# The impact of TLR signaling on osteoclast-mediated bone remodeling and inflammation in osteoarthritis.

> **NIH NIH F31** · UNIVERSITY OF PENNSYLVANIA · 2024 · $48,974

## Abstract

Project Summary/ Abstract
Osteoarthritis (OA), one of the leading causes of disability in the US, is characterized by cartilage degradation, synovitis,
and subchondral bone remodeling. While there are currently no treatments for OA, there is increasing evidence that
chronic low-level inflammation plays a role in driving disease progression. Inflammation during OA manifests as the
infiltration of joint tissues (especially the synovium and subchondral bone) by immune cells, including macrophages, T
cells, and NK cells. Although mechanisms driving synovial inflammation are currently an intense area of study, little is
known regarding how inflammation in the subchondral bone (SCB) occurs and its consequences on remodeling and
joint homeostasis. Recently, Toll-like receptor (TLR)-mediated inflammatory pathways have been implicated in OAassociated
synovitis, cartilage erosion, and bone remodelling. Our previous work demonstrated that mice deficient in
CD14, a TLR co-receptor, are partially protected from disease in a post-traumatic OA model. Specifically, CD14-
deficiency resulted in a significant reduction in SCB bone thickening and cartilage damage after joint-injury compared
to wild type mice, with the most substantial amelioration of the SCB pathology. OA bone pathology extends beyond
signs of remodeling, and also includes an increase in inflammatory cells in the bone marrow. 1bis inflammation may
contribute to pain in OA, but the mechanisms driving SCB inflammation are poorly studied. Thus, I propose that TLR
signalling in osteoclasts modulates the osteoclast secretome, resulting in osteoblastogenesis as well as T cell
migration. To explore this, I will first show in vitro that TLR signaling leads to the release of factors that are both proinflammatory
and osteoblastogenic (Aim 1 ). Next, I will use IMC to characterize the T cell landscape in the subchondral
bone of osteoarthritic mice and determine anatomic associations between T cells and osteoclasts 1 (Aim 2a). Lastly, I
plan to develop a novel osteoclast T cell migration assay to show that TLR signaling in osteoclasts increases proinflammatory
T cell migration (Aim 2b). Successful completion of these Aims will provide a better understanding of
the cellular and tissue-level changes that occur in the subchondral bone in OA, as well as new targets for therapeutic
intervention. I have collected a significant amount of preliminary data, motivating the direction of these aims and
showcasing the skillset and tools I have already become proficient in. Additionally, with the help of my mentors as well
as my collaborators Dr. Su and Dr. Liu, I have all the necessary expertise to ensure the successful completion of this
project.

## Key facts

- **NIH application ID:** 10996052
- **Project number:** 1F31AR084868-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Lance Avery Murphy
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $48,974
- **Award type:** 1
- **Project period:** 2024-08-01 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10996052

## Citation

> US National Institutes of Health, RePORTER application 10996052, The impact of TLR signaling on osteoclast-mediated bone remodeling and inflammation in osteoarthritis. (1F31AR084868-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10996052. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*