# KLF4 in joint degradation and regeneration

> **NIH NIH R01** · SCRIPPS RESEARCH INSTITUTE, THE · 2020 · $453,868

## Abstract

Aging and Osteoarthritis (OA) related changes in joint tissues are in part due to an imbalance in expression of
cartilage matrix genes and tissue degradation enzymes in chondrocytes. Elucidation of new molecules and
mechanisms responsible for chondrocyte maintenance has potential to advance our understanding of OA
pathogenesis and lead to new approaches to prevent or slow tissue damage.
 Krueppel-like factors (KLF) are transcription factors are involved in various biological and pathological
mechanisms, including differentiation, apoptosis, cell reprogramming and tissue/organ homeostasis and
protection against aging-related changes; however, their role in cartilage and joint homeostasis has not yet
been examined.
 In preliminary studies we observed a profound reduction in the expression of several KLFs in human OA
cartilage and in aged and OA-affected mouse joints. KLF overexpression or knock down in chondrocytes
revealed KLF4 as a potent regulator of cartilage matrix genes Col2A1 and aggrecan. KLF4 also attenuated the
IL-1 induced expression of catabolic factors
 These findings support the hypothesis that ‘Aging and OA-related reduction of KLF4 expression is a
principal mechanism of tissue destruction and that restoring KLF4 protects against OA.’
Aim 1: Regulation of KLF expression and KLF function in chondrocytes: To investigate mechanisms of
KLF4 suppression in OA, we will identify the role of cytokines/growth factors in regulating KLF4 expression. The
role of KLF4 in regulating chondrocyte functions will be tested in cell and tissue culture models.
Aim 2: The KLF4 signaling network in cartilage: Consequences of KLF4 suppression for signaling and gene
expression networks are unknown in cartilage. We will use RNA-seq on cartilage from knock out mice, ChIP-
seq and ChIP-seq for histone marks to identify KLF4-regulated target genes and signaling networks.
Aim 3: Role of KLF4 in cartilage homeostasis, aging and experimental OA: We will delete KLF4 in mature
mice using Acan-CreERT and examine mice for aging-related changes and severity of experimental OA.
Aim 4: Protective effects of KLF4 overexpression and activation: Potential protective effects of KLF4 will
be tested using novel transgenic mice that overexpress KLF4 in cartilage to balance the OA-associated KLF
suppression and we will determine outcomes with respect to homeostasis mechanisms and OA severity.
 The potential impact of the proposed studies is that they will be the first to determine the role of KLF4 in
cartilage homeostasis and the consequences of KLF4 suppression for joint aging and OA pathogenesis. We
will also establish proof of concept for KLF4 as a therapeutic target in OA.

## Key facts

- **NIH application ID:** 9927548
- **Project number:** 5R01AG056144-03
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** Martin K Lotz
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $453,868
- **Award type:** 5
- **Project period:** 2018-09-30 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9927548

## Citation

> US National Institutes of Health, RePORTER application 9927548, KLF4 in joint degradation and regeneration (5R01AG056144-03). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/9927548. Licensed CC0.

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