Glycation cross-linking induced mechanical–enzymatic cleavage of microscale tendon fibers

Abstract

Recent molecular modeling data using collagen peptides predicted that mechanical force transmitted through intermolecular cross-links resulted in collagen triple helix unwinding. These simulations further predicted that this unwinding, referred to as triple helical microunfolding, occurred at forces well below canonical collagen damage mechanisms. Based in large part on these data, we hypothesized that mechanical loading of glycation cross-linked tendon microfibers would result in accelerated collagenolytic enzyme damage. This hypothesis is in stark contrast to reports in literature that indicated that individually mechanical loading or cross-linking each retards enzymatic degradation of collagen substrates. Using our Collagen Enzyme MechanoKinetic Automated Testing (CEMKAT) System we mechanically loaded collagen-rich tendon microfibers that had been chemically cross-linked with sugar and tested for degrading enzyme susceptibility. Our results indicated that cross-linked fibers were >5 times more resistant to enzymatic degradation while unloaded but became highly susceptible to enzyme cleavage when they were stretched by an applied mechanical deformation.

Molecular-based nonlinear viscoelastic chemomechanical model incorporating thermal denaturation kinetics of collagen fibrous biomaterials

“…Mechanical loading of collagen molecules may lead to partial collagen unfolding [52,53], which may result in unveiled cleavage active sites. The presence of collagenolytic enzymes or collagenases accelerates the degradation process [54]. Thus, these findings confirm that both elevated temperatures and mechanical load, serve as a driving force for the degradative processes in collagenous tissues.…”

Tendinopathy in diabetes mellitus patients—Epidemiology, pathogenesis, and management

“…The collagen cross‐links reduced fiber sliding and viscoelasticity of tendon and hence increased its stiffness and brittleness . While cross‐linked fibers of tendon were more resistant to collagenase digestion when unloaded, the fibers became susceptible to collagenase digestion upon mechanical loading . This was due to the local microunfolding of the triple helix of the glycated collagen during tensile load transmission, which increased its susceptibility to proteolytic cleavage.…”

Direct ab‐initio molecular dynamics study on the radiation effects on catalytic triad composed of Ser‐His‐Glu residues

“…Many experimental and theoretical works on the DNA damage have been carried out in the last decade . On the other hand, the studying of radiation enzyme damages is limited . Acetylcholinesterase (AChE) is one of the enzymes which is composed of catalytic triad in the active site consisting of the amino acids, serine (Ser), histidine (His), and glutamic acid (Glu) .…”

“…High energy irradiation to the hydrogen bonded system is important in relevance with the initial process of DNA damages [1][2][3] and enzyme damages. [4][5][6][7] If DNA base pair is ionized by the irradiation, a proton is transferred into the neighbored base along the hydrogen bond, while a defect is formed in the damaged DNA. [8,9] The defect leads to replication and transcriptional errors in DNA.…”

“…[1][2][3]8,9] On the other hand, the studying of radiation enzyme damages is limited. [4][5][6][7] Acetylcholinesterase (AChE) is one of the enzymes which is composed of catalytic triad in the active site consisting of the amino acids, serine (Ser), histidine (His), and glutamic acid (Glu). [10][11][12] AChE can synthesize neurotransmitter acetylcholine (ACh) by the transition of acetyl groups of acetyl CoA.…”