title: Exercise increases pyridinoline cross-linking and counters the mechanical effects of concurrent lathyrogenic treatment.
abstract: The collagen cross-link profile of bone, associated with bone strength and fracture toughness, is tightly regulated (affecting cross-link quantity, type, lysine hydroxylation and maturity) and may contribute to the improvements in bone quality during exercise. We hypothesized that 1) exercise promotes mature cross-link formation, 2) increased mature cross-linking is accompanied by shifts in lysine hydroxylation, and 3) these changes in collagen cross-link profile have positive effects on mechanical properties. Growing male C57Bl6 mice were treated with 30 min/day of running exercise, 350 mg/kg/day β-aminopropionitrile (BAPN) injected subcutaneously to inhibit enzymatic collagen cross-linking, or both exercise and BAPN, from 5 to 8 weeks of age. Bone collagen cross-linking profile, mechanical properties, morphology, and mineralization were measured from the tibiae. Cross-link measures, including immature, pyridinoline, pyrrole and pentosidine cross-links, ratios reflecting cross-link maturity and hydroxylation, and mineralization were tested for their importance to mechanical properties across 8 week groups through correlation analyses and step-wise linear regressions. BAPN treatment significantly reduced lysylpyridinoline, pyrrole, hydroxylysinorleucine, and total mature collagen cross-linking, resulting in decreased bone elastic modulus and increased yield strain despite a marginal increase in TMD. Exercise caused a shift toward pyridinoline cross-linking, with increased hydroxylysylpyridinoline and decreased pyrrole cross-linking resulting in total mature cross-linking and estimated tissue level mechanical properties matching sedentary control levels. Exercise superimposed on BAPN treatment increased total mature cross-linking from BAPN to control levels, but did so by increasing pyridinoline, not pyrrole, cross-links. Exercise also counteracted the BAPN effects on modulus and strain, without a change in TMD. Pyrrole cross-linking was the strongest correlate of modulus (r=0.470, p<0.01) and yield strain (r=-0.467, p<0.01). Cross-links with similar levels of telopeptide lysine hydroxylation to pyrrole (lysylpyridinoline and hydroxylysinorleucine) also correlated with modulus and strain to a lesser extent. In conclusion, exercise in growing mice promotes pyridinoline collagen cross-linking in bone, the resulting increase in total mature cross-linking is sufficient to counteract the mechanical effects of concurrent cross-link inhibition, and this responsiveness to loading is a potential means by which exercise might improve bone quality in diseased or otherwise compromised bone.
authors.affiliation: Department of Biomedical Engineering, College of Engineering and Medical School, University of Michigan, MI, USA.
authors.forename: Erin M B
authors.initials: EMB
authors.lastname: McNerny
authors.affiliation: Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, MI, USA.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Gardinier
authors.affiliation: Department of Biomedical Engineering, College of Engineering and Medical School, University of Michigan, MI, USA; Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, MI, USA. Electronic address: dhkohn@umich.edu.
authors.forename: David H
authors.initials: DH
authors.lastname: Kohn
mesh_terms: D000596:Amino Acids / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001696:Biomechanical Phenomena / Q000187:drug effects / Q000502:physiology; D003432:Cross-Linking Reagents / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010012:Osteogenesis / Q000187:drug effects / Q000502:physiology*; D010805:Physical Conditioning, Animal / Q000379:methods / Q000502:physiology*; D057185:Sedentary Behavior
chemical_list: D000596:Amino Acids; D003432:Cross-Linking Reagents; C015484:pyridinoline
keywords: Bone quality; Collagen cross-linking; Exercise; Lathyrism; Mechanics; β-Aminopropionitrile