# Novel Imaging Probe for Early Detection of Charcot Foot

> **NIH NIH R21** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2023 · $400,638

## Abstract

PROJECT SUMMARY/ABSTRACT
Charcot neuroarthropathy (CN) is a progressive, denervation-induced degeneration of weight bearing joints. Any
patient with loss of afferent proprioceptive fibers is susceptible to this degeneration. CN presents as a discrete
local inflammatory reaction resulting in the sterile destruction of joint bone in the foot and ankle. The 5-year
mortality in patients is as high as 28% with greater than 67% of these patients developing severe ulcerative
complications that may lead to amputation. The CN inflammatory process results in localized osteopenia in a
focal area of the foot or ankle causing instability and collapse when bearing weight. It is a self-limiting process
which appears to be triggered by a trauma or repetitive microtrauma. Once activated, CN is characterized by
resorptive osteoclastic activity leading to a progressive bone lesion. CN is often misdiagnosed as cellulitis or
osteomyelitis, delaying diagnosis and increasing bone destruction. Osteolysis of bone contributes significantly
to the morbidity and mortality of patients with CN and early assessment is critical to preserve function and to
reduce the risk of major amputation. There are currently no prognostic tests available for early detection of CN.
Cathepsin K (CatK) is a cysteine protease produced by osteoclasts that is overexpressed in many resorptive
bone diseases, including CN. We have designed a novel molecular imaging probe, OFS (Osteoadsorptive
Fluorogenic Substrate), to detect CatK on bone surfaces. This probe incorporates a bisphosphonate moiety to
allow it to target bone with very high tissue selectivity, together with a fluorophore linked to a Förster resonance
energy transfer (FRET) quenching dye by a peptide that is specifically cleaved by CatK, thereby generating a
strong fluorescent signal in the presence of the enzyme. OFS thus offers a unique method to detect abnormal
osteoclast-mediated bone resorption with high sensitivity. We propose to develop this highly innovative molecular
probe for early detection of osteolysis and surveillance of CN by mapping OFS fluorescence in intraoperative
bone samples from CN patients, using healthy bone as a control and radiography as the reference diagnostic
imaging technology. If successful, the proposed research would provide the foundation for a powerful new
diagnostic and prognostic tool to improve outcomes for CN patients, among whom disadvantaged minorities are
disproportionately represented. The project, led by Dr. Laura Shin, DPM, PhD (expert on limb salvage, bone
reconstruction related to CN, cell culture and confocal microscopy) and Dr. Charles McKenna, PhD (expert on
imaging bisphosphonates), will be performed in the PIs’ laboratories at the University of Southern California’s
Keck School of Medicine (Shin) and Drug Discovery Center (McKenna).

## Key facts

- **NIH application ID:** 10593866
- **Project number:** 1R21AR077322-01A1
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Laura Shin
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $400,638
- **Award type:** 1
- **Project period:** 2023-09-20 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10593866

## Citation

> US National Institutes of Health, RePORTER application 10593866, Novel Imaging Probe for Early Detection of Charcot Foot (1R21AR077322-01A1). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10593866. Licensed CC0.

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