# Senescence of Pre-Osteoclasts in Non-Traumatic OA

> **NIH NIH P01** · JOHNS HOPKINS UNIVERSITY · 2022 · $352,308

## Abstract

SUMMARY/ABSTRACT
Osteoarthritis (OA) is the most prevalent age-associated chronic joint disease. Although direct joint injury and
excessive mechanical overloading are considered as important contributors to the development of OA, only
approximately 12% of the overall prevalence of symptomatic OA is attributable to posttraumatic OA of the hip,
knee, or ankle. Aging is recognized as the most important risk factor for OA, and the metabolic phenotype
becomes the second most frequent subtype of OA among patients enrolled in clinical studies. Recently, it has
been recognized that cellular senescence is a key driver for the progression of post-traumatic OA. However,
whether and how senescent cells (SnCs) are involved in the development of non-traumatic OA remain poorly
understood. In our preliminary study, we found accumulated SnCs at the joint subchondral bone marrow of both
spontaneous aging OA mice and STR/Ort mice, a spontaneous OA mice associated with metabolic dysregulation.
Increased SnCs were not detected in subchondral bone marrow of a post-traumatic OA mice. Therefore,
subchondral bone marrow cell senescence may represent a unique feature of non-traumatic subtype of OA
distinguishable from post-traumatic OA. Moreover, we identified that close to 80% of the SnCs are bone marrow
Pre-osteoclast (Pre-OC). Pre-OCs isolated from old mice, relative to young mice, had increased expression of
common senescence-associated secretory phenotype (SASP) factors and much higher expression of
angiogenesis factor PDGF-BB, a potent angiogenesis factor. It is known that increased subchondral bone
angiogenesis is a major contributor to the development of OA. Therefore, the excessive PDGF-BB secreted by
subchondral bone marrow SnCs may contribute to aberrant subchondral bone angiogenesis. Our central
hypothesis is that senescent Pre-OCs induce aberrant subchondral bone angiogenesis by secreting excessive
PDGF-BB, leading to OA-related joint structural damage. The hypothesis will be tested by the following Specific
Aims. In Aim 1, we will trace the SnCs in synovial tissue, articular cartilage, and subchondral bone tissue of the
joints by detecting the cellular senescence markers in spontaneous aging OA mice and STR/Ort mice. We will
also trace the SnCs at different stages of OC lineage and verify the SASP phenotype of the cells in bone marrow
of the mice. Aim 2 will examine the necessity and sufficiency of Pre-OCs-derived PDGF-BB in age-associated
subchondral bone angiogenesis and OA development. In Aim 3, we will first define the contribution of cellular
senescence to subchondral bone angiogenesis and osteogenesis by selectively eliminating the SnCs in OA mice.
We will then test if blockage of Pre-OC senescence using both genetic and pharmacologic approaches
attenuates OA progression.

## Key facts

- **NIH application ID:** 10326804
- **Project number:** 5P01AG066603-02
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Mei Wan
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $352,308
- **Award type:** 5
- **Project period:** 2021-01-15 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10326804

## Citation

> US National Institutes of Health, RePORTER application 10326804, Senescence of Pre-Osteoclasts in Non-Traumatic OA (5P01AG066603-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10326804. Licensed CC0.

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