Extracellular post-translational modifications of collagen are major determinants of biomechanical properties of fetal bovine cortical bone

Garnero, Patrick; Borel, Olivier; Gineyts, Évelyne; Duboeuf, F.; Solberg, Helene; Bouxsein, Mary L.; Christiansen, Claus; Delmas, Pierre D.

doi:10.1016/j.bone.2005.09.014

Cited by 158 publications

(120 citation statements)

References 38 publications

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“…By incubating bone samples at 37 ° C for 60 days, we showed that the increase in PYD and DPD was positively associated with an increase of ultimate stress and post-yield energy absorption. 34 Thus, all together these experimental data clearly indicate that marked changes in enzymatic trivalent crosslinks are associated with alteration in post-yield mechanical properties both in cortical and trabecular bone.…”

Section: Collagen Post-translational Modifications and Bone Strengthmentioning

confidence: 61%

The contribution of collagen crosslinks to bone strength

Garnero¹

2012

BoneKEy Reports

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Collagen crosslinking is a major post-translational modification of collagen which has important roles in determining the biomechanical competence of bone. Crosslinks can be divided into enzymatic lysil oxidase-mediated and nonenzymatic glycation-induced (advanced glycation end products, AGE) molecules. In addition, collagen in bone can also undergo spontaneous isomerization and racemization of the aspartic acid residues with the C-telopeptide (CTX), leading to the formation of two isomers namely ␣ (newly formed collagen) and ␤ (matured isomerized collagen) CTX. Several in vitro and ex vivo studies, relating the bone content of these crosslinks with bone strength, have shown that they contributed to the mechanical competence of trabecular and cortical bone -mainly on the post-yield properties -in part independent of the bone mineral content. In addition, AGEs such as pentosidine have been reported to alter the formation and propagation of microdamage by making the bone more brittle. The bone content of AGEs and isomerization can also be modified by antiresorptive and anabolic therapies. They may thus explain part of the antifracture efficacy of these treatments. The main challenge consists in the transposition of these in vitro / ex vivo studies to clinical applications for the development of a non-invasive biomarker, as none of currently identified collagen crosslinks (both enzymatic and nonenzymatic) is bone specific. Nevertheless, serum or urine levels of pentosidine and the ratio of ␣ / ␤ CTX have been reported to predict fracture risk in postmenopausal women, in men and in patients with type 2 diabetes.

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Section: Collagen Post-translational Modifications and Bone Strengthmentioning

confidence: 61%

The contribution of collagen crosslinks to bone strength

Garnero¹

2012

BoneKEy Reports

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102

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“…Several prior studies found that higher levels of AGEs are associated with decreased postyield properties of cortical and trabecular bone. 23,24,29,58 Moreover, in trabecular bone from human femora, Tang et al 27 reported a negative relationship between PEN and postyield mechanical properties, but no association with preyield properties. We did not evaluate postyield properties in this study because they are problematic for compression tests since the trabecular bone compresses upon itself, thus our finding that PEN was not associated with mechanical properties is consistent with previous studies.…”

Section: Discussionmentioning

confidence: 99%

“…21,22 Furthermore, in vitro models showed that both enzymatic pyridinoline (PYD) and deoxypyridinoline (DPD) and the nonenzymatic advanced glycation end products (AGEs) contribute to bone mechanical behavior. [23][24][25][26][27] Whereas the content of PYD and DPD in bone matrix were related to bone strength in the lathyric model, in ex vivo studies, the role of these enzymatic cross-links remains unclear. 25,26,28,29 In comparison, the accumulation AGEs such as pentosidine (PEN) in the bone matrix is consistently associated with impairment of the postyield properties of trabecular and cortical bone.…”

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confidence: 99%

Effects of preexisting microdamage, collagen cross‐links, degree of mineralization, age, and architecture on compressive mechanical properties of elderly human vertebral trabecular bone

Follet

Viguet-Carrin

Burt‐Pichat

et al. 2010

Journal Orthopaedic Research

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Previous studies have shown that the mechanical properties of trabecular bone are determined by bone volume fraction (BV/ TV) and microarchitecture. The purpose of this study was to explore other possible determinants of the mechanical properties of vertebral trabecular bone, namely collagen cross-link content, microdamage, and mineralization. Trabecular bone cores were collected from human L2 vertebrae (n ¼ 49) from recently deceased donors 54-95 years of age (21 men and 27 women). Two trabecular cores were obtained from each vertebra, one for preexisting microdamage and mineralization measurements, and one for BV/TV and quasi-static compression tests. Collagen cross-link content (PYD, DPD, and PEN) was measured on surrounding trabecular bone. Advancing age was associated with impaired mechanical properties, and with increased microdamage, even after adjustment by BV/TV. BV/TV was the strongest determinant of elastic modulus and ultimate strength (r 2 ¼ 0.44 and 0.55, respectively). Microdamage, mineralization parameters, and collagen cross-link content were not associated with mechanical properties. These data indicate that the compressive strength of human vertebral trabecular bone is primarily determined by the amount of trabecular bone, and notably unaffected by normal variation in other factors, such as crosslink profile, microdamage and mineralization. Keywords: bone strength; microdamage; microarchitecture; mineralization; collagen cross-links; vertebral trabecular bone Several studies have shown that the mechanical properties of trabecular bone are influenced by bone volume fraction (BV/TV) and microarchitecture. 1,2 However, additional factors, such as degree of mineralization, preexisting microdamage, and collagen cross-link profile may also play a role, yet the contribution of these factors to human trabecular bone mechanical properties remains incompletely understood.Increased mineralization of cortical bone is exponentially related to increased stiffness, but decreased energy absorption. 3 A similar trend was seen in human trabecular bone from the calcaneus, with a positive relationship between mineralization and elastic modulus, after adjusting for BV/TV. 4 It has also been suggested that a reduction in the heterogeneity of mineralization density distribution leads to increased bone fragility, 5 but there are few data to support this assertion.Microdamage has been largely studied in animal models and in human cortical bone, with only a few studies reporting microdamage in human trabecular bone either naturally occurring 6-11 or due to loading ex-vivo. 12 In cortical bone, microdamage accumulation leads to decreased mechanical properties, 13,14 and therefore has been implicated in skeletal fragility and stress fractures. 15 However, the association between microdamage and cortical bone fracture toughness was weak, 16 raising questions as to the role of microdamage in cortical bone. Increased microdamage has also been associated with decreased strength in human vertebral cancellous bone; 1...

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“…(8) Accumulation of pentosidine impairs the mechanical properties of bone and is associated with brittleness of collagen fibers. (9)(10)(11) We previously reported significant associations between urinary pentosidine and incidence of vertebral fracture in untreated (12) and treated (13) Japanese women. The results from the OFELY study were similar in the univariate analysis but not significant in the adjusted analysis.…”

Section: Introductionmentioning

confidence: 97%

Urinary pentosidine improves risk classification using fracture risk assessment tools for postmenopausal women

Tanaka

Kuroda²,

Saito

et al. 2011

Journal of Bone and Mineral Research

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We investigated whether measurement of pentosidine, in addition to the conventional risk assessment tool, the Fracture and Immobilization Score (FRISC), improves early identification of fracture cases. A total of 765 postmenopausal Japanese women with baseline measurement of urinary pentosidine were followed in a hospital-based cohort study. Endpoints were incidence of vertebral fracture, incidence of long bone fracture, and incidence of long bone and vertebral fracture. To assess the effect of pentosidine on fracture risk, we fitted multivariate Cox regression models adjusted for age, body weight, diabetes mellitus, lumbar BMD, prior fracture, and presence of back pain. To explore potential nonlinear relationships, we fitted a multivariate generalized additive model. To assess the discriminatory power of pentosidine, we performed receiver operating characteristic analysis. The hazard ratios for a 1 SD increase in pentosidine were 1.18 (95% CI 1.05-1.33, p < 0.01) for vertebral fracture and 1.20 (95% CI 1.07-1.33, p < 0.01) for long bone and vertebral fractures. The relationship was approximately linear, and there was no indication of the presence of a threshold. The C statistics were 0.732 (95% CI 0.686-0.778) for the model with both pentosidine and the 10-year risk and 0.702 (95% CI 0.654-0.750) for the 10-year risk alone. Eighty-three subjects (11%) in the whole cohort were in the highest quartile of pentosidine, although their 10-year risks were less than 15% and included 17 incident vertebral fracture cases. Urinary pentosidine improves risk classification using conventional risk assessment tools. Optimal clinical strategies of diagnosis and treatment remain uncertain and in need of additional investigation. ß

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Extracellular post-translational modifications of collagen are major determinants of biomechanical properties of fetal bovine cortical bone

Cited by 158 publications

References 38 publications

The contribution of collagen crosslinks to bone strength

The contribution of collagen crosslinks to bone strength

Effects of preexisting microdamage, collagen cross‐links, degree of mineralization, age, and architecture on compressive mechanical properties of elderly human vertebral trabecular bone

Urinary pentosidine improves risk classification using fracture risk assessment tools for postmenopausal women

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