# The Role of Fat in Osteoarthritis

> **NIH NIH K99** · WASHINGTON UNIVERSITY · 2022 · $90,876

## Abstract

PROJECT SUMMARY
Osteoarthritis (OA) is the leading cause of pain and disability worldwide, and there are currently no disease
modifying treatments available. While obesity-induced OA involves both metabolic and biomechanical factors, a
key link is excess fat, or adipose tissue – a source of inflammatory mediators implicated in the pathogenesis of
OA. The mechanistic influence of adiposity, biomechanical alterations, and metabolic syndrome have been
difficult to determine and disentangle. To separate these factors, we used a mouse model of lipodystrophy (LD),
in which the animals completely lack fat but maintain normal body mass. The LD mouse demonstrates many
clinical signs observed in individuals with obesity-induced OA (sclerotic subchondral bone, systemic
inflammation, insulin resistance, metabolic disturbance, and muscle weakness). Unexpectedly, we observed that
LD knee joints are protected from OA. When fat was transplanted into LD mice protection from OA was reversed,
implicating that adipose tissue, and factors secreted by adipose tissue called adipokines – but not body weight
– are critical mediators of joint degeneration. These results suggest that adipose tissue and the mediators
(adipokines) secreted by adipose tissue adversely affect cartilage health.
In the mentored K99 portion of this grant, we will generate bioengineered designer adipose implants using murine
induced pluripotent stem cells (iPSCs) to provide a platform to deconstruct adipokine signaling and investigate
the mechanisms linking adipose tissue and joint health. This approach, which was not possible previously without
creating complex and expensive transgenic mice, addresses a gap fundamental in our understanding of obesity
and OA. In the independent R00 portion of this grant, we will leverage recent advances in regenerative medicine
to develop and test a self-regulating cell-based implant that can provide biologic drugs to combat OA, laying the
platform for Dr. Collins’ independent research career, and the groundwork for a first R01. The value of this
platform is the flexibility to interchangeably deliver a wide range of potential therapeutics. Using this novel and
flexible platform, we will hijack adipokine signaling to deliver anti-inflammatory mediators in a tunable and well-
controlled manner as a novel regenerative therapy for OA. Since this iPSC platform could readily accommodate
edits and alterations of targets of interest in a variety of cell types, the potential for this therapy is far-reaching,
as many chronic diseases (cancer, cardiovascular disease, diabetes, etc.) have links to pathologic inflammatory
signaling.

## Key facts

- **NIH application ID:** 10370593
- **Project number:** 1K99AR078949-01A1
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Kelsey Helen-Marie Collins
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $90,876
- **Award type:** 1
- **Project period:** 2022-04-24 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10370593

## Citation

> US National Institutes of Health, RePORTER application 10370593, The Role of Fat in Osteoarthritis (1K99AR078949-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10370593. Licensed CC0.

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