called deHdihydroxylysinonorleucine (DHLNL), deHhydroxylysinonorleucine (HLNL), and deH-lysinonorleucine (LNL). The divalent cross-links reacts spontaneously with another telopeptide Lys or Hyl aldehyde to form trivalent pyridinium or pyrrole cross-links. The amount of immature divalent cross-links decreased with age in human bone. These immature cross-links convert partially into mature cross-link [11, 44, 45]. Mature cross-links are pyridinium cross-links such as pyridinoline (PYD) and deoxypyridinoline (DPD) are formed via the hydroxyallysine pathway. Pyrrole cross-links, such as
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Fig. 1 A plausible mechanism of poor bone quality in diabetes
(pyrrolodine) PYL and deoxy-pyrrololine (DPL) are also characterized as mature trivalent cross-links [46, 47]. The mechanism of pyrrole cross-link formation is by condensation of de-HLNL/ de-DHLNL reacting with another allysine [48], or by rearrangement of 2 divalent cross-links including deH-HLNL [49]. Several investigations concerning enzymatic cross-links have focused only on mature pyridinium cross-links, without accounting for the presence of immature divalent cross-links. However, immature as well as mature cross-links may affect the physiological function of bone for the following reasons. Immature cross-linkages are the most frequently observed cross-link forms in bone, because the conversion rate of immature forms into mature forms is lower than that of other connective tissues, such as tendons and ligaments. The result is that they are present at 2– 4 times the content of mature pyridinium cross-links. It was reported that the immature cross-linking in bone is an independent determinant of bone strength in ovariectomized monkey model [50•]. Thus, the immature form is the major type of crosslink found in bone. Additionally, immature cross-links reflect changes in bone metabolic turnover and drug influences with higher sensitivity than mature cross-links. These observations have led to the proposal that a simultaneous estimation of both immature and mature cross-links is important for elucidating the actual dynamic state of enzymatic cross-link formation. The Disadvantageous AGEs Formation in Bone Collagen Nonenzymatic AGEs type of cross-links within collagen fibers deteriorates the biological and mechanical functions of bone although enzymatic immature and mature cross-links
have the beneficial effects on bone strength [3, 5, 51]. Pen is an intermolecular AGEs cross-linking in bone although Pen is minor type of AGEs [11, 28, 41, 52–55]. Because the content of Pen in bone correlates positively to total amount of fluorescent AGEs, the measurement of pen used as a surrogate marker of total AGEs formation [56]. There is no data regarding the existence of the other AGEs cross-links, such as vesperlysine [57] identified from AGEs-induced bovine serum albumin, nonfluorescent component-1 (NFC-1) identified from aorta [58], and glucosepane [59] in human bone collagen. Pen is measured commonly while Pen can be easily and precisely quantified in small specimens by HPLC [11, 60]. This suggests that the pathway of their formation may be similar and Pen may be a useful marker of whole AGEs in bone. The first step of AGEs formation is to react between the aldehyde of an open chain form of glucose, ketose, or other metabolic intermediate (glyoxal, methylglyoxal, and 3deoxyglucosone) and a free ε- amino group of collagenbound Lys or Hyl to form a glycosyl-Lys via Schiff base formation [61]. The hexosyl Lys or Hyl is stabilized by spontaneous Amadori rearrangement. The Amadori adduct reaction with amino acids such as Lys or arginine (Arg) in adjacent collagen to form AGEs cross-links [62]. AGEs crosslinks such as Pen are likely to be formed between helical Lys and Arg. Increasing inter-helical cross-linking Pen may result tissue brittleness and resistance to breakdown by pepsin [45, 63]. Non-cross-link types of AGEs such as carboxymethyl lysine (CML) as well as cross-linking type of AGEs inhibit osteoblastic mineralization process [64, 65••, 66••, 67] via the
