# The Role of Calcitonin Gene-Related Peptide in rapidly progressive osteoarthritis induced by anti-nerve growth factor

> **NIH NIH R21** · INDIANA UNIVERSITY INDIANAPOLIS · 2022 · $237,750

## Abstract

Osteoarthritis (OA) is a major cause of pain and disability and there are currently no treatments that
reverse the joint deterioration with OA. The current standard of care involves pain management and
ultimately, joint replacement surgery for advanced OA. A recent strategy to treat OA pain is focused on
inhibition of nerve growth factor (NGF), a major mediator of nociceptive pain in OA. NGF antibodies
effectively reduce OA pain; however, a small percentage of patients treated with anti-NGF antibodies
develop a rapidly progressive/ destructive OA (RPOA) of the knee and hip that requires joint replacement;
however, the precise etiology of RPOA is unclear. The long term goal of this collaboration is to understand
the pathophysiology of RPOA and identify strategies to prevent it. NGF upregulates ion channels,
receptors for inflammatory mediators, and signaling neuropeptides, including substance P (SP) and
calcitonin gene-related peptide (CGRP) in sensory neurons and can enhance the outgrowth and
branching of peripheral axons: both effects likely contribute to OA pain and underscore the mechanism by
which anti-NGF antibodies achieve antinociception. In addition to their role in detecting pain via
orthodromic neurotransmitter release; however, sensory neurons also can affect peripheral tissues
through the antidromic release of neurotransmitters into the local microenvironment. In the joint, neuronal
release of CGRP stimulates bone formation, reduces bone resorption and stimulates angiogenesis and
vasodilatation of blood vessels. Based on this novel role of CGRP, we hypothesize that local release
of CGRP in the subchondral bone is required for maintenance of bloodflow and bone formation in
the OA joint, and that loss of CGRP signaling, induced by anti-NGF, facilitates accelerated
degeneration of the OA joint by compromising subchondral bone integrity. The risk for RPOA is
increased by high doses of anti-NGF antibodies, concomitant NSAID use and low bone mineral
density caused by low estrogen levels, all factors that diminish the neuronal release of CGRP, supporting
the notion that local CGRP could be protective against progressive OA. In Aim 1, we will determine the
effects of anti-NGF therapy, in the absence and presence of NSAIDs, on the severity of knee OA in aged
male and female mice. We will test the hypothesis that treatment with anti-NGF and NSAIDs reduce
CGRP in subchondral bone in animals with surgical destabilization of the medial meniscus (DMM),
resulting in altered subchondral bone mass and trabecular structure, and that this is associated with knee
OA severity. If successful, Aim 1 will generate the first animal model of RPOA. In Aim 2, we will determine
if anti-CGRP treatment will recapitulate the degeneration of the OA joint induced by anti-NGF therapy in
aged female mice with DMM to test the hypothesis that inhibition of CGRP signaling compromises the
integrity of subchondral bone in the animal model of OA. These studies will help to id...

## Key facts

- **NIH application ID:** 10459878
- **Project number:** 1R21AG073921-01A1
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** JILL C FEHRENBACHER
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $237,750
- **Award type:** 1
- **Project period:** 2022-06-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10459878

## Citation

> US National Institutes of Health, RePORTER application 10459878, The Role of Calcitonin Gene-Related Peptide in rapidly progressive osteoarthritis induced by anti-nerve growth factor (1R21AG073921-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10459878. Licensed CC0.

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