# Roles of Collagen and Water in the Fracture Resistance of Bone

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2021 · $454,343

## Abstract

A critical barrier to the development of new strategies for preventing costly fractures of the hip, spine, and
proximal humerus is an incomplete understanding of the key age- and disease-related changes occurring in
bone tissue. In particular, little is known about the pathogenic mechanisms by which the deterioration in the
extracellular matrix (ECM) reduces the fracture resistance of bone or increases fracture risk. Non-enzymatic
post-translational modifications (NE-PTMs) are potential contributors to poor ECM because they accumulate in
matrix proteins as fracture risk increases. Therefore, the overall goals of this project are i) to determine which
NE-PTMs of collagen I, the predominant ECM protein of bone, predict bone fracture resistance and are clinically
relevant in osteoporosis and ii) to establish whether non-crosslinking or crosslinking NE-PTMs contribute to a
decrease in fracture resistance of bone and whether they do so via alterations in the structure and hydration of
collagen I. To achieve our goals, we will first generate specimens of cortical bone (dense) and trabecular bone
(spongy) using cadaveric femurs collected from both female and male donors between 50 years and 100 years
of age (Aim 1a). These specimens will be comprehensively analyzed to quantify: bone mineral density, bone
volume fraction, ECM-bound water, secondary structure of collagen I, mature enzymatic & non-enzymatic
collagen crosslinks, integrity of collagen I fibrils, the resistance to yielding (strength), the ability to deform after
yielding (toughness), the resistance to crack growth (fracture toughness), and the resistance to damage
accumulation (fatigue). From adjacent bone samples, we will also extract ECM proteins including collagen I and
quantify NE-PTMs at specific amino acid residues that form its triple helix using mass spectrometry. By fitting
the data to statistical models, we will determine whether the levels of certain NE-PTMs help explain differences
among the donors in fracture resistance, collagen fibril integrity, ECM-bound water, and spectroscopic markers
of helical structure. We will also generate bone specimens from proximal femurs acquired from cadavers without
osteoarthritis (OA) and two types of orthopaedic surgical cases: total hip arthroplasty (THA) for OA and hemi-
arthroplasty (HA) to fix a fragility fracture (Aim 1b). The specimens will be analyzed as in Aim 1a to determine
whether NE-PTM levels are significantly higher while ECM-bound water and fracture resistance are significantly
lower in HA (osteoporosis) vs. THA (OA) or the cadaveric controls. To identify a mechanism whereby NE-PTMs
lowers fracture resistance of bone, we will treat bones ex vivo to accumulate specific types of NE-PTMs (Aim
2a). Following treatment, we will assess the bones to determine which specific NE-PTMs significantly affect the
fracture resistance of bone in a manner similar to that of aging as determined in Aim 1. Lastly, we will perform
molecular dynamics s...

## Key facts

- **NIH application ID:** 10298413
- **Project number:** 2R01AR063157-07A1
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Jeffry Stephen Nyman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $454,343
- **Award type:** 2
- **Project period:** 2012-09-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10298413

## Citation

> US National Institutes of Health, RePORTER application 10298413, Roles of Collagen and Water in the Fracture Resistance of Bone (2R01AR063157-07A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10298413. Licensed CC0.

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