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interaction with the cell surface receptor of AGEs, RAGE [68, 69•, 70, 71•]. The roles of AGEs on bone resorption by osteoclast are controversial. A nonhistone nuclear protein, high-mobility group box 1 (HMGB1) is released from bone marrow macrophages in response to, RANKL stimulation. The extracellular HMGB1, through RAGE, in large, regulates osteoclastic actin cytoskeleton remodeling, differentiation, and function [72]. Thus, AGEs may increase osteoclast activity [73]. These results are consistent with other evidence that an excessive accumulation of AGEs occurs in bone from patients with postmenopausal osteoporosis [41, 54] and chronic renal failure [74••] with high turnover bone, However, an opposite conclusion in an in vitro study using rabbit and human mature osteoclasts was reported [75]. This result seems to explain the increase in AGEs formation in bone from type 1 and 2 diabetic animal models showing low bone turnover [22, 76] and the patients with type 2 diabetes [77] with low bone turnover. The levels of AGEs formation in tissue is regulated by glycemic control, tissue life span [28, 41, 50•, 53–56]. Not only poor glycemic control and tissue life span, but also oxidative stress itself induces AGEs in bone [78], resulting in bone fragility [79••]. Bone from mice deficient in cytoplasmic copper/zinc superoxide dismutase (CuZn-SOD, encoded by the Sod1 gene; Sod1(-/-)) exhibits an impaired enzymatic cross-links and a marked increase of AGEs cross-links [79••]. While hyperhomocysteinemia contributes to increase oxidative stress in general population [80], hyperhomocysteinemia may induce the excessive formation of AGEs in bone. Hyperhomocysteinemia induced by methionine fed rabbit model induced a significant increase of AGEs formation in bone [28]. Thus, hyperhomocysteinemia commonly observed in diabetes may cause both an impaired enzymatic and an excessive formation of AGEs in bone. Importantly, the formation of AGEs inhibits competitively enzymatic cross-link formation because AGEs are formed between Lys residues, which are essential sites of enzymatic cross-linking in collagen molecules.
Bone Collagen in Diabetes Mellitus The fracture risk in type 1 and 2 diabetes increased significantly more than what could be explained from a reduction in BMD. Thus, both type 1 and 2 diabetes may be associated with a reduction of bone strength in vertebra and femoral neck that does not necessarily reflect BMD [81•]. Therefore, diabetes deteriorates “bone quality” rather than bone mass and BMD, which suggests poor material properties induced by abnormal collagen cross-link formation [3]. Recently, Hammond et al. [82••] demonstrated that bone from Zucker diabetic Sprague-Dawley had a significantly different distribution of collagen D-spacing than nondiabetic rat, which was
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more variable and shifted to higher values. However, little is known for collagen enzymatic and AGEs cross-links abnormalities in diabetes. Because bone collagen quality in diabetes is influenced by many factors including age of onset, disease duration, insulin status, and glycemic control, a suitable animal model for type 1 and type 2 diabetes is needed in terms of bone material properties [22, 76]. We reported that impaired immature enzymatic cross-links and an excessive formation of AGEs cross-link Pen in bone collagen decreased bone strength without change in collagen content and BMD in a spontaneously WBN/Kob rat [22]. A marked decreases of immature enzymatic cross-links in the subclinical diabetes stage was due to a significant reduction in bone strength without an accumulation of AGEs crosslinking. The impaired enzymatic cross-links in the preclinical diabetic stage may result in a vitamin B6 deficiency. Vitamin B6 is essential for the action of LOX [19]. Serum levels of vitamin B6 such as pyridoxal (PL) and pyridoxamine (PM) in the WBN/Kob rats decreased after 6 months of age with age and the serum levels of PL and PM in the WBN/Kob rats were significantly lower than those in the nondiabetic rats after 6 months of age. The content of enzymatic cross-linking associated significantly with PL level, whereas the content of Pen had modest association with blood glucose, serum PL, and PM levels. Vitamin B6 deficiency are occurred when upregulation of gluconeogenesis takes place in both subclinical and clinical diabetic stages, a latent deficiency of vitamin B6 may cause impaired LOX-controlled enzymatic cross-link formation. We previously reported vitamin B6 deficiency in normal rats reduced enzymatic cross-link formation in bone compared with regularly fed rats [21]. Enzymatic cross-link formation in physiological conditions is proportional to the mechanical properties of collagen fibers within a beneficial range without brittleness [22, 30, 31, 46, 50•]. Thus, the reduction of LOX activity by lathyrogens such as betaaminopropionitrile (BAPN) and copper deficiency as well as vitamin B6 deficiency induces impaired enzymatic crosslinks, resulting in