# Fibrosis, inflammation, and osteophyte formation in post-traumatic osteoarthritis

> **NIH NIH K99** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $103,080

## Abstract

Post-traumatic osteoarthritis (PTOA) is a degenerative joint disease that arises after injury and affects millions
worldwide. There are currently no disease-modifying treatments. PTOA is a complex, multi-tissue joint disease
characterized by pain, cartilage degradation, synovial inflammation and fibrosis, and formation of ectopic bone
growths called osteophytes. The inherent complexity of this disease is a barrier to developing effective
treatments, as little is known about the intricate tissue crosstalk that underlies PTOA progression. Our long-
term goal is to uncover and comprehensively characterize cellular and molecular mechanisms central to key
pathological sequalae of PTOA: synovial fibrosis, inflammation, and osteophyte formation. We will focus on
canonical Wnt/β-catenin (cWnt) signaling. cWnt overactivation has recently been implicated as a driving factor
of arthritis. Our data show that the cWnt signaling agonist R-spondin 2 (Rspo2) is strongly induced in multiple
joint tissues during PTOA, and that Rspo2 alone is sufficient to induce pathological features characteristic of
PTOA. Using single-cell RNA-seq, we profiled synovium of mice with PTOA and found that Rspo2 is produced
by synovial lining fibroblasts. We identified a novel population of pro-fibrotic cells that arise after injury and
express Lgr cell surface receptors for Rspo2. We showed that synovial fibroblasts respond to Rspo2 by
secreting cytokines that in turn activate pro-inflammatory macrophages (known to drive synovial pathology in
PTOA). Single-cell profiling also revealed a novel subset of injury-induced, Lgr-expressing osteochondral
progenitors in synovium, which we propose give rise to osteophytes. We hypothesize that Rspo2-driven cWnt
signaling mediates pathological crosstalk between joint-resident cell types to potentiate PTOA. To test this, our
aims in the K99 phase are to: 1) determine the role of Rspo2-driven cWnt signaling in the emergence and
function of pro-fibrotic synovial cells during PTOA using transgenic reporter mice, multi-omic analyses, and in
vitro differentiation assays, and 2) characterize crosstalk between cWnt-active synovial fibroblasts and pro-
inflammatory macrophages, using knockout mice and crosstalk assays. To extend upon my molecular biology
and immunology expertise, I will receive rigorous technical and conceptual training from my diverse mentorship
committee during the K99 phase, and valuable career guidance. This expert training in bioinformatics; cWnt
signaling; bone, cartilage, and synovial biology; and multi-modal imaging, will be crucial for carrying out my
K99 aims and especially critical for successfully launching my independent career. These skills will be utilized
in my R00 phase to: 3) determine how Rspo2/Lgr signaling promotes osteophyte formation in PTOA, using
tissue-specific deletion and reporter mice, and in vitro differentiation assays. This work will significantly extend
our understanding of cellular and molecular mechani...

## Key facts

- **NIH application ID:** 10830258
- **Project number:** 5K99AR081894-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Alexander John Knights
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $103,080
- **Award type:** 5
- **Project period:** 2023-05-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10830258

## Citation

> US National Institutes of Health, RePORTER application 10830258, Fibrosis, inflammation, and osteophyte formation in post-traumatic osteoarthritis (5K99AR081894-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10830258. Licensed CC0.

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