# Skeleton and Joint Degeneration with Aging

> **NIH NIH P01** · JOHNS HOPKINS UNIVERSITY · 2021 · $1,888,834

## Abstract

PROJECT SUMMARY/ABSTRACT
Decreased mobility significantly increases the risk of many chronic diseases leading to an acceleration of the
normal aging process. Skeletal degeneration, particularly of the spine and joints, are among the most prevalent
diseases leading to a decline in mobility and to frailty. Frailty, defined as a state of decreased physiologic reserve,
often develops with aging and influences a person’s ability to compensate for the additional burden of disease.
With development of frailty, the natural homeostatic reserve is reduced and the ability of the body to compensate
for perturbations is reduced. Degeneration of the spine and joints can substantially accelerate development of
frailty; however, the underlying pathophysiology of this degeneration in aging and the development and
progression of resulting low back pain (LBP) and osteoarthritis (OA) is not well understood. There is no disease-
modifying treatment for either, largely due to the lack in the understanding of pathophysiology of pain and the
unique cellular signaling changes among OA subtypes.
LBP commonly results from degeneration of the amphiarthrodial spinal joints, with pain correlating most strongly
with changes in vertebral endplate morphology. Degeneration of diarthrodial joints is a set of diverse processes
that are frequently lumped together under the umbrella term “osteoarthritis” but represent a heterogeneous
disease process. Osteoclasts (OC) in both vertebral endplates and subchondral bone undergo senescence
during aging to generate porous sclerotic endplates, uncoupled remodeling in subchondral bone, and senescent
OC secrete Netrin-1 to induce axonal extrusion and innervation that potentially lead to pain. Therefore, we
hypothesize that porous sclerotic endplates and uncoupled remodeling of subchondral bone by
senescent OC lead to skeletal joint degeneration and pain, severely limiting mobility and increasing
frailty to accelerate aging. In Project 1, we will investigate how endplate porosity with aging induces spinal
degeneration and sensory innervation to result in LBP. In Project 2, we will investigate the mechanism of the
translational application of intermittent parathyroid hormone injection (iPTH) – increased intervertebral disc (IVD)
volume to spinal degeneration and reduce endplate nerve innervation and LBP by remodeling of porous sclerotic
endplates. In Projects 3, we will characterize the mechanism of cellular senescence in two different subtypes of
OA: non-traumatic OA that is orchestrated by senescence of pre-OC. Together, these 3 projects, supported by
common Administrative and Biostatistics (Core A) and In Vivo Model and Histology (Core B) Cores, will result
in nuanced understanding of the pathophysiology of joint and spinal degeneration associated with aging and will
provide foundational mechanistic insights for potential therapeutic targets.

## Key facts

- **NIH application ID:** 10090193
- **Project number:** 1P01AG066603-01A1
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Xu Cao
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,888,834
- **Award type:** 1
- **Project period:** 2021-01-15 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10090193

## Citation

> US National Institutes of Health, RePORTER application 10090193, Skeleton and Joint Degeneration with Aging (1P01AG066603-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10090193. Licensed CC0.

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