a decrease of bone strength [83, 84]. Therefore, even in preclinical diabetic stage, bone strength may be decreased by the impaired enzymatic cross-link formation. After the onset of diabetes, enzymatic cross-links reduced continuously and a marked increase of AGEs cross-link, Pen, which was consistent with a significant reduction of bone strength compared with nondiabetic rats in spite of a lack of change in the content of collagen and BMD. As described above, AGEs are thought to be formed in the essential sites of enzymatic cross-linking in collagen, resulting in competitive inhibition of enzymatic cross-link formation [62]. Therefore, not only vitamin B6 deficiency, but also accumulation of AGEs may inhibit enzymatic cross-link formation after the onset of diabetes. Such abnormal cross-link pattern in type 1 and 2 diabetes may result in accelerated bone fragility without a change in BMD. AGEs cross-links in bone makes collagen
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fibers brittle, thereby inducing microdamage formation. These changes in material properties cause deterioration of postyield properties and toughness [22, 28, 55, 85–87]. Induction of AGEs in bovine [85, 87] and human [88] bone collagen by ribosylation in vitro decreases in post-yield strain and energy. These incubation studies are enable us to know the direct effects of AGEs formation on bone mechanical properties because these studies exclude the cellular action by AGEs/RAGE interaction and maintain constant bone architecture and BMD. Therefore , AGEs cross-link formation itself impaired bone mechanical strength at a material level. Regarding type 1 diabetes using the streptozotocin-induced diabetic rodent model, an increase in collagen-linked fluorescence (an indicator of AGEs) caused reduced bone strength, BMD and bone turnover as estimated by serum levels of osteocalcin compared with control rats [89]. Silva et al. [76] demonstrated trabecular bone loss, a reduction in diaphyseal growth and a significant accumulation of AGEs cross-link, Pen, without alteration in the content of enzymatic mature pyridinium cross-links and collagen concentration in bone from in type 1 diabetes. An increase in AGEs cross-link, Pen, modestly reduced material properties of bone from type 1 diabetic rats. Recent literature regarding collagen cross-links faces a new era. For instance, serum or urine AGEs such as pentosidine and CML levels are now being used to estimate future fracture risk in osteoporosis and diabetes because plasma level of Pen has a significant linear correlation with Pen in bone from 104 nondiabetic patients (74 women and 30 men; 72 +/- 1 years old) [90]. While plasma and urine Pen levels are significantly higher in diabetic patients compared with age-matched healthy patients [91, 92], plasma or urinary levels of Pen may correlate with an independent fracture risk in diabetic patients with low bone quality. A high level of serum Pen or low level of the endogenous secretory receptor for AGEs (esRAGE) acting as decoy receptor of AGEs was independent of prevalent and incident fracture risk in elderly diabetic women [93, 94]. Schwartz et al. [95] reported that the levels of urinary excretion of Pen were associated with incident clinical fracture or prevalent vertebral fracture, as well as bone turnover markers, in older adults with diabetes in the Health Aging and Body Composition (Health ABC) study. Similarly, a high level of urinary excretion of Pen was an independent risk factor for osteoporotic incidence of vertebral fractures in a 5-year prospective study in 432 elderly Japanese women without diabetes [96]. Oxidative stress induced by hyperhomocysteinemia may cause induction of poor bone material quality in terms of collagen cross-linking [41, 97]. Urinary excretion of Pen improves risk classification using conventional risk assessment tools such as FRAX and the Fracture and Immobilization Score (FRISC) from a total of 765 postmenopausal Japanese women in a hospital-based cohort study [98]. Among older adults with type 2 diabetes, femoral neck
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BMD T score and FRAX score were associated with hip and nonvertebral fracture risk. However, in these patients compared with participants without diabetes, the fracture risk was higher for a given T score and age or for a given FRAX score from 3 prospective observational studies [99••]. Therefore, simultaneous estimation of BMD, bone turnover markers, and a surrogate marker for AGEs may be suitable for estimation of fracture risk with or without diabetes.
