Abstract
The specifics of how the nanoscale properties of collagen (e.g., the crosslinking profile) affect the mechanical integrity of bone at larger length scales is poorly understood despite growing evidence that collagen’s nanoscale properties are altered with disease. Additionally, mass independent increases in postyield displacement due to exercise suggest loading-induced improvements in bone quality associated with collagen. To test whether disease-induced reductions in bone quality driven by alterations in collagen can be rescued or prevented via exercise-mediated changes to collagen’s nanoscale morphology and mechanical properties, the effects of treadmill exercise and β-aminopropionitrile treatment were investigated. Eight week old female C57BL/6 mice were given a daily subcutaneous injection of either 164 mg/kg β-aminopropionitrile or phosphate buffered saline while experiencing either normal cage activity or 30 min of treadmill exercise for 21 consecutive days. Despite differences in D-spacing distribution (P = 0.003) and increased cortical area (tibial: P = 0.005 and femoral: P = 0.015) due to β-aminopropionitrile treatment, an overt mechanical disease state was not achieved as there were no differences in fracture toughness or 4 point bending due to β-aminopropionitrile treatment. While exercise did not alter (P = 0.058) the D-spacing distribution of collagen or prevent (P < 0.001) the β-aminopropionitrile-induced changes present in the unexercised animals, there were differential effects in the distribution of the reduced elastic modulus due to exercise between control and β-aminopropionitrile-treated animals (P < 0.001). Fracture toughness was increased (P = 0.043) as a main effect of exercise, but no significant differences due to exercise were observed using 4 point bending. Future studies should examine the potential for sex specific differences in the dose of β-aminopropionitrile required to induce mechanical effects in mice and the contributions of other nanoscale aspects of bone (e.g., the mineral–collagen interface) to elucidate the mechanism for the exercise-based improvements in fracture toughness observed here and the increased postyield deformation observed in other studies.
Highlights
Type I collagen is the most abundant form of the most abundant protein in the human body, yet how its properties at the nanoscale influence the mechanical integrity of bone at larger length scales is poorly understood
While the response to BAPN was less severe than expected, the results reported here and in previous studies indicate that this dose of BAPN did have an effect at the nanoscale over the 8 to 11 weeks of age time frame [10], but it is likely that not enough of the tissue was affected by the BAPN treatment compared to previous studies due to the variations in protocol previously discussed
While exercise does not affect D-spacing, nanoscale indentation modulus was shifted to higher values with exercise in the absence of BAPN
Summary
Type I collagen is the most abundant form of the most abundant protein in the human body, yet how its properties at the nanoscale influence the mechanical integrity of bone at larger length scales is poorly understood. There is growing evidence that the profile of collagen crosslinking plays an important role in determining the mechanical properties of bone, and this profile may be altered with disease [1]. Experimental osteolathyrism can be used to bridge this knowledge gap because it offers the ability to create a specific nanoscale deficiency in enzymatic collagen crosslinking. The disease is due to dietary intake of the β-aminopropionitrile (BAPN) toxin [2] and is well represented by animal models which are given a controlled dose of BAPN [3,4,5]. Unlike non-enzymatic crosslinks, which can detrimentally affect bone, enzymatic crosslinks are typically associated with increased mechanical integrity
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