Alteration of Type I collagen microstructure induced by estrogen depletion can be prevented with drug treatment

Cauble, Meagan A.; Rothman, Edward D.; Welch, Kathleen B.; Fang, Ming; Duong, Le T.; Pennypacker, Brenda L; Orr, Bradford G.; Holl, Mark M. Banaszak

doi:10.1038/bonekey.2015.66

Cited by 6 publications

(37 citation statements)

References 19 publications

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“…We have demonstrated non-Gaussian distributions in collagen nanomorphology with D -spacing measured from 59 to 75 nm. 13−20 We found that, in general, there is very little variation in D -spacings within bundles (groups of aligned fibrils) but large variations between bundles. 18 Existing models of collagen structure cannot explain these D -spacing distributions, but a recent study documented changes in collagen structure at all levels of hierarchy, including D -spacing, as a function of disease.…”

Section: Introductionmentioning

confidence: 79%

“…20 We documented surface heterogeneity and changes in collagen microstructure that would not be reflected in average values incorporating measurements from many fibrils over a larger area of the tissue surface.…”

Section: Introductionmentioning

confidence: 99%

“…(a) Parallel region showing multiple aligned fibrils (yellow arrows); (b) oblique region showing multiple fibrils with varying alignment (yellow arrows). Reproduced with permission from ref (20). Copyright 2015, Nature Springer.…”

Section: Introductionmentioning

confidence: 99%

“…In sum, the study involved analyzing a total of 5,673 fibrils from 84 rabbits split into seven treatment groups. 20,21 After ovariectomy-induced estrogen depletion, the osteoporosis drugs were given to the rabbits as a preventive, not as treatment. Note that all the imaging and analysis was carried out blind to the identity of the samples.…”

Section: Introductionmentioning

confidence: 99%

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Distributions: The Importance of the Chemist’s Molecular View for Biological Materials

2018

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Characterization of materials with biological applications and assessment of physiological effects of therapeutic interventions are critical for translating research to the clinic and preventing adverse reactions. Analytical techniques typically used to characterize targeted nanomaterials and tissues rely on bulk measurement. Therefore, the resulting data represent an average structure of the sample, masking stochastic (randomly generated) distributions that are commonly present. In this Perspective, we examine almost 20 years of work our group has done in different fields to characterize and control distributions. We discuss the analytical techniques and statistical methods we use and illustrate how we leverage them in tandem with other bulk techniques. We also discuss the challenges and time investment associated with taking such a detailed view of distributions as well as the risks of not fully appreciating the extent of heterogeneity present in many systems. Through three case studies showcasing our research on conjugated polymers for drug delivery, collagen in bone, and endogenous protein nanoparticles, we discuss how identification and characterization of distributions, i.e., a molecular view of the system, was critical for understanding the observed biological effects. In all three cases, data would have been misinterpreted and insights missed if we had only relied upon spatially averaged data. Finally, we discuss how new techniques are starting to bridge the gap between bulk and molecular level analysis, bringing more opportunity and capacity to the research community to address the challenges of distributions and their roles in biology, chemistry, and the translation of science and engineering to societal challenges.

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Section: Introductionmentioning

confidence: 79%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Distributions: The Importance of the Chemist’s Molecular View for Biological Materials

2018

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“…Rabbit cortical femur images analyzed were from our previously published data set (Cauble et al, 2015). There were a total of 663 images (3.5 μm 2 ) for cortical femur samples taken from 48 animals (11 Sham, 12 OVX + Veh, 12 OVX + ALN, and 13 OVX + CatKI).…”

Section: Methodsmentioning

confidence: 99%

Estrogen depletion and drug treatment alter the microstructure of type I collagen in bone

et al. 2016

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The impact of estrogen depletion and drug treatment on type I collagen fibril nanomorphology and collagen fibril packing (microstructure) was evaluated by atomic force microscopy (AFM) using an ovariectomized (OVX) rabbit model of estrogen deficiency induced bone loss. Nine month-old New Zealand white female rabbits were treated as follows: sham-operated (Sham; n = 11), OVX + vehicle (OVX + Veh; n = 12), OVX + alendronate (ALN, 600 μg/kg/wk., s.c.; n = 12), and OVX + cathepsin-K inhibitor L-235 (CatKI, 10 mg/kg, daily, p.o.; n = 13) in prevention mode for 27 weeks. Samples from the cortical femur and trabecular lumbar vertebrae were polished, demineralized, and imaged using AFM. Auto-correlation of image patches was used to generate a vector field for each image that mathematically approximated the collagen fibril alignment. This vector field was used to compute an information-theoretic entropy that was employed as a quantitative fibril alignment parameter (FAP) to allow image-to-image and sample-to-sample comparison. For all samples, no change was observed in the average FAP values; however significant differences in the distribution of FAP values were observed. In particular, OVX + Veh lumbar vertebrae samples contained a tail of lower FAP values representing regions of greater fibril alignment. OVX + ALN treatment resulted in a FAP distribution with a tail indicating greater alignment for cortical femur and less alignment for trabecular lumbar vertebrae. OVX + CatKI treatment gave a distribution of FAP values with a tail indicating less alignment for cortical femur and no change for trabecular lumbar vertebrae. Fibril alignment was also evaluated by considering when a fibril was part of discrete bundles or sheets (classified as parallel) or not (classified as oblique). For this analysis, the percentage of parallel fibrils in cortical femur for the OVX group was 17% lower than the Sham group. OVX + ALN treatment partially prevented the proportion of parallel fibrils from decreasing and OVX + CatKI treatment completely prevented a change. In trabecular lumbar vertebrae, there was no difference in the percentage of parallel fibrils between Sham and any of the other treatment groups.

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Atomic force microscopy imaging for nanoscale and microscale assessments of extracellular matrix in intervertebral disc and degeneration

et al. 2020

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Degeneration of the intervertebral disc (IVD) is a condition that is often associated with debilitating back pain. There are no disease-modifying treatments available to halt the progression of this ubiquitous disorder. This is partly due to a lack of understanding of extracellular matrix (ECM) changes that occur at the micro-and nanometer size scales as the disease progresses. Over the past decade, atomic force microscopy (AFM) has been utilized as a tool to investigate the impact of disease on nanoscale structure of ECM in bone, skin, tendon, and dentin. We have expanded this methodology to include the IVD and report the first quantitative analysis of ECM structure at submicron size scales in a murine model for progressive IVD degeneration. Collagen D-spacing, a metric of nanoscale structure at the fibril level, was observed as a distribution of values with an overall average value of 62.5 ± 2.5 nm.

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Alteration of Type I collagen microstructure induced by estrogen depletion can be prevented with drug treatment

Cited by 6 publications

References 19 publications

Distributions: The Importance of the Chemist’s Molecular View for Biological Materials

Distributions: The Importance of the Chemist’s Molecular View for Biological Materials

Estrogen depletion and drug treatment alter the microstructure of type I collagen in bone

Atomic force microscopy imaging for nanoscale and microscale assessments of extracellular matrix in intervertebral disc and degeneration

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