Conclusions Diabetes showing hyperglycemia, an elevated oxidative stress, and hyperhomocysteinemia most likely reduces bone material properties in terms of collagen post-translational modification such as enzymatic cross-links and AGEs formation. Furthermore, the adverse effects of AGEs on bone cells via the interaction to RAGEs. Proper collagen cross-link formation induces the physiological mineralization process. AGEs could explain the molecular link between primary osteoporosis with poor bone material quality and diabetes. If so, the agent for inhibiting AGEs formation in bone such as raloxifene [28], teriparatide [50•] and vitamin B6 [100] may reduce fracture risk. The development of a noninvasive biomarker that reflects the actual cross-link formation in bone is needed to investigate susceptibility to bone fractures. Plasma and urinary levels of Pen may be candidates for the surrogate estimation of low bone quality. Compliance with Ethics Guidelines Conflict of Interest M. Saito, Y. Kida, S. Kato, and K. Marumo declare that they have no conflicts of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
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BIOMECHANICS (M SILVA AND P ZYSSET, SECTION EDITORS)
Diabetes, Collagen, and Bone Quality Mitsuru Saito & Yoshikuni Kida & Soki Kato & Keishi Marumo
Published online: 13 March 2014 # Springer Science+Business Media New York 2014
Abstract Diabetes increases risk of fracture, although type 2 diabetes is characterized by normal or high bone mineral density (BMD) compared with the patients without diabetes. The fracture risk of type 1 diabetes as well as type 2 diabetes increases beyond an explained by a decrease of BMD. Thus, diabetes may reduce bone strength without change in BMD. Whole bone strength is determined by bone density, structure, and quality, which encompass the micro-structural and tissue material properties. Recent literature showed that diabetes reduces bone material properties rather than BMD. Collagen intermolecular cross-linking plays an important role in the expression of bone strength. Collagen cross-links can be divided into beneficial enzymatic immature divalent and mature trivalent cross-links and disadvantageous nonenzymatic cross-links (Advanced glycation end products: AGEs) induced by glycation and oxidation. The formation pathway and biological function are quite different. Not only hyperglycemia, but also oxidative stress induces the reduction in enzymatic cross-links and the formation of AGEs. In this review, we describe the mechanism of low bone quality in diabetes and the usefulness of the measurement of plasma or urinary level of AGEs for estimation of fracture risk.
Keywords Diabetes . Bone quality . Collagen . Cross-links . Advanced glycation end products . Pentosidine . Homocysteine . Fracture risk
Introduction Diabetes is associated with increased risk of fracture [1], although type 2 diabetes is often characterized by normal or high bone mineral density (BMD). Thus, diabetes may be associated with a reduction of bone strength that is not reflected in the measurement of BMD. The important determinants of bone strength are bone mineral density, structural properties, and tissue material quality. Bone is composed of a 2-phase composite material. Hence, the mineral composition contributes to stiffness. In contrast, collagen fibers provide the intrinsic material properties such as tensile strength, ductility and toughness. Material property of bone is regulated by not only tissue turnover rate, but also the cellular activity and the levels of oxidative stress and glycation [2]. Collagen enzymatic and nonenzymatic cross-linking affect primary mineralization process and bone mechanical properties. Impaired enzymatic cross-linking and/ or an excessive formation of nonenzymatic cross-links, pentosidine (Pen), which is a surrogate marker of advanced glycation end products (AGEs), may be a major cause of bone fragility in aging, osteoporosis, and diabetes mellitus [3, 4••, 5]. We summarize the roles of collagen enzymatic and nonenzymatic cross-linking and how bone quality in diabetes deteriorates.
Cross-Link Formation in Collagen Fibers
M. Saito (*) : Y. Kida : S. Kato : K. Marumo Department of Orthopaedic Surgery, Jikei University School of Medicine, 3-25-8, Nishi-Shinbashi, Minato-ku, Tokyo 105-8461, Japan e-mail: [email protected]
Type I collagen is the most major component of protein in bone. Type I collagen has 2 nonhelical telopeptides at the amino and carboxyl terminal and a central triple helical domain. Collagen fiber shows crucial roles in bone strength and this is attributed in part to the formation of intermolecular cross-linking formation between the adjacent collagen molecules.
