The contribution of collagen crosslinks to bone strength

Abstract

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.

Are Changes in Composition in Response to Treatment of a Mouse Model of Osteogenesis Imperfecta Sex-dependent?

“…Glycated chains formed by nonenzymatic reactions [22] are not detected by this method. There are data suggesting that crosslinking estimated by FTIR imaging is related to bone strength [17] with higher values found in more brittle bones; thus, this finding merits further investigation.…”

Aging Versus Postmenopausal Osteoporosis: Bone Composition and Maturation Kinetics at Actively-Forming Trabecular Surfaces of Female Subjects Aged 1 to 84 Years

“…Enzymatic collagen cross-links are known to contribute to bone strength, affecting both the stiffness and the toughness. (53)(54)(55) Interestingly, in cases where predicted bone strength and actual fracture incidence considerations were divergent, collagen enzymatic cross-links, to date, always correlated with the latter. (18,48,50,52,(56)(57)(58)(59) One possible explanation for this is that although stiffness depends on modulus, bone toughness depends on interfaces, (60) and in the actively-forming trabecular bone areas examined in the present study a major interface close to TA3 is present, namely the cement line.…”

Periostin function in communication with extracellular matrices

“…Moreover, in silico structural analysis indicated possible direct binding between the FAS 1 domains and BMP-1 (Hwang et al 2014). This interaction enhances proteolytic activation of lysyl oxidase (LOX), which is associated with the EMI domain of periostin via fibronectin (Maruhashi et al 2010;Garnero 2012). LOX is an enzyme that catalyzes intermolecular crosslinking between collagen molecules (Trackman 2016), which is crucial for collagen fibrillogenesis.…”