# Subchondral Bone Cavities in Osteoarthritis Pain

> **NIH NIH RF1** · JOHNS HOPKINS UNIVERSITY · 2020 · $2,521,652

## Abstract

ABSTRACT
Chronic pain is the most prominent symptom of osteoarthritis (OA) and a key reason why patients seek medical
help. Persistent pain at rest profoundly affects the quality of life and daily physical activity. Pain itself is a risk
factor for the development of future functional decline and increasing pain is a predictor of physical functional
limitation and disability. Osteoarthritic pain is thought to emanate from small myelinated or unmyelinated fibers
in one or more tissues including synovium, ligament, subchondral bone, and meniscus. In clinic, subchondral
bone marrow edema-like lesions (BMLs) visualized by MRI are highly correlated with OA pain. Thus, the
observation suggests that the source of pain is likely from subchondral bone. The detailed mechanism how
subchondral bone generates OA pain, however, is largely unknown. During OA progression, aberrant osteoclast
(OC) bone resorption enlarges subchondral bone cavity, which promotes sensory innervation and leads to OA
pain. PGE2 mediates sensory nerve regulation of bone density. PGE2 concentration in bone negatively
correlated with bone density. Our pilot data showed PGE2 levels and sensory innervation significantly increased
in the cavity of OA subchondral bone which resembles extreme low bone density as seen in osteoporosis. This
prompted us to propose that high levels of PGE2 sensitize the highly specialized sensory neurons, nociceptors,
in the subchondral bone to promote pain. During the pathogenesis of OA, senescent cells are increased in the
subchondral bone with at least 40% being osteoclastic cells. We have recently shown that OC secrete Netrin-1,
an axonal guidance molecule, to induce sensory nerve axon growth in the subchondral bone to mediate OA pain.
Therefore, we hypothesize that enlarged subchondral bone cavity by senescent OCs elevates PGE2 levels and
further enhances sensory innervation to mediate OA pain. To test the hypothesis, we will investigate the role of
senescent OC in inducing subchondral bone cavity and sensory innervation. We will examine the role of
subchondral bone cavity by senescent OC induced abnormal bone remodeling in the elevation of PGE2 and
subsequent OA pain. We will then test the effect of eliminating senescent osteoclast on subchondral bone cavity
and sensory innervation for OA pain by administration of senolytic drug ABT263 to OA mice. Finally, we will
investigate the effect of rescuing subchondral bone remodeling on sensory innervation and OA pain. We have
developed a novel conjugate that bone-specifically delivers a TGFβ inhibitor and OC inhibitor alendronate. The
effect of this small molecule conjugate will be examined on sensory innervation in subchondral bone and OA
pain.

## Key facts

- **NIH application ID:** 10054792
- **Project number:** 1RF1AG068997-01
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Xu Cao
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $2,521,652
- **Award type:** 1
- **Project period:** 2020-09-30 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10054792

## Citation

> US National Institutes of Health, RePORTER application 10054792, Subchondral Bone Cavities in Osteoarthritis Pain (1RF1AG068997-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10054792. Licensed CC0.

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