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Stabilization of newly secreted collagen fibers is initially formed by the formation of covalent cross-links between neighboring collagen molecules as post-translational modification. As a result, collagen cross-link formation affects the mechanical properties of bone at a material level. Collagen cross-links can be divided into lysyl oxidase regulated crosslinking and glycation or oxidation induced AGEs crosslinking. These 2 types vary in the mechanism of formation and display functional differences. The Beneficial Enzymatic Cross-Links of Bone Collagen Enzymatic cross-link formation is controlled by 2 enzymes such as the lysine hydroxylases (Procollagen-lysine, 2oxyglutarate, 5-dioxigenase, PLOD, LH) and lysyl oxidase (LOX, LOXL1-5a,5b). Tissue specific enzymatic cross-link pattern is regulated by PLOD intracellularly [6–9]. After hydroxylation, collagen molecules are secreted into the extracellular space. LOX binds to specific Lys or hydroxylysine (Hyl) residues in the telopeptides to determine total amount of enzymatic cross-link formation. Collagen molecules are aligned as quarter-stagger model. The initial step of cross-link formation extracellularly is conversion of ε-amino groups of specific for cross-linking site such as Lys and Hyl in the telopeptide domains. This reaction occurs via the action of LOX following aggregation of collagen molecules into fibers [10]. No excessive formation of enzymatic cross-linking occurs in the physiological mineralization process in vivo [11–13] and in vitro [7, 8, 14, 15] because the enzymatic cross-link formation is regulated by the expression of LOX [16•, 17]. Four isoforms of LOX likeproteins (LOXL1-4) were identified although a specific function of each isoform remains unclear [18]. Various regulatory factors of LOX expression are reported. Pyridoxal phosphate (vitamin B6) acts as an essential co-factor of LOX [19, 20]. Vitamin B6 deficiency in rats induced 25 % reduction in enzymatic cross-linking in bone compared with regularly fed rats [21]. It is well known that vitamin B6 deficiency commonly occurs in diabetes [22]. Vitamin B6 deficiency shows the adverse effects on cross-link formation in diabetes described the later section [22]. Various growth factors acting in bone formation such as transforming growth factor beta (TGF-β) [23], connective tissue growth factor (CTGF) [24], and insulin-like growth factor I (IGF-I) [25] are positive regulatory factors of LOX expression. Estrogen is a crucial regulatory factor of LOX expression. Estrogen deficiency induced by ovariectomy in rodent led to decrease the activity of LOX down to 25 %, but this reduced activity was rescued by estradiol injection [26]. Furthermore, ageing-related reduction in estrogen correlates to the activity of LOX in bone [27]. Ovariectomized rabbits exhibited a significant reduction in content of both immature, and mature enzymatic cross-links compared with the sham group [28]. This reduction of the
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enzymatic cross-link formation was improved by the administration of selective estrogen receptor modulator raloxifene [28]. This result indicates that estrogen like action via the receptor of estrogen may play a crucial role of LOX mediated enzymatic cross-link formation. Active vitamin D3 (alfacalcidol) also acts as a positive regulator of LOX expression from osteoblastic MC3T3-E1 cells in vitro [29]. In contrast, native vitamin D did not show any action for LOX expression. Thus, the pharmacological action of alfacalcidol may increase the expression of LOX. Similarly, in vivo, the administration of alfacalcidol induced enzymatic cross-link formation in bone from ovariectomized rat [30]. In contrast, the negative regulatory factors of LOX are reported. Glucocorticoid [31], fibroblast growth factor (FGF) [32], prostaglandin E2 [33], and tumor necrosis factor-alpha (TNF-alpha) [34] suppresses LOX gene expression and enzymatic activity. Deficient enzymatic cross-link formation by beta-aminopropionitrile treatment hampers osteoblastic differentiation [35]. These results indicate that proper enzymatic cross-link formation is essential for osteoblastic differentiation. Homocysteine (Hcys) inhibits enzymatic cross-link formation via a reduction in gene expression and enzymatic activity of LOX [36•, 37]. Hcys binds competitively to the aldehydic groups of precursor of cross-linking sites and results in a marked decrease in cross-linking [38]. Recently, mildly elevated plasma homocysteine in the general population was reported to be an independent fracture risk [39••]. This plausible mechanism is thought to low bone quality induced by abnormal collagen cross-link formation [36•, 37, 40, 41]. Hyperhomocysteinemia is a risk factor of arteriosclerosis as well as fracture risk in general population [42]. Type 2 diabetes also increases plasma level of homocysteine, resulting in arteriosclerosis [43•]. Hyperhomocysteinemia induced by methionine fed rabbit model exhibit a marked decrease of enzymatic cross-link formation in bone [28]. Thus, hyperhomocysteinemia in diabetes may show an additive adverse effect of bone quality (Fig. 1). The precursor of enzymatic cross-linking amino-acids such as the telopeptide Lys aldehydes (allysine) and Hyl aldehydes (hydroxyallysine) in the N-terminal telopeptide and in the Cterminal telopeptide then react and condensate with Lys or Hyl residues in the triple helical region of an adjacent collagen molecule to form divalent immature cross-links called deHdihydroxylysinonorleucine (DHLNL), deHhydroxylysinonorleucine (HLNL), and deH-lysinonorleucine (LNL). The divalent cross-links reacts spontaneously with another telopeptide Lys or Hyl aldehyde to form trivalent pyridinium or pyrrole cross-links. The amount of immature divalent cross-links decreased with age in human bone. These immature cross-links convert partially into mature cross-link [11, 44, 45]. Mature cross-links are pyridinium cross-links such as pyridinoline (PYD) and deoxypyridinoline (DPD) are formed via the hydroxyallysine pathway. Pyrrole cross-links, such as
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Fig. 1 A plausible mechanism of poor bone quality in diabetes
(pyrrolodine) PYL and deoxy-pyrrololine (DPL) are also characterized as mature trivalent cross-links [46, 47]. The mechanism of pyrrole cross-link formation is by condensation of de-HLNL/ de-DHLNL reacting with another allysine [48], or by rearrangement of 2 divalent cross-links including deH-HLNL [49]. Several investigations concerning enzymatic cross-links have focused only on mature pyridinium cross-links, without accounting for the presence of immature divalent cross-links. However, immature as well as mature cross-links may affect the physiological function of bone for the following reasons. Immature cross-linkages are the most frequently observed cross-link forms in bone, because the conversion rate of immature forms into mature forms is lower than that of other connective tissues, such as tendons and ligaments. The result is that they are present at 2– 4 times the content of mature pyridinium cross-links. It was reported that the immature cross-linking in bone is an independent determinant of bone strength in ovariectomized monkey model [50•]. Thus, the immature form is the major type of crosslink found in bone. Additionally, immature cross-links reflect changes in bone metabolic turnover and drug influences with higher sensitivity than mature cross-links. These observations have led to the proposal that a simultaneous estimation of both immature and mature cross-links is important for elucidating the actual dynamic state of enzymatic cross-link formation. The Disadvantageous AGEs Formation in Bone Collagen Nonenzymatic AGEs type of cross-links within collagen fibers deteriorates the biological and mechanical functions of bone although enzymatic immature and mature cross-links
have the beneficial effects on bone strength [3, 5, 51]. Pen is an intermolecular AGEs cross-linking in bone although Pen is minor type of AGEs [11, 28, 41, 52–55]. Because the content of Pen in bone correlates positively to total amount of fluorescent AGEs, the measurement of pen used as a surrogate marker of total AGEs formation [56]. There is no data regarding the existence of the other AGEs cross-links, such as vesperlysine [57] identified from AGEs-induced bovine serum albumin, nonfluorescent component-1 (NFC-1) identified from aorta [58], and glucosepane [59] in human bone collagen. Pen is measured commonly while Pen can be easily and precisely quantified in small specimens by HPLC [11, 60]. This suggests that the pathway of their formation may be similar and Pen may be a useful marker of whole AGEs in bone. The first step of AGEs formation is to react between the aldehyde of an open chain form of glucose, ketose, or other metabolic intermediate (glyoxal, methylglyoxal, and 3deoxyglucosone) and a free ε- amino group of collagenbound Lys or Hyl to form a glycosyl-Lys via Schiff base formation [61]. The hexosyl Lys or Hyl is stabilized by spontaneous Amadori rearrangement. The Amadori adduct reaction with amino acids such as Lys or arginine (Arg) in adjacent collagen to form AGEs cross-links [62]. AGEs crosslinks such as Pen are likely to be formed between helical Lys and Arg. Increasing inter-helical cross-linking Pen may result tissue brittleness and resistance to breakdown by pepsin [45, 63]. Non-cross-link types of AGEs such as carboxymethyl lysine (CML) as well as cross-linking type of AGEs inhibit osteoblastic mineralization process [64, 65••, 66••, 67] via the
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interaction with the cell surface receptor of AGEs, RAGE [68, 69•, 70, 71•]. The roles of AGEs on bone resorption by osteoclast are controversial. A nonhistone nuclear protein, high-mobility group box 1 (HMGB1) is released from bone marrow macrophages in response to, RANKL stimulation. The extracellular HMGB1, through RAGE, in large, regulates osteoclastic actin cytoskeleton remodeling, differentiation, and function [72]. Thus, AGEs may increase osteoclast activity [73]. These results are consistent with other evidence that an excessive accumulation of AGEs occurs in bone from patients with postmenopausal osteoporosis [41, 54] and chronic renal failure [74••] with high turnover bone, However, an opposite conclusion in an in vitro study using rabbit and human mature osteoclasts was reported [75]. This result seems to explain the increase in AGEs formation in bone from type 1 and 2 diabetic animal models showing low bone turnover [22, 76] and the patients with type 2 diabetes [77] with low bone turnover. The levels of AGEs formation in tissue is regulated by glycemic control, tissue life span [28, 41, 50•, 53–56]. Not only poor glycemic control and tissue life span, but also oxidative stress itself induces AGEs in bone [78], resulting in bone fragility [79••]. Bone from mice deficient in cytoplasmic copper/zinc superoxide dismutase (CuZn-SOD, encoded by the Sod1 gene; Sod1(-/-)) exhibits an impaired enzymatic cross-links and a marked increase of AGEs cross-links [79••]. While hyperhomocysteinemia contributes to increase oxidative stress in general population [80], hyperhomocysteinemia may induce the excessive formation of AGEs in bone. Hyperhomocysteinemia induced by methionine fed rabbit model induced a significant increase of AGEs formation in bone [28]. Thus, hyperhomocysteinemia commonly observed in diabetes may cause both an impaired enzymatic and an excessive formation of AGEs in bone. Importantly, the formation of AGEs inhibits competitively enzymatic cross-link formation because AGEs are formed between Lys residues, which are essential sites of enzymatic cross-linking in collagen molecules.
Bone Collagen in Diabetes Mellitus The fracture risk in type 1 and 2 diabetes increased significantly more than what could be explained from a reduction in BMD. Thus, both type 1 and 2 diabetes may be associated with a reduction of bone strength in vertebra and femoral neck that does not necessarily reflect BMD [81•]. Therefore, diabetes deteriorates “bone quality” rather than bone mass and BMD, which suggests poor material properties induced by abnormal collagen cross-link formation [3]. Recently, Hammond et al. [82••] demonstrated that bone from Zucker diabetic Sprague-Dawley had a significantly different distribution of collagen D-spacing than nondiabetic rat, which was
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more variable and shifted to higher values. However, little is known for collagen enzymatic and AGEs cross-links abnormalities in diabetes. Because bone collagen quality in diabetes is influenced by many factors including age of onset, disease duration, insulin status, and glycemic control, a suitable animal model for type 1 and type 2 diabetes is needed in terms of bone material properties [22, 76]. We reported that impaired immature enzymatic cross-links and an excessive formation of AGEs cross-link Pen in bone collagen decreased bone strength without change in collagen content and BMD in a spontaneously WBN/Kob rat [22]. A marked decreases of immature enzymatic cross-links in the subclinical diabetes stage was due to a significant reduction in bone strength without an accumulation of AGEs crosslinking. The impaired enzymatic cross-links in the preclinical diabetic stage may result in a vitamin B6 deficiency. Vitamin B6 is essential for the action of LOX [19]. Serum levels of vitamin B6 such as pyridoxal (PL) and pyridoxamine (PM) in the WBN/Kob rats decreased after 6 months of age with age and the serum levels of PL and PM in the WBN/Kob rats were significantly lower than those in the nondiabetic rats after 6 months of age. The content of enzymatic cross-linking associated significantly with PL level, whereas the content of Pen had modest association with blood glucose, serum PL, and PM levels. Vitamin B6 deficiency are occurred when upregulation of gluconeogenesis takes place in both subclinical and clinical diabetic stages, a latent deficiency of vitamin B6 may cause impaired LOX-controlled enzymatic cross-link formation. We previously reported vitamin B6 deficiency in normal rats reduced enzymatic cross-link formation in bone compared with regularly fed rats [21]. Enzymatic cross-link formation in physiological conditions is proportional to the mechanical properties of collagen fibers within a beneficial range without brittleness [22, 30, 31, 46, 50•]. Thus, the reduction of LOX activity by lathyrogens such as betaaminopropionitrile (BAPN) and copper deficiency as well as vitamin B6 deficiency induces impaired enzymatic crosslinks, resulting in a decrease of bone strength [83, 84]. Therefore, even in preclinical diabetic stage, bone strength may be decreased by the impaired enzymatic cross-link formation. After the onset of diabetes, enzymatic cross-links reduced continuously and a marked increase of AGEs cross-link, Pen, which was consistent with a significant reduction of bone strength compared with nondiabetic rats in spite of a lack of change in the content of collagen and BMD. As described above, AGEs are thought to be formed in the essential sites of enzymatic cross-linking in collagen, resulting in competitive inhibition of enzymatic cross-link formation [62]. Therefore, not only vitamin B6 deficiency, but also accumulation of AGEs may inhibit enzymatic cross-link formation after the onset of diabetes. Such abnormal cross-link pattern in type 1 and 2 diabetes may result in accelerated bone fragility without a change in BMD. AGEs cross-links in bone makes collagen
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fibers brittle, thereby inducing microdamage formation. These changes in material properties cause deterioration of postyield properties and toughness [22, 28, 55, 85–87]. Induction of AGEs in bovine [85, 87] and human [88] bone collagen by ribosylation in vitro decreases in post-yield strain and energy. These incubation studies are enable us to know the direct effects of AGEs formation on bone mechanical properties because these studies exclude the cellular action by AGEs/RAGE interaction and maintain constant bone architecture and BMD. Therefore , AGEs cross-link formation itself impaired bone mechanical strength at a material level. Regarding type 1 diabetes using the streptozotocin-induced diabetic rodent model, an increase in collagen-linked fluorescence (an indicator of AGEs) caused reduced bone strength, BMD and bone turnover as estimated by serum levels of osteocalcin compared with control rats [89]. Silva et al. [76] demonstrated trabecular bone loss, a reduction in diaphyseal growth and a significant accumulation of AGEs cross-link, Pen, without alteration in the content of enzymatic mature pyridinium cross-links and collagen concentration in bone from in type 1 diabetes. An increase in AGEs cross-link, Pen, modestly reduced material properties of bone from type 1 diabetic rats. Recent literature regarding collagen cross-links faces a new era. For instance, serum or urine AGEs such as pentosidine and CML levels are now being used to estimate future fracture risk in osteoporosis and diabetes because plasma level of Pen has a significant linear correlation with Pen in bone from 104 nondiabetic patients (74 women and 30 men; 72 +/- 1 years old) [90]. While plasma and urine Pen levels are significantly higher in diabetic patients compared with age-matched healthy patients [91, 92], plasma or urinary levels of Pen may correlate with an independent fracture risk in diabetic patients with low bone quality. A high level of serum Pen or low level of the endogenous secretory receptor for AGEs (esRAGE) acting as decoy receptor of AGEs was independent of prevalent and incident fracture risk in elderly diabetic women [93, 94]. Schwartz et al. [95] reported that the levels of urinary excretion of Pen were associated with incident clinical fracture or prevalent vertebral fracture, as well as bone turnover markers, in older adults with diabetes in the Health Aging and Body Composition (Health ABC) study. Similarly, a high level of urinary excretion of Pen was an independent risk factor for osteoporotic incidence of vertebral fractures in a 5-year prospective study in 432 elderly Japanese women without diabetes [96]. Oxidative stress induced by hyperhomocysteinemia may cause induction of poor bone material quality in terms of collagen cross-linking [41, 97]. Urinary excretion of Pen improves risk classification using conventional risk assessment tools such as FRAX and the Fracture and Immobilization Score (FRISC) from a total of 765 postmenopausal Japanese women in a hospital-based cohort study [98]. Among older adults with type 2 diabetes, femoral neck
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BMD T score and FRAX score were associated with hip and nonvertebral fracture risk. However, in these patients compared with participants without diabetes, the fracture risk was higher for a given T score and age or for a given FRAX score from 3 prospective observational studies [99••]. Therefore, simultaneous estimation of BMD, bone turnover markers, and a surrogate marker for AGEs may be suitable for estimation of fracture risk with or without diabetes.
Conclusions Diabetes showing hyperglycemia, an elevated oxidative stress, and hyperhomocysteinemia most likely reduces bone material properties in terms of collagen post-translational modification such as enzymatic cross-links and AGEs formation. Furthermore, the adverse effects of AGEs on bone cells via the interaction to RAGEs. Proper collagen cross-link formation induces the physiological mineralization process. AGEs could explain the molecular link between primary osteoporosis with poor bone material quality and diabetes. If so, the agent for inhibiting AGEs formation in bone such as raloxifene [28], teriparatide [50•] and vitamin B6 [100] may reduce fracture risk. The development of a noninvasive biomarker that reflects the actual cross-link formation in bone is needed to investigate susceptibility to bone fractures. Plasma and urinary levels of Pen may be candidates for the surrogate estimation of low bone quality. Compliance with Ethics Guidelines Conflict of Interest M. Saito, Y. Kida, S. Kato, and K. Marumo declare that they have no conflicts of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
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