2 research outputs found
Bone Fracture Toughness and Strength Correlate With Collagen CrossâLink Maturity in a DoseâControlled Lathyrism Mouse Model
Collagen crossâlinking is altered in many diseases of bone, and enzymatic collagen crossâlinks are important to bone quality, as evidenced by losses of strength after lysyl oxidase inhibition (lathyrism). We hypothesized that crossâlinks also contribute directly to bone fracture toughness. A mouse model of lathyrism using subcutaneous injection of up to 500âmg/kg ÎČâaminopropionitrile (BAPN) was developed and characterized (60 animals across 4 dosage groups). Three weeks of 150 or 350âmg/kg BAPN treatment in young, growing mice significantly reduced cortical bone fracture toughness, strength, and pyridinoline crossâlink content. Ratios reflecting relative crossâlink maturity were positive regressors of fracture toughness (HP/[DHLNLâ+âHLNL] r2â=â0.208, pâ<â0.05; [HPâ+âLP]/[DHNLâ+âHLNL] r2â=â0.196, pâ<â0.1), whereas quantities of mature pyridinoline crossâlinks were significant positive regressors of tissue strength (lysyl pyridinoline r2â=â0.159, pâ=â0.014; hydroxylysyl pyridinoline r2â=â0.112, pâ<â0.05). Immature and pyrrole crossâlinks, which were not significantly reduced by BAPN, did not correlate with mechanical properties. The effect of BAPN treatment on mechanical properties was dose specific, with the greatest impact found at the intermediate (350âmg/kg) dose. Calcein labeling was used to define locations of new bone formation, allowing for the identification of regions of normally crossâlinked (preexisting) and BAPNâtreated (newly formed, crossâlinkâdeficient) bone. Raman spectroscopy revealed spatial differences attributable to relative tissue age and effects of crossâlink inhibition. Newly deposited tissues had lower mineral/matrix, carbonate/phosphate, and Amide I crossâlink (matrix maturity) ratios compared with preexisting tissues. BAPN treatment did not affect mineral measures but significantly increased the crossâlink (matrix maturity) ratio compared with newly formed control tissue. Our study reveals that spatially localized effects of shortâterm BAPN crossâlink inhibition can alter the wholeâbone collagen crossâlink profile to a measureable degree, and this crossâlink profile correlates with bone fracture toughness and strength. Thus, crossâlink profile perturbations associated with bone disease may provide insight into bone mechanical quality and fracture risk. © 2014 American Society for Bone and Mineral Research.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/110745/1/jbmr2